Dehydrogenation and α-functionalization of secondary amines by visible-light-mediated catalysis

Article abstract of DOI:10.1039/c9ob02699a

A visible-light-mediated process for dehydrogenation of amines has been described. The given protocol showed a broad substrate scope, mild reaction conditions and excellent results without the requirement of tedious purification. This process can be applied in one-pot functionalization of secondary amines with various nucleophiles through the cooperation of visible-light and Lewis acid catalysis, leading to the structurally varied essential components of biologically active molecules. In addition, Stern-Volmer studies and quenching experiments revealed the role of a catalyst and led to the proposed mechanism of this transformation.

Full text of DOI:10.1039/c9ob02699a

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Dehydrogenation and α-functionalization of
secondary amines by visible-light-mediated
Cite this: DOI: 10.1039/c9ob02699a
catalysis†
Filip Stanek,a Robert Pawlowski, a Paulina Morawska,b Robert Bujok a and
a
Maciej Stodulski
*
A visible-light-mediated process for dehydrogenation of amines has been described. The given protocol
showed a broad substrate scope, mild reaction conditions and excellent results without the requirement
of tedious purification. This process can be applied in one-pot functionalization of secondary amines with
various nucleophiles through the cooperation of visible-light and Lewis acid catalysis, leading to the struc-
turally varied essential components of biologically active molecules. In addition, Stern–Volmer studies
and quenching experiments revealed the role of a catalyst and led to the proposed mechanism of this
transformation.
Received 19th December 2019,
Accepted 24th February 2020
DOI: 10.1039/c9ob02699a
rsc.li/obc
mation of imines eliminating the purification step are highly
desirable.
Introduction
Imines are versatile building blocks that can be found in many
Over the last few years, application of visible-light-mediated
natural and bioactive compounds (Fig. 1). Many of them have catalysis in organic chemistry has become a topic of immense
important biological properties finding wide applications in importance.6 Many of the synthetic strategies have been devel-
pharmaceuticals, agricultural chemicals or chemical syn- oped and applied in the preparation of various heterocycles,7
thesis.1 Therefore, significant efforts have been undertaken to natural products8 and numerous other compounds.9 Imines
develop useful methods for their preparation.2 Imines are typi- and their derivatives are widely used intermediates in the syn-
cally generated from carbonyl compounds and corresponding thesis of N-containing heterocycles; therefore application of
amines and are often isolable with either great effort or not at visible-light-induced catalysis in this topic is particularly inter-
all, due to their low stability.3 Moreover, the existence of equi- esting. It has already been shown that photoredox catalysis can
librium conditions between the reactants and products
affects the yield of the reaction and often requires the
addition of various dehydrating agents, azeotropic distillation
and high temperatures. The availability of imines can be also
limited by the possibility of obtaining the corresponding car-
bonyl compounds. On the other hand, amines are stable,
easily prepared and widely found in natural products,4 acting
as suitable precursors for imine derivatives. Aerobic oxidation
of amines into imines has been already intensively studied;5
however the application of stoichiometric reagents, high
temperatures, formation of side products or additional costly
oxidants can cause limitations in the synthesis of low stability
or complex molecules. Above all, synthetic strategies that
allow for quantitative, straightforward and convenient for-
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland. E-mail: maciej.stodulski@icho.edu.pl
bUniversity of Warsaw, Faculty of Chemistry, Pasteura 1, 02-093 Warsaw, Poland
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02699a
Fig. 1 Example of bioactive compounds containing an imine group.
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be applied in the synthesis of imine scaffolds, however with was found that acetonitrile and a reaction time of six hours
limited scope and mostly related to cyclic compounds.9a,10 lead to the formation of imine 5a in quantitative yield.
Therefore development of new methods, based on different Finally, various catalysts and catalyst loadings were tested
approaches, is an ongoing challenge, as these may offer (see the ESI† for more detailed work). We found that two
different reagent scope, selectivity and functional group toler- catalysts are the best for this transformation, promoting the
ance. Herein, we wish to report our results on a simple formation of the expected product 5a in quantitative
method for the synthesis of imines based on dehydrogenation yield: [Ru(bpy)3](PF6)2 and Rose Bengal (Table 1, entries 6
of amines under visible-light-mediated conditions and and 8).
α-functionalization of secondary amines by the cooperation of
visible-light-mediated and Lewis acid catalysis.
It should be pointed out however that a ruthenium based
catalyst promoted product formation 5a in six hours with a
catalyst loading of 0.5 mol%, whereas significantly more time
and more catalyst were needed to obtain the same results in
the case of the Rose Bengal catalyst (5 mol%, 18 h). Although
it would be more suitable to use Rose Bengal in terms of green
chemistry, at this stage we decided to stay with the ruthenium
metal catalyst due to the significantly shorter reaction time
and better results.
With the optimized conditions in hand, we explored the
scope of the given transformation (Scheme 1). The examined
process generally occurs with very good yields (quantitatively)
and does not require tedious purification. Variation of the aro-
matic functionality in aromatic ring A showed that electron
donating groups and halogen substituents are tolerated,
although leading to the corresponding products in lower
yields. The best substituent in ring A was found to be a methyl
Results and discussion
As part of our efforts to develop more practical catalytic
systems,11 including the synthesis of non-cyclic imines under
mild conditions, we focused our attention on the oxidation of
secondary amines through the visible-light-induced catalytic
process. First, we tried to determine the optimal reaction con-
ditions, based on previous studies by our group.12 We began
our course by choosing a model reaction where as a substrate
the simple aryl amine, N-benzyl-4-methylaniline 4a, was
selected. We observed that treatment of compound 4a with a
[Ru(bpy)3](PF6)2 catalyst under an oxygen atmosphere and blue
LED irradiation afforded the imine 5a in 50% yield (entry 1,
Table 1). To facilitate product 5a formation, the effects of
various additives and oxidants were tested next (entries 2–7,
Table 1). Our optimization studies showed that the best results
were achieved using a compact fluorescent lamp (CFL, 23 W)
and [Ru(bpy)3](PF6)2 as a catalyst with the addition of mole-
cular sieves (MS 4 Å) to eliminate any possible side reactions
related to the imine hydrolysis. These conditions promoted
the formation of imine 5a in quantitative yield (entry 6,
Table 1). Other oxidants, for example t-BuO2H, promoted the
reaction as well but with lower yield (86%, entry 4, Table 1)
and a significant amount of an oxidant (5 equiv.). In this
context application of cheap and environmentally benign
oxygen seemed to be more suitable in terms of green chem-
istry. The solvents and reaction times were examined next. It
Table 1 Optimization of reaction conditionsa
No
Photocatalyst [2 mol%]
Additive
Oxidant
Yield [%]
1
2
3
4
5
6
7
8
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
Rose Bengal
—
—
—
O2
O2
50b
75
Trace
86
>99
>99e
16d
>99f
Air
—
tBuO2Hc
O2
MS 4 Åd
MS 4 Åd
O2
O2
O2
d
MgSO4
MS 4 Åd
a Unless otherwise indicated, all reactions were performed as follows:
reaction scale: 0.25 mmol, 2 mol% of [Ru(bpy)3](PF6)2, O2 (balloon),
0.8 mL MeCN, temp.: 35 °C, reaction time: 16 h, CFL: 23 W, isolated
yield. b Blue LED. c 5 equiv. d Additive amount: 30 mg. e Catalyst
loading: 0.5 mol% and reaction time: 6 h. f Catalyst loading: 5 mol%
and reaction time: 18 h.
Scheme 1 Visible-light-mediated synthesis of N-benzyl anilines 5a–5o.
Unless otherwise indicated, all reactions were performed as follows:
reaction scale: 0.25 mmol, 0.5 mol% of photocatalyst, 30 mg MS 4 Å, O2
(balloon), 0.8 mL MeCN, temp.: 35 °C, reaction time: 16 h, CFL: 23 W,
isolated yield; a reaction time: 48 h.
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group (100%, 5a and 5c). Surprisingly much lower yield was
observed when a bare phenyl group was used (21%, 5b). The
significant drop of the yield can be explained by the fact that
the amine group in phenyl amine 4b is less electron rich (less
reactive) and indicates lower fluorescence quenching of the Ru
catalyst compared to that with the p-tollyl amine 4a (see the
ESI†). From this reason substrates containing strongly electron
withdrawing groups such as CN in ring A are also not effective
(5e). Halogen groups are less reactive compared to the model
substrate and corresponding imine 5f can be obtained in 52%
yield. Moreover, the impact of the substituent position in the
aryl ring B and the effect of substituents were also examined. A
broad range of substituents, such as methyl, halogen,
naphthyl or electron withdrawing groups, are compatible with
this protocol (5h–5n) giving generally very good results (quanti-
tatively). However, it is worth mentioning that the reaction is
blocked when the starting material contains an additional
methyl substituent in the α-position to the amine group (5o).
Considering the broader spectrum of reagents, we turned
our attention to dehydrogenation of various N-alkyl anilines.
However, we did not observe product 7a formation under pre-
viously optimized reaction conditions in the model reaction
presented in Table 2 (entry 1). To overcome this problem, we
found that the addition of a base and longer reaction time sig-
nificantly improved the reaction results. Addition of Na3PO4
Scheme 2 Visible-light-mediated synthesis of N-alkyl aromatic amines
7a–7j. a Unless otherwise indicated, all reactions were performed as
follows: reaction scale: 0.25 mmol, 2 mol% of photocatalyst, 30 mg MS
4 Å, 1.0 equiv. Na3PO4, O2 (balloon), 0.8 mL MeCN, temp.: 35 °C, reac-
tion time: 16 h, CFL: 23 W, isolated yield; b reaction time: 48 h; c isolated
yield.
(1.0 equiv.), 2 mol% of the Ru catalyst and 16 hours reaction unstable and easily decomposed. In the case of dihydroindole
time led to the formation of imine 7a in quantitative yield derivatives, rearomatization was observed leading to appropri-
(Table 2, entry 3). Unfortunately, the oxidation of N-alkyl tolui- ate indoles 7e–7f in up to 76% yield. Moreover, glyceryl 7g or
dine 6a did not work well with the Rose Bengal catalyst 1,2-diamino derivatives 7h–7i were also obtained in quantitat-
(Table 2, entries 4–6). Higher catalyst loadings or even longer ive yields, opening the way to the easy synthesis of various 1,2-
reaction time did not help the reaction at all, indicating the amino alcohols or 1,2-diamino derivatives, which serve as
superiority of the metal catalyst over an organic one.
With the modified reaction conditions in hand we surveyed tute fragments of countless bioactive molecules.14
the scope of the N-alkyl anilines 6 (Scheme 2). Amines with
The most challenging part of visible-light catalysis is an
important templates for stereoselective synthesis,13 and consti-
branched alkyl groups and cyclic amines were converted into in situ addition to the generated imine. Secondary amines are
the corresponding imines 7a–7i with moderate to excellent the most demanding substrates in contrast to the tertiary
yields (43%–99%). However, non-branched reagents such as amines, amides or THIQ analogues.9a For this reason, our
6b, although easily converted into imine 7b, proved to be very further studies have been focused on the functionalization of
imines through the cooperative effect of visible-light-induced
catalysis and Lewis acid catalysis by using a wide range of
nucleophiles. To our satisfaction, combinations of many
nucleophiles with metal triflates were successfully employed in
this procedure (Table 3). Zn(OTf)2 proved to be a useful Lewis
acid to promote the addition of various silyl enolates in a coop-
erative manner with the [Ru(bpy)3](PF6)2 catalyst under visible-
light-mediated conditions. Utilization of acetophenone enol
trimethylsilyl ether led to the formation of the corresponding
β-aminoketone 8a in 57% yield (entry 1). Other silyl deriva-
tives, such as 2-(trimethylsiloxy)furan, gave aminolactone 8b in
41% yield after 48 h (entry 2). Danishefsky’s diene was also
successfully employed in this process, giving amine derivative
8c in 89% yield (entry 3). Cyano derivatives also worked well in
the described process and TMSCN was employed to incorpor-
ate the cyano function into the structure of amine 4a (entry 4),
which could be further easily modified through acid hydrolysis
providing the structurally varied amino acids – essential com-
Table 2 Oxidation of N-alkyl toluidine 6aa
No Catalyst
Catalyst loading Additive Base
Yield [%]
1
2
3
4
5
6
[Ru(bpy)3](PF6)2 0.5 mol%
[Ru(bpy)3](PF6)2 0.5 mol%
[Ru(bpy)3](PF6)2 2 mol%
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
MS 4 Å
—
—
Na3PO4 48
Na3PO4 >99b
Rose Bengal
Rose Bengal
Rose Bengal
2 mol%
2 mol%
5 mol%
—
Na3PO4
Na3PO4
—
—
—
b
b
a Unless otherwise indicated, all reactions were performed as follows:
reaction scale: 0.25 mmol, 2 mol% of photocatalyst, 30 mg of MS 4 Å,
1.0 equiv. base, O2 (balloon), 0.8 mL MeCN, temp.: 35 °C, reaction
time: 6 h, CFL: 23 W, isolated yield. b Reaction time: 16 h.
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Table 3 One-pot functionalization of N-benzyl toluidine 4a through the cooperation of visible-light- and Lewis acid catalysisa
No
1
Nucleophile
Conditions
Product
Yield [%]
57b
Zn(OTf)2, MeOH, 18 h
2
3
Zn(OTf)2, MeCN, 48 h
Zn(OTf)2, MeCN, 18 h
41
89
4
5
TMSCN
Zn(OTf)2, MeCN, 18 h
63
Bi(OTf)3, MeCN, 80 °C, 48 h
73c
6
Zn(OTf)2, DCE/MeCN (2/1), 18 h
51
a Unless otherwise indicated, all reactions were performed as follows: reaction scale: 0.25 mmol, 2 mol% of photocatalyst, 30 mg MS 4 Å,
20 mol% of Lewis acid, 1.2 equiv. nucleophile, O2 (balloon), 1 mL solvent, CFL: 23 W, temp.: 35 °C, isolated yield. b Nucleophile: 2.0 equiv.
c Nucleophile: 4.0 equiv.
ponents of pharmaceutically active derivatives.15 In this oxygen intermediates, experiments with the addition of
context, α-aminonitrile 8d was obtained in 63% yield. To different quenchers were performed next (entries 4–8).17
further illustrate the synthetic potential of the developed meth- Addition of TEMPO (entry 5) or 2,4,6-TTBP (entry 6) blocked
odology phenyl acetylene was tested. In this case, quinoline the reaction, pointing likely to the radical mechanism.
analogue 8e was isolated in 73% yield (entry 5), by utilizing the Additional experiments with benzoquinone demonstrated the
cooperation of a Bi(OTf)3 Lewis acid and the [Ru(bpy)3](PF6)2 importance of the superoxide radical anion (entry 7).
catalyst. Bisindoles are an important class of compounds Furthermore, the addition of tert-butanol to the reaction
being significant targets for a chemist, due to many interesting mixture has no effect (entry 8), indicating no involvement of
bioactive properties.16 Therefore indole as a nucleophile was hydroxide radicals in the reaction mechanism. Moreover, no
tested next. It was found that the corresponding bisindole 8f suppression of the oxidation reaction was observed in the pres-
can be also obtained in good yield (entry 6). The described ence of a DABCO 1O2 quencher (entry 9).
process serves as a proof of principle that many essential phar-
The interaction between the excited state of the photo-
maceutically active components and templates for multistep catalyst and the amine can be in direct competition with the
synthesis can be efficiently generated by utilizing secondary quenching of the photocatalyst by oxygen itself, producing
amines, appropriate nucleophiles and a combination of metal 1O2.12,18 Therefore, additional Stern–Volmer quenching experi-
triflate and photoredox chemistry.
ments were next performed to investigate a plausible reaction
To gain more information about the possible mechanistic mechanism. Stern–Volmer analyses for each of the reaction
pathway of imine formation, several additional experiments components clearly showed that the starting material
were carried out (Table 4). Control experiments showed no (N-benzyl toluidine 4a) exhibits strong quenching of
product formation without a light source, a photocatalyst or an Ru(bpy)32+, with a quenching rate constant of kq = 8.87 × 107
oxygen atmosphere indicating that some chemical quenching s−1 M−1 indicating most likely Ru+ formation in the reaction
occurs in the reaction among the substrates, photocatalyst and mechanism rather than the involvement of a singlet oxygen
oxygen (entries 2–4). To identify the existence of reactive reaction pathway (Fig. 2). However, it can be seen that N-benzyl
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Table 4 Control experiments for the visible-light-mediated oxygenation of aminesa
No
Photocatalyst [0.5 mol%]
Additive [1.0 equiv.]
Yield [%]
Comment
1
2
3
4
5
6
7
8
9
[Ru(bpy)3](PF6)2
—
—
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
—
—
100
—
—
—
20
—
—
100
100
Model reaction
Photo-induced reaction
Photo-induced reaction
Importance of oxygen intermediates
Radical mechanism
b
—
—
c
TEMPO
2,4,6-TTBP
Benzoquinone
tBuOH
Radical mechanism
Superoxide radical involvement
No hydroxide radical dependence
No 1O2 involvement
DABCO
a Unless otherwise indicated, all reactions were performed as follows: reaction scale: 0.25 mmol, 0.5 mol% of [Ru(bpy)3](PF6)2, 30 mg MS 4 Å, O2
(balloon), 0.8 mL MeCN, temp.: 35 °C, reaction time: 6 h, CFL: 23 W, isolated yield. b No light. c No oxygen.
2+
Scheme 3 Proposed reaction mechanism of imine generation.
Fig. 2 Stern–Volmer quenching experiments of Ru(bpy)3 for 4a, 4b,
and 5a. The concentration of [Ru(bpy)3](PF6)2 in MeCN was 1.17 × 10−5
M. The lifetime of the photocatalyst in the excited state τ = 890 ns in
MeCN.19
depicted in Scheme 3. A proposed reaction mechanism for the
imine 5a formation begins with SET to the amine 4a from the
excited state of [Ru(bpy)3]2+, generated by the visible light
irradiation (Scheme 3). This process leads to the formation of
cation radical 9. Subsequent oxidation of [Ru(bpy)3]+ by SET
from oxygen regenerates the ruthenium catalyst along with the
superoxide radical formation. Subsequent loss of the α-proton
from 9 followed by the oxidation of the resulting radical pro-
duces the imine 5a.
aniline 4b which is not substituted shows much lower quench-
2+
ing of Ru(bpy)3 (kq = 5.69 × 107 s−1
M
−1) than oxygen
(kq = 6.61 × 107 s−1 M−1) indicating in this case rather type II
(energy transfer) of the reaction pathway (see the ESI†) and
explaining the poor results generated by 4b.12 N-Alkyl toluidine
2+
6a also exhibits strong quenching of Ru(bpy)3 (Fig. 3), with a
quenching rate constant of kq = 2.16 × 108 s−1 M−1
.
Based on the performed experiments and literature
studies,9a,12 a plausible reaction pathway of the process is Conclusions
In summary, we have described a visible-light-mediated proto-
col for the synthesis of various imines. The given protocol
showed a broad substrate scope, mild reaction conditions and
excellent results without the requirement of tedious purifi-
cation. We showed that many structurally varied N-benzyl ani-
lines can be converted into imines using 0.5 mol% of the
ruthenium catalyst in the presence of molecular sieves. Less
reactive N-alkyl anilines can be dehydrogenated as well;
however an additional base such as Na3PO4, 2 mol% of the
[Ru(bpy)3](PF6)2 catalyst and a longer reaction time are
needed. We showed that the given reaction can be applied
in one-pot functionalization with various nucleophiles
through the cooperation of visible-light and Lewis acid cata-
2+
Fig. 3 Stern–Volmer quenching experiments of Ru(bpy)3 for 6a. The
concentration of [Ru(bpy)3](PF6)2 in MeCN was 1.17 × 10−5 M. The life-
time of the photocatalyst in the excited state τ = 890 ns in MeCN.19
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lysis, leading to the structurally varied essential com- After cooling to room temperature, KPF6 (1.9 g, 10.0 mmol,
ponents of biologically active molecules. In addition, Stern– 3.8 equiv.) was added, and the solid was collected by
Volmer studies and quenching experiments revealed the vacuum filtration. The red solid was washed with water and
role of the catalyst and additives and led to the proposed then washed through a fritted funnel with acetone to
mechanism of this transformation. We think that the appli- removed excess ruthenium salts. The acetone eluent was
cation of this concept in other contexts will lead to the dis- diluted with Et2O to precipitate the ruthenium complex. The
covery of new synthetically useful reactions. Further explora- resulting red solid was filtered and dried in vacuo. The
tion of the presented strategy is currently under way in our product was obtained as an orange solid (1.0 g, 46%). MS
laboratory.
(ESI) [m/z]: m/z: [M − 2(PF6)]2+ calcd for C30H24N6Ru, 285.05;
found, 285.2; [M − PF6]+ calcd for C30H24F6N6PRu, 714.6;
found, 714.7.
Experimental section
General procedure A for synthesis of secondary amines
General methods
To a suspension of Pd/C (1.28 g, 1.1 mmol, 0.1 equiv.) in iso-
propyl alcohol (40 mL) aqueous solution (8 mL) of ammonium
formate (4.01 g, 63.6 mmol, 6.0 equiv.) was added. The reac-
tion mixture was stirred for 1 minute to activate Pd/C. Next, an
amine (10.6 mmol, 1.0 equiv.) and an aldehyde (10.6 mmol,
1.0 equiv.) were added and the reaction mixture was stirred at
room temperature (60 min). After completing the reaction based
on TLC monitoring, the Pd/C catalyst was filtered off on Celite
and the solvent was removed by rotary evaporation. The reaction
mixture was diluted with CH2Cl2 and washed with brine solu-
tion. The organic phase was collected, dried with anhydrous
MgSO4, and concentrated by rotary-evaporation. The residue
was purified by silica flash column chromatography.
The reagents were purchased from Sigma Aldrich, Alfa Aesar
or ABCR and used without further purification. All reactions
involving air- and moisture-sensitive materials were carried out
under an argon atmosphere in oven-dried glassware with mag-
netic stirring. Solvents were dried prior to use. THF and PhMe
were distilled from Na and benzophenone and CH2Cl2 from
CaH2. Column chromatography was performed with Kiesel gel
(230–400 mesh). Analytical TLC was performed with silica gel
60 F254 aluminum plates (Merck) with visualization using UV
light and charring with aqueous ninhydrin, KMnO4 or
Pancaldi reagent ((NH4)6MoO4, Ce(SO4)2, H2SO4, and H2O).
NMR analyses were performed with a Bruker 400 MHz Avance
III, Bruker DRX 500 Avance or Varian 200 MHz spectrometer.
Chemical shifts were calibrated using residual solvent signals
(CDCl3: δ (H) = 7.26, δ (C) = 77.16) or TMS and are reported in
ppm. Infrared spectra (IR) were recorded on an FT-IR-1600-
PerkinElmer spectrophotometer and are reported in frequency
of absorption cm−1. High-resolution mass spectra were in
general recorded using ESI-MS-TOF (MicrOTOF II, Bruker,
Germany).
The reaction setup consists of a self-constructed light
source configuration, made up of a rectangular box with a
length of 200 mm and a height of 40 mm. Inside of the box in
the central position, a commercially available (CFL): DIALL
SPIRAL, 23 W, 1450 LM light bulb is placed (the light source
can be replaced with any other lamp if necessary). Around
the light source, at a distance of 50 mm there are 8 holes for
placing 4 mL reaction vials. Cooling of the setup is per-
formed with a W1209 digital temperature control switch
connected with a commercially available 50 mm computer
fan. During the first experiments, the temperature was
monitored inside the reactor and it did not exceed the
desired temperature of 35 °C. The reactor was placed on a
magnetic plate stirrer and stirring was performed at
400 rpm.
General procedure B for visible-light-mediated synthesis of
imines 5a–5o
A vial was charged with [Ru(bpy)3](PF6)2 (0.00125 mmol, 0.005
equiv.), and then N-substituted arylamine (0.25 mmol, 1.0
equiv.) was added. Subsequently, 30 mg of MS 4 Å was added,
followed by the addition of 0.8 mL dry MeCN saturated with
oxygen. The suspension was stirred for 16 h under an oxygen
atmosphere and irradiated using the CFL at 35 °C. After the
specified time, the crude was washed with pentane and filtered
through the short pad of silica to obtain the pure product.
General procedure C for visible-light-mediated synthesis of
imines 7a–7i
A vial was charged with [Ru(bpy)3](PF6)2 (0.005 mmol, 0.02
equiv.), and then N-substituted arylamine (0.25 mmol, 1.0
equiv.) was added. Subsequently 30 mg of MS 4 Å and anhy-
drous Na3PO4 (0.25 mmol, 1.0 equiv.) were added, followed by
the addition of 0.8 mL dry MeCN saturated with oxygen. The
suspension was stirred for 16 h under an oxygen atmosphere
and irradiated using CFL at 35 °C. After the specified time, the
crude was washed with pentane and filtered through the short
pad of silica to obtain the pure product.
Procedure for the synthesis of [Ru(bpy)3](PF6)2
4-Methyl-N-(2-methylbutyl)aniline (6a)
[Ru(bpy)3](PF6)2 was prepared according to a modified litera- 4-Methyl-N-(2-methylbutyl)aniline (6a) was prepared according
ture procedure.20 To a 250 mL round-bottomed flask RuCl3 to the general procedure A. The product was obtained as a
(540 mg, 2.6 mmol, 1.0 equiv.), 2,2′-bipyridine (2.5 g, yellow oil (1.49 g, 85%, eluent: hexane/AcOEt = 95/5). IR
16.0 mmol, 6.1 equiv.) and EtOH (100 mL) were added. The (CHCl3, cm−1) 3416, 3015, 2960, 2922, 2872, 1521, 1461, 806;
reaction mixture was heated to reflux for 12 h under argon. 1H NMR (400 MHz, CDCl3) δ 7.01–6.57 (m, 4H, AA′XX′), 3.65
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(bs, 1H), 3.07 (dd, J = 12.2, 6.0 Hz, 1H), 2.91 (dd, J = 12.2, 6.0 50.6, 46.3, 28.2, 19.0, 19.0; HRMS (ESI) m/z: [M + H]+: calcd for
Hz, 1H), 2.27 (s, 3H), 1.81–1.62 (m, 1H), 1.62–1.44 (m, 1H), C15H24N2O2 287.1735, found 287.1729.
1.35–1.14 (m, 1H), 1.07–0.86 (m, 6H); 13C{1H} NMR (101 MHz,
2-Methylbutyraldehyde-4-methylaniline (7a)
CDCl3) δ 146.4, 129.7, 126.1, 112.8, 50.3, 34.5, 27.3, 20.5, 17.6,
11.3; HRMS (EI) m/z: [M+] calcd for C12H19N 177.1517, found 2-Methylbutyraldehyde-4-methylaniline (7a) was prepared
177.1519.
according to the general procedure C. The product was
obtained as a yellow oil (44 mg, 100%). IR (CHCl3, cm−1) 3269,
2965, 2873, 1687, 1520, 1302, 815; H NMR (600 MHz, CDCl3)
N-(2-Methyl-1,3-dioxolan-5-ylmethyl)-4-methylaniline (6g)
1
N-(2-Methyl-1,3-dioxolan-5-ylmethyl)-4-methylaniline (6g) was δ 7.68 (d, J = 5.8 Hz, 1H), 7.12–6.95 (m, 4H, AA′XX′), 2.48–2.38
prepared according to the general procedure A. [α]2D5 = −5.0 (c (m, 1H), 2.33 (s, 3H), 1.66 (m, 1H), 1.58–1.45 (m, 1H), 1.17 (d, J
1.0, EtOH); IR (CHCl3, cm−1) 3384, 2986, 2932, 2878, 1518, = 6.8 Hz, 3H), 1.03–0.94 (t, J = 6.8 Hz, 3H); 13C{1H} NMR
1
1070, 614, 511; H NMR (500 MHz, CDCl3) δ 6.99–6.56 (m, 4H, (151 MHz, CDCl3) δ 170.0, 149.8, 134.9, 129.5, 120.5, 41.5,
AA′XX′), 4.35 (qd, J = 6.4, 4.5 Hz, 1H), 4.08 (dd, J = 8.2, 6.4 Hz, 27.0, 20.9, 16.8, 11.6; HRMS (EI) m/z: [M+]: calcd for C12H17N
1H), 3.82 (bs, 1H), 3.76 (dd, J = 8.2, 6.4 Hz, 1H), 3.28 (dd, J = 175.1361, found 175.1365.
12.6, 4.5 Hz, 1H), 3.22–3.12 (m, 1H), 2.24 (s, 3H), 1.45 (s, 3H),
N-Phenyl-2,3-O-isopropyliden-D-glyceraldimin (7g)
1.37 (s, 3H).13C{1H} NMR (126 MHz, CDCl3) δ 145.7, 129.7,
127.0, 113.2, 109.4, 74.6, 67.3, 47.0, 26.9, 25.4, 20.4; HRMS (EI) N-Phenyl-2,3-O-isopropyliden-D-glyceraldimin (7g) was pre-
m/z: [M+] calcd for C13H19NO2 221.1416, found 221.1423.
pared according to the general procedure C. The product was
obtained as an oil (58 mg, 100%). [α]2D5 = 7.6 (c 1.0, EtOH; IR
(CHCl3, cm−1) 3384, 3380, 2986, 2932, 2878, 1518, 1070, 614;
1H NMR (200 MHz, CDCl3) δ 7.85 (d, J = 5.0 Hz, 1H), 7.16–7.00
tert-Butyl (2S)-3-methyl-1-[(4-methylphenyl)amino]butan-2-
ylcarbamate (6h)
To a stirred solution of (2S)-N1-(4-methylphenyl)-3-methyl-1,2- (m, 4H, AA′XX′), 4.83–4.68 (m, 1H), 4.35–4.24 (m, 1H), 4.07
butanediamine (0.63 g, 3.45 mmol, 1.0 equiv.) in dioxane (dd, J = 8.5, 6.1 Hz, 1H), 2.35 (s, 3H), 1.50–1.43 (m, 6H); 13C
(3 mL) 1 M NaOH (3 mL) was added. The reaction mixture was {1H} NMR (50 MHz, CDCl3) δ 162.85, 136.5, 129.9, 120.8, 110.6,
cooled to 5 °C and Boc2O (0.75 g, 3.62 mmol, 1.05 equiv.) was 77.7, 67.7, 26.8, 25.7, 21.2; HRMS (EI) m/z: [M+]: calcd for
added. The reaction mixture was stirred overnight at rt. C13H17NO2 219.1261, found 219.1259.
Thereafter the solution was washed with DCM (3 × 10 mL) and
tert-Butyl (2S)-3-methyl-1-[(4-methylphenyl)imino]butan-2-
ylcarbamate (7h)
dried over anhydrous Na2SO4. Evaporation of the solvent in
vacuo gave the crude in 6 h, which was purified by column
chromatography. The product was obtained as a white solid tert-Butyl
(2S)-3-methyl-1-[(4-methylphenyl)imino]butan-2-
(1.08 g, 59%, eluent: hexane/AcOEt = 9/1); [α]2D5 = −16.0 (c 1.0, ylcarbamate (7h) was prepared according to the general pro-
DCM); IR (CHCl3, cm−1) 3386, 2965, 2930, 1690, 1523, 1173, cedure C. The product was obtained as an oil (73 mg, 100%).
1
807, 507. H NMR (500 MHz, CDCl3) δ 6.99–6.56 (m, 4H, AA′ [α]2D5 = 11.4 (c 1.0, DCM); IR (CHCl3, cm−1) 3386, 2965, 2930,
1
XX′), 4.53 (bs, 1H), 3.68 (bs, 1H), 3.24 (m, 1H), 3.08–2.96 (m, 1698, 1523, 1365, 1173, 807; H NMR (400 MHz, CDCl3) δ 7.87
1H), 2.24 (s, 3H), 1.86 (m, 1H), 1.46 (s, 9H), 0.97 (dd, J = 14.4, (s, 1H), 7.15–6.98 (m, 4H, AA′XX′), 5.74 (bs, 1H), 4.39 (bs, 1H),
6.8 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 156.5, 146.2, 2.41 (s, 3H), 2.31 (m, 1H), 1.49 (s, 9H), 1.07–0.98 (m, 6H); 13C
129.7, 126.5, 112.8, 79.4, 55., 47.3, 30.5, 28.3, 20.3, 19.4, 18.0; {1H} NMR (126 MHz, CDCl3) 200.3, 162.1, 135.6, 129.65, 120.4,
HRMS (ESI) m/z: [M + H]+: calcd for C17H28N2O2 293.2229, 114.2, 82.4, 28.7, 28.0, 20.9, 19.0, 18.9, 18.1; HRMS (ESI) m/z:
found 293.2229.
[M + Na]+: calcd for C17H26N2O2Na 313.1892, found 313.1895.
tert-Butyl (2S)-1-[(4-methylphenyl)amino]butan-2-ylcarbamate (6i) tert-Butyl (2S)-1-[(4-methylphenyl)imino]butan-2-ylcarbamate (7i)
To a stirred solution of (2S)-N-(4-methylphenyl)-1,2-propane- tert-Butyl (2S)-3-methyl-1-[(4-methylphenyl)imino]butan-2-
diamine (0.78 g, 4.76 mmol, 1.0 equiv.) in dioxane (5 mL) 1 M ylcarbamate (7h) was prepared according to the general pro-
NaOH (5 mL) was added. The reaction mixture was cooled to cedure C. The product was obtained as an oil (66 mg, 100%).
5 °C and Boc2O (1.09 g, 5.00 mmol, 1.05 equiv.) was added [α]2D5 = 6.2 (c 0.7, DCM); IR (CHCl3, cm−1) 3347, 2977, 1708,
1
portion-wise. The reaction mixture was stirred overnight at rt. 1505, 1366, 1169, 1057, 816; H NMR (500 MHz, CDCl3) δ 7.81
Thereafter the solution was washed with DCM (3 × 10 mL) and (s, 1H), 7.11–6.96 (m, 4H, AA′XX′), 5.74 (bs, 1H), 4.43 (bs, 1H),
dried over anhydrous Na2SO4. Evaporation of the solvent in 2.29 (s, 3H), 1.53–1.28 (m, 12H); 13C{1H} NMR (126 MHz,
vacuo gave the crude 6i, which was purified by column chrom- CDCl3) δ 162.8, 155.3, 148.2, 135.6, 129.6, 120.5, 79.4, 49.9,
atography. The product was obtained as a yellowish solid 28.4, 20.9, 18.5; HRMS (ESI) m/z: [M + Na]+: calcd for
(0.78 g, 62%, eluent: hexane/AcOEt = 95/5). [α]2D5 = −14.0 (c 1.0, C15H22N2O2Na 285.1579, found 285.1568.
DCM); IR (CHCl3, cm−1) 3378, 2976, 2870, 1693, 1522, 1168,
1
1,3-Diphenyl-3-(4-methylphenylamino)propan-1-one (8a)
1054, 807; H NMR (600 MHz, CDCl3) δ 6.96–6.52 (m, 4H, AA′
XX′), 4.60 (bs, 1H), 3.90 (bs, 2H), 3.11 (m, 1H), 3.04 (m, 1H), To
a
suspension of N-benzyl-N-(4-methylphenyl)amine
2.22 (s, 3H), 1.44 (s, 9H), 1.18 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (39.50 mg, 0.200 mmol, 1.00 equiv.), [Ru(bpy)3](PF6)2 (3.40 mg,
(151 MHz, CDCl3) δ 155.8, 145.7, 129.7, 126.3, 112.8, 79.6, 0.004 mmol, 0.02 equiv.) and molecular sieves 4 Å in MeOH
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(1 mL), respectively 1-styrenyloxytrimethylsilane (77.00 mg, 0.20 equiv.) were added. Stirring was continued for 18 h at
0.400 mmol, 2.00 equiv.) and Zn(OTf)2 (14.50 mg, 0.040 mmol; 35 °C under an oxygen atmosphere and irradiated using the 23
0.20 equiv.) were added. Stirring was continued for 18 h at W CFL. The solvent was evaporated and the residue was sub-
35 °C under an oxygen atmosphere and irradiated using the jected to column chromatography (eluent: hexane/AcOEt = 8/2)
1
23 W CFL. The solvent was evaporated and the residue to afford the pure product as a white solid (28 mg, 63%). H
was subjected to column chromatography (eluent: hexane/ NMR (200 MHz, CDCl3): δ 7.59–7.64 (m, 2H), 7.44–7.49 (m,
AcOEt = 9/1) to afford the pure product as a yellow oil (36 mg, 3H), 7.09 (d, J = 7.8 Hz, 2H), 6.72 (d, J = 7.8 Hz, 2H), 5.42 (s,
57%). 1H NMR (200 MHz, CDCl3): δ 7.92 (d, J = 6.8 Hz, 2H), 1H), 2.29 (s, 3H); the results correspond to literature data.23
7.41–7.62 (m, 5H), 7.19–7.37 (m, 3H), 6.92 (d, J = 8.7 Hz, 2H),
6.51 (d, J = 8.7 Hz, 2H), 4.99 (t, J = 7.4 Hz, 1H), 3.49 (t, J =
5.2 Hz, 2H), 2.19 (s, 3H); the results correspond to literature
data.21
2,4-Diphenyl-6-methylquinoline (8e)
A mixture of N-substituted arylamine (0.25 mmol, 1.0 equiv.),
phenylacetylene (125 mL, 1.12 mmol, 4.5 equiv.), [Ru(bpy)3]
(PF6)2 (0.004 mmol, 0.02 mmol.), Bi(OTf)3 (32 mg, 0.05 mmol,
0.2 equiv.) and 30 mg MS 4 Å in 0.8 mL dry MeCN saturated
with oxygen was stirred for 48 h under an oxygen atmosphere
at 80 °C and irradiated using the 23 W CFL. Afterward, the
reaction mixture was quenched by adding 200 μL N,N,N′,N′-
tetramethylethylenediamine. Thereafter the solution was
washed with DCM (3 × 10 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent in vacuo gave the crude of
2,4-diphenyl-6-methylquinoline, which was purified by column
chromatography. The product was obtained as a yellowish
5-[(4-Methoxy-phenylamino)-phenyl-methyl]-5H-furan-2-one (8b)
To
a
suspension of N-benzyl-N-(4-methylphenyl)amine
(39.50 mg, 0.200 mmol, 1.00 equiv.), [Ru(bpy)3](PF6)2 (3.40 mg,
0.004 mmol, 0.02 equiv.) and molecular sieves 4 Å in MeCN
(1 mL), respectively 2-(trimethylsiloxy)furan (37.50 mg,
0.240 mmol, 1.20 equiv.) and Zn(OTf)2 (14.50 mg,
0.040 mmol; 0.20 equiv.) were added. Stirring was continued
for 48 h at 35 °C under an oxygen atmosphere and irradiated
using the 23 W CFL. The solvent was evaporated and the
residue was subjected to column chromatography (eluent:
hexane/AcOEt = 8/2) to afford the pure product as a yellow oil
(23 mg, 41%). 1H NMR (400 MHz, CDCl3): δ 7.28–7.43 (m, 6H),
6.9 (d, J = 8.3 Hz, 2H), 6.48 (d, J = 8.4 Hz, 2H), 6.16 (dd, J = 2.0,
5.8 Hz, 1H), 5.23 (dt, J = 1.8, 6.8 Hz, 1H), 4.45 (d, J = 6.8 Hz,
1H), 2.18 (s, 3H); the results correspond to literature data.22
1
solid (55.0 mg, 73%, hexane/DCM = 4/1); H NMR (500 MHz,
CDCl3) δ 8.22–8.11 (m, 3H), 7.78 (s, 1H), 7.66 (s, 1H), 7.60–7.49
(m, 8H), 7.46 (m, 1H), 2.48 (s, 3H); the results correspond to
literature data.24
3,3′-Bis-indolyl(phenyl)methane (8f)
1-(4-Methylphenyl)-2-phenyl-2,3-dihydro-1H-pyridin-4-one (8c)
A suspension of N-benzyl-N-(4-methylphenyl)amine (39.50 mg,
0.200 mmol, 1.00 equiv.), [Ru(bpy)3](PF6)2 (3.40 mg,
0.004 mmol, 0.02 equiv.), indole (58.50 mg, 0.500 mmol; 2.50
equiv.), Zn(OTf)2 (14.50 mg, 0.040 mmol; 0.20 equiv.) and
molecular sieves 4 Å in MeCN/DCE (v/v: 1/2; 1 mL) was
stirred for 18 h at 35 °C under an oxygen atmosphere and irra-
diated using the 23 W CFL. The solvent was evaporated
and the residue was subjected to column chromatography
(eluent: hexane/AcOEt = 8/2) to afford the pure product as a
red-brown solid (33 mg, 51%). 1H NMR (400 MHz, CDCl3):
δ 7.88 (s, 2H), 7.32–7.42 (m, 6H), 7.27–7.31 (m, 2H), 7.13–7.22
(m, 3H), 6.66 (s, 2H), 5.89 (s, 1H); the results correspond to
literature data.25
A
suspension of N-benzyl-N-(4-methylphenyl)amine (39.50,
0.200 mmol, 1.00 equiv.), [Ru(bpy)3](PF6)2 (3.40 mg,
0.004 mmol, 0.02 equiv.) and molecular sieves 4 Å in MeCN
(1 mL) was stirred at 35 °C and irradiated using the 23 W CFL.
After 6 h, the lamp was turned off and respectively trans-1-
methoxy-3-trimethylsiloxy-1,3-butadiene
(41.50
mg,
2.400 mmol, 1.20 equiv.) and Zn(OTf)2 (14.50 mg, 0.040 mmol;
0.20 equiv.) were added. Stirring at rt. was continued for 18 h in
darkness. The solvent was evaporated and the residue was sub-
jected to column chromatography (eluent: hexane/AcOEt = 7/3)
to afford the pure product as a yellow oil (47 mg, 89%). 1H NMR
(400 MHz, CDCl3): δ 7.62 (dd, J = 1.2, 7.6 Hz, 1H), 7.23–7.34 (m,
5H), 7.08 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.25–5.27
(m, 2H), 3.28 (dd, J = 7.2, 16.4 Hz, 1H), 2.78 (ddd, J = 1.2, 3.2,
16.4 Hz, 1H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
190.1, 148.7, 142.4, 138.1, 134.3, 130.0, 128.9, 127.8, 126.2,
118.9, 102.3, 61.9, 43.4, 20.7; IR (CHCl3, cm−1) 3029, 1647, 1590,
1575, 1512, 1308, 1275, 1206; HR-EI-MS m/z [M+]: calc. for:
C18H17NO 286.1208, found: 286.1200.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
2-Phenyl-2-(4-methylphenylamino)acetonitrile (8d)
To
a
suspension of N-benzyl-N-(4-methylphenyl)amine The authors acknowledge the Foundation for Polish Science
(39.50 mg, 0.200 mmol, 1.00 equiv.), [Ru(bpy)3](PF6)2 (3.40 mg, (TEAM/2017-4/38) for financial support. F. S. acknowledges
0.004 mmol, 0.02 equiv.) and molecular sieves 4 Å in MeCN financial support from the National Science Centre, Poland
(1 mL), respectively trimethylsilyl cyanide (24.00 mg, (2016/23/N/ST5/00117) and R. P. acknowledges the Ministry of
0.240 mmol, 1.20 equiv.) and Zn(OTf)2 (14.50 mg, 0.040 mmol; Science and Higher Education (Diamond Grant 0019/DIA/
Org. Biomol. Chem.
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