Redox-Activated Amines in C(sp3)-C(sp) and C(sp3)-C(sp2) Bond Formation Enabled by Metal-Free Photoredox Catalysis

Article abstract of DOI:10.1021/acscatal.8b03437

The amino group represents one of the most prevalent structural motifs in organic chemistry. Therefore, application of amines as alkylating agents in synthesis is highly compelling. Herein, we present a metal-free photoredox strategy for the formation of C(sp³)-C(sp) and C(sp³)-C(sp²) bonds from redox-activated primary amine derivatives. The developed reaction of 2,4,6-triphenylpyridinium salts with alkynyl p-tolylsulfones, leading to functionalized alkynes, is easily scalable and offers broad substrate scope, high chemoselectivity, and mild conditions. Its potential is also highlighted by diversification of complex molecular scaffolds. Additionally, the approach is also suitable for synthesis of (E)-alkenes from vinyl phenyl sulfones. Mechanistic studies contribute to the elucidation of unexpected differences in reactivity of primary and secondary alkyl substituted pyridinium salts.

Full text of DOI:10.1021/acscatal.8b03437

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Article
Redox-activated amines in C(sp3)-C(sp) and C(sp3)-C(sp)2
bond formation enabled by metal-free photoredox catalysis
Micha# Ociepa, Joanna Turkowska, and Dorota Gryko
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03437 • Publication Date (Web): 12 Oct 2018
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Redox-activated amines in C(sp3)-C(sp) and C(sp3)-
C(sp2) bond formation enabled by metal-free
photoredox catalysis
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Michał Ociepa,a Joanna Turkowska,a and Dorota Gryko*a
aInstitute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw,
Poland
ABSTRACT The amino group represents one of the most prevalent structural motifs in organic
chemistry. Therefore, application of amines as alkylating agents in synthesis is highly
compelling. Herein, we present a metal-free photoredox strategy for the formation of C(sp3)-
C(sp) and C(sp3)-C(sp2) bonds from redox-activated primary amine derivatives. The developed
reaction of 2,4,6-triphenylpyridinium salts with alkynyl p-tolylsulfones, leading to functionalized
alkynes, is easily scalable, offers broad substrate scope, high chemoselectivity, and mild
conditions. Its potential is also highlighted by diversification of complex molecular scaffolds.
Additionally, the approach proved to be also suitable for synthesis of (E)-alkenes from vinyl
phenyl sulfones. Mechanistic studies contribute to the elucidation of unexpected differences in
reactivity of primary and secondary alkyl substituted pyridinium salts.
KEYWORDS: photoredox, pyridinium, catalysis, amine, alkyne, deaminative
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INTRODUCTION
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The amine functionality is widely represented in various areas of chemical science - from
feedstock molecules, to natural products and complex pharmaceuticals.1 In 1884, Sandmeyer
disclosed potential of primary aryl amines as valuable synthetic intermediates by their
straightforward transformation into aryl diazonium salts.2 Owing to its feasibility of harnessing
aforementioned advantages in synthesis, this strategy rapidly became one of the cornerstones in
organic chemistry.3 On the other hand, due to the low stability of alkyl diazonium salts,
development of a complementary approach employing amines as alkylating agents represents a
longstanding challenge. Recent studies in this area led to transition-metal catalyzed methods for
the formation of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds using alkyl amine derivatives such as
diazo compounds,4 ammonium5 or pyridinium salts.6,7 Conversely, to the best of our knowledge,
a general deaminative alkynylation strategy via the formation of C(sp3)-C(sp) bond has not been
described yet.
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Alkynes found numerous applications in chemical biology,8 medicinal chemistry,9 and material
sciences.10 In recent years, they have been prominently featured in cycloaddition reactions
broadly utilized for connecting biologically relevant molecules.11,12 In organic synthesis, alkynes
are versatile building blocks due to their ability to act both as nucleophiles and electrophiles as
well as to undergo oxidation and reduction.11 Classic methods for their synthesis such as Corey-
Fuchs13 or Seyferth-Gilbert reactions14 are associated with the use of strong bases and therefore
are rarely applicable to late-stage functionalization or diversifications of complex molecules.
This issue has been recently addressed by Baran’s15 and Weix’s groups16 which reported elegant
Ni-catalyzed decarboxylative cross-coupling procedures. In addition, decarboxylative17 and
deboronative18 alkynylation under mild conditions are accessible by visible-light photoredox
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catalysis. In this context, complementary deaminative strategy would open new vistas in
chemical sciences by harnessing molecular scaffolds exclusive to alkyl amines for the synthesis
of C(sp3) -C(sp) bonds.
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We wondered whether the activation/functionalization approach, applied for over a century
for aromatic compounds, could be adapted to synthesis of functionalized alkynes from alkyl
amines. In this line, Watson6 and Glorius7 showed that Katritzky salts (2,4,6-triphenylpyridinium
salts, 3)19 can be employed as alkyl radicals precursors in nickel- or photoredox-iridium-
catalyzed deaminative alkylation of arenes and heteroarenes (Scheme 1). These redox-active
species are easily prepared from unactivated primary amines 1 and commercially available
pyrylium salts 2 via straightforward, chromatography-free procedure (Scheme 1).19 We
envisioned that alkyl radicals, generated from Katritzky salts 3 via visible-light photoredox
catalysis, could be trapped by electrophilic alkyne and alkene derivatives17,20 leading to the
formation of internal alkynes 7 and alkenes 9.
C-N activation
one-step
chromatography-free
chemoselective
air and moisture tolerant
Ph
Ph
-
BF4
-
BF4
NH2
R2
2
Ph
O+ Ph
N+
Ph
Ph
R1
EtOH, reflux, 4 h
Functionalization
R1
R2
1
3
R3
Ts
R3
PhO2S
R4
Het
R3B(OH)2
cat. Ni
6
8
cat. eosin Y
Green LEDs
cat. eosin Y
Green LEDs
cat. Ir
Blue LEDs
R2
R2 R3
R2
R1
R2
R3
R1
R3
R1
R1
R4
Het
7
9
5
4
Watson
C(sp3)-C(sp2) C(sp3)-C(sp2)
Glorius
This work
C(sp3)-C(sp) C(sp3)-C(sp2)
Scheme 1. Katritzky salts as redox-activated amines in C-C bond formation reactions.
Herein, we report an unprecedented metal-free, photo-catalytic approach for deaminative
formation of C(sp3)-C(sp) and C(sp3)-C(sp2) bonds (Scheme 1). In addition to its mild conditions,
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this reaction tolerates a broad range of starting materials and exhibit excellent chemoselectivity.
The feasibility of this method in late-stage functionalization and synthesis of pharmaceuticals is
highlighted by diversification of several complex drug-like molecules.
RESULTS AND DISCUSSION
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Model Studies To attain an access to C(sp3)-C(sp) bonds from primary amines, we explored
reactivity of Katritzky salts 3 in reaction with alkynyl derivatives 11. Our studies commenced
with the choice of a photocatalytic system. Glorius et al. reported that ruthenium and iridium
polypyridyl complexes generate alkyl radicals from pyrdinium salts 3 via light-induced reductive
single-electron transfer process.7 Encouraged by an increasing interest in the use of organic
photocatalysts21 and considering reduction potential values of Katritzky salts 3 (E1/2 = ca. -0.95 V
vs. Ag/AgCl in MeOH, see SI), we hypothesized that similar outcome should be possible with
nontoxic and inexpensive organic dyes. Such an approach merging unique capabilities of
photoredox catalysis with benefits of “metal-free” catalytic system would be advantageous for
development of sustainable transformations. To this end, using pyridinium salt 10, we performed
fluorescence-quenching studies of a series commonly employed in photoredox catalysis xanthene
dyes (with redox potentials E1/2(PC+/PC*) < -0.95 V): eosin Y, rose bengal, erythrosin B and
rhodamine 6G.21 Pleasingly, compound 10 quenched the fluorescence of all of the
aforementioned dyes, with eosin Y being quenched the most efficiently (kq = 8.1·1010 s-1·M-1)
(see SI).
Following the evaluation of a catalyst, we sought to establish a suitable alkyne acceptor (Table
1). After considerable optimization studies, we found that alkynyl bromides and p-tolylsulfones
enabled the desired reaction, with the latter providing the highest yield of desired product 12
(entries 2 and 3). Unsurprisingly, terminal alkynes did not furnish product 12 (entry 1). Control
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experiments identified the catalyst, light, and the sacrificial reductant (DIPEA) as essential
components of the reaction (entries 7, 8, 9). Comparison of the studied catalysts under the
optimal conditions showed that eosin Y performed superior to other organic dyes (see SI) and
equally with transition-metal-based catalysts (entries 5, 6). Importantly, the use of both
anhydrous solvents and inert atmosphere was not required (entry 10) (for optimization details see
SI).
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Table 1. Model studies.a
Ph
Ph
Ph
X
11
Ph
-
N+
2 mol% eosin Y, DIPEA
BF4
MeOH/DCE (3:1)
Green LEDs
Ph
10
12
Entry
Catalyst
X
Light
Yield
(%)b
1
2
eosin Y
eosin Y
eosin Y
eosin Y
H
green
green
green
green
blue
0
Br
Ts
BI
34
3
86 (84)c
4
0
5
Ru(bpy)3Cl2·6H2O
[Ir(ppy)2(dtbbpy)]PF6
none
Ts
Ts
Ts
Ts
Ts
Ts
80
6
blue
85
7
white
none
green
green
0
8
eosin Y
0
0
9d
10e
eosin Y
eosin Y
79 (78)c
aReaction conditions: alkyne 11 (0.10 mmol), pyridinium salt 10 (1.4 equiv.), catalyst (2.0
mol%), DIPEA (3.25 equiv.), MeOH/DCE (3:1, c = 0.033 M), ambient temperature (20-22 °C),
16 h, under Ar atmosphere, light source: LED tape (for more details see SI). bGC yield. cIsolated
yield. dWithout DIPEA. eAir atmosphere. BI – benziodoxole, DCE – 1,2-dichloroethane.
Scope and Limitations With the optimized conditions in hand, we explored scope and
limitations of the developed reaction. To this end, a range of pyridinium salts 3 were prepared
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and tested (Scheme 2A-D).19 Substrates derived from secondary alkyl, primary benzyl and allyl
tethered primary amines smoothly underwent the examined transformation. The reaction proved
to be suitable for the synthesis of simple cyclic (12-15), heterocyclic (16), and acyclic (19, 20)
alkynes. Importantly, products bearing a range of functional groups including: carbamate (17),
unprotected hydroxyl group (18, 21, 22, 23), sulfide (23), halogens (26, 27, 28), ester (29), basic
nitrogen atom (33, 34), and alkene (35) were easily obtained, highlighting utility of the
developed method in synthesis of valuable building blocks. For example, bromo- (26) and
iodoarenes (27) are favorable substrates in metal-catalyzed cross-coupling reactions,22 while 1,4-
enynes, such as 35, are applicable in rapid synthesis of complex carbon frameworks via Pt-
catalyzed cycloisomerization.23 Moreover, merging this strategy with well-established methods
for amine synthesis can be used to transform different functional groups into alkynes. In this line,
halogenated compound 30 was obtained from corresponding nitrile, while steroid 24 was derived
from commercially available 5α-cholestan-3-one.
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While secondary alkyl substituted pyridinium salts furnished products in good to excellent
yields under optimized conditions, benzyl derivatives required a higher excess of a Katritzky
salts, due to the concurrent dimerization of benzyl radicals. Noteworthy, regarding the
benzylation of alkynes, the developed method is complementary to the recently reported Ni-
catalyzed decarboxylative alkynylation reactions,15,16 which are unsuitable for the synthesis of
this type of products.
Based on Katritzky’s works, poor reactivity of electron rich benzyl salts (36) can be explained
by their diminished stability due to activation towards the competing nucleophilic substitution.24
For primary alkyl substituted substrates, the reaction proceeded remarkably slow, giving only
traces of product 37 even after prolonged reaction time. Moreover, the reaction of amino ester
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derived pyridinium salts 3 with alkynyl sulfones 6 led to formation of inseparable mixtures of
β,γ-alkynyl esters and isomeric allenes.
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Ph
R1
Ph
> 40 examples
metal-free
broad functional group tolerance
scalable
air and moisture tolerant
Ts
R2
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R2
-
N+
2 mol% eosin Y, DIPEA
BF4
R1
MeOH/DCE (3:1)
Green LEDs
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A. Secondary pyridinium salts
Me
Me
O
Ph
Ph
Ph
Ph
BocN
17
Ph
Ph
H
Me
16
13
(75%)
(78%)
(58%)
Ph
12
14 (70%)
(84%)
(82%)
Me
H
15
(83%)
Me
b
[gram scale]
OMe
H
H
MeS
Ph
X
HO
Ph
24
(83%)
d.r. 2:1
H
Ph
Et
Ph
(83%)
HO
HO
18
(82%)
Me
23
(77%)
19
(81%)
20
X = -H 21
-Br 22
Me
(75%)
(77%)
cis/trans ratio: 1.25 : 1
B. Benzyl pyridinium saltsc
R = -H
-Br
F
Br
25
26
27
28
(71%)
(70%)
(66%)
(66%)
(50%)
N
Cl
F
N
R
Ph
Ph
Ph
Ph
Ph
Ph
-I
-CF3
-CO2Me 29
F3C
F3C
30
31
32
33
34
(70%)
(66%)
(71%)
(68%)
(46%)
Ph
C. Allyl pyridinium saltd
F. Complex targets
D. Limitations
MeO
OH
Ph
Me
Me
OMe
Ph
HO
O
Ph
37
e
f
Me
(66%)
(4%) ; (9%)
36
(0%)
35
(40%)
Ph
Me
52
E. Alkynyl p-tolylsulfones
53
h
(44%)
erythro/threo ratio: 2 : 1
Metaraminol derivative
X
X
Mexiletine derivative
O
Me
O
X = -Cl
-Me
-CF3
41
42
43
(76%)
(80%)
(57%)
X = -OMe 38
-Br 39
(77%)
(79%)
(76%)
44
(64%)
Me
H
O
-F
40
Me
g
54
(70%)
H
H
O
S
Dehydrocholic acid derivative
OMe
O
H
O
R =
OMe
R
Me
45
46 (81%)
(78%)
47
(50%)
g
N
55
56
(70%)
O
O
g
R = -TIPS
49
(34%)
R
N
Me
-n-Hex 50
(42%)
51
(34%)
g
Cl
-t-Bu
OTBDMS
48
(70%)
g
Indometacin derivatives
(52%)
Scheme 2. Scope of deaminative alkynylation.a
aReaction conditions: alkyne 6 (0.25 mmol), pyridinium salt 3 (1.4 eqiuv.), eosin Y (2.0 mol%),
DIPEA (3.25 equiv.), MeOH/DCE (3:1, c = 0.033 M), ambient temperature (20-22 °C), 16 h,
under Ar atmosphere, light source: green LEDs tape. All reported yields are mean values of
b
isolated yields from at least two independent experiments. 5.0 mmol scale, reaction time: 40 h.
cPyridinium salt 3 (2.0 equiv.), DIPEA (3.75 equiv.). dPyridinium salt 3 (3.0 equiv.), DIPEA (4.5
equiv.). eGC yield, reaction time: 48 h. fGC yield, at 60 °C. gIn DCE (c = 0.033 M). hPyridinium
salt 3 (0.25 mmol), alkyne 6 (5 equiv.).
Continuing with the evaluation of the reaction scope, several alkynyl p-tolylsulfones 6 were
prepared from terminal17a and silyl protected alkynes25 via the literature procedures (Scheme 2E).
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Phenyl derivatives with electron-donating (38, 42) as well as mildly electron-withdrawing
substituents (39, 40, 41) reacted equally well. The presence of a strongly electron-withdrawing
substituent as in 43 reduced the reaction yield. Additionally, the reaction outcome was not
affected by the substitution pattern on the aromatic ring, as demonstrated by the excellent yields
of the para (42), meta (47) and ortho (46) substituted products. Furthermore, heteroaryl alkyne
derivatives were well tolerated under the studied conditions (45). The preference of alkyl radicals
for the reaction with electrophilic alkynyl p-tolylsulfones compared with terminal alkynes,
permits the synthesis of unsymmetrical dialkynes via regioselective functionalization (47).
Finally, silyl (49) and alkyl (50, 51) substituted alkynes were also possible to obtain in workable
yields, without additional optimization.
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Consequently, to show the utility of the developed methodology for diversification of drug
molecules two commercially available drugs bearing a primary amino group, mexiletine (anti-
arrhythmic) and metaraminol (antihypotensive) were converted into the corresponding Katritzky
salts and subjected to the title transformation. Initially, the derivatization of mexiletine proved to
be challenging due to the concurrent β-fragmentation of the resulting alkyl radical. However, the
use of an excess of alkynyl derivative (5 equiv.) provided product 52 in satisfactory 44% yield.
Conversely, the metaraminol derivative smoothly underwent alkynylation giving compound 53
with full retention of the configuration at the stereogenic center adjacent to reaction site. These
examples highlight the possibility of application of the reaction to rapidly access complex
structural motifs.
Furthermore, to examine applicability of our approach in late-stage functionalization, drug-like
alkynyl p-tolylsulfones were synthesized from complex substrates: dehydrocholic acid (steroid)
and indometacin (non-steroidal anti-inflammatory drug). Steroidal derivative 54 bearing reactive
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ketone groups and multiple stereogenic centers was obtained in excellent yield as a single
enantiomer. Similarly, highly functionalized indometacin derivative proved to be a suitable
coupling partner for both secondary (55) and benzylic Katritzky salts (56), underscoring mild
conditions and high chemoselectivity of the developed method.
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The successful development of deaminative alkynylation prompted us to further explore the
possibility of constructing other types of C-C bonds via the studied approach. Pleasingly, vinyl
sulfones 8 proved to be suitable acceptors of alkyl radicals under previously developed
conditions, leading to functionalized alkenes (Scheme 3). The reaction provided a range of aryl
(58-65) and heteroaryl (66, 67, 68) substituted olefins with excellent diastereoselectivity leading
to theromodynamically favoured (E)-alkenes. Moreover, 1,1-disubstitued substrate provided
product 65 in significantly higher yield, presumably due to better stabilization of intermediate
benzyl radical. Most importantly, the ability to access alkenes from unstabilized (secondary)
alkyl radicals makes this reaction complementary to recently published Ni-catalysed cross-
coupling of benzylic Katritzky salts with vinyl boronic acids.6c
R1
PhO2S
Ph
R1
Ph
R2
8
R1
-
N+
1 mol% eosin Y, DIPEA
BF4
MeOH/DCE (3:1)
R2
Ph
Green LEDs
3
57
Pyridinium salts
Ph
Ph
OMe
Ph
Et
60
(65%)
Ph
HO
(E/Z > 99:1)
BocN
MeS
Ph
Me
59
(E/Z > 99:1)
62
(45%)
58
(70%)
(72%)
61
(58%)
(E/Z > 99:1)
(E/Z > 99:1)
HO
(E/Z > 99:1)
Vinyl sulfones
CF3
OMe
Ph
Ph
65
(96%)
64
63
(79%)
(65%)
(E/Z > 99:1)
(E/Z > 99:1)
S
N
O
N
68
(66%)
(E/Z = 98:2)
67
66
(52%)
(E/Z = 96:4)
(83%)
(E/Z > 99:1)
Scheme 3. Scope of deaminative alkynylation.a
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aReaction conditions: alkene 8 (0.25 mmol), pyridinium salt 3 (2.0 eqiuv.), eosin Y (1.0 mol%),
DIPEA (2.5 equiv.), MeOH/DCE (3:1, c = 0.033 M), ambient temperature (20-22 °C), 40 h,
under Ar atmosphere, light source: green LEDs tape. E/Z ratios were established based on GC-
MS analysis of crude reaction mixtures.
7
8
9
Mechanistic Consideration To gain mechanistic insight into our photocatalytic system, several
experiments were conducted. Based on Watson’s6 and Glorius’s work,7 a radical mechanism is
postulated. To corroborate this hypothesis, the reaction of pyridinium salt 10 with alkyne 69 in
the presence of TEMPO [(2,2,6,6-tetramethylpiperindin-1-yl)oxyl] was performed (Scheme 4A).
Expectedly, the addition of a radical trap had a detrimental effect on the reaction outcome due to
the formation of the alkylated TEMPO derivative 70 (detected by LR-MS and NMR). Moreover,
the reaction with enantiomerically pure pyridinium salt 71 gave racemic product 20, which is
typical for reactions proceeding via readily epimerizable radical intermediates (Scheme 4B). The
alkenylation reactions with pure E-isomer as well as a mixture geometric isomers of vinyl
sulfone 72 led to comparable results both in terms of the product 58 yield and stereochemical
outcome, which is characteristic for the reactions proceeding via radical addition-elimination
mechanism (Scheme 4C).24b,24c,26
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A.
Ph
Ts
Ph 69
Ph
Ph
TEMPO (2 equiv.)
12
(0%)
Me
-
N+
2 mol% Eosin Y, DIPEA
BF4
Me
MeOH/DCE (3:1)
Green LEDs
O
N
Ph
10
Me
Me
70
(46% NMR)
B.
Ph
Ph
Ts
Ph 66
-
Cy
N+
Cy
BF4
2 mol% Eosin Y, DIPEA
Ph
MeOH/DCE (3:1)
Green LEDs
Me
20
Me Ph
71
(ee > 99%)
(83%, ee = 0%)
PhO2S
72
C.
Ph
(E/Z > 99:1)
Ph
Ph
Ph
-
N+
BF4
1 mol% Eosin Y, DIPEA
MeOH/DCE (3:1)
Green LEDs
58
(70%, E/Z > 99:1)
Ph
10
PhO2S
72'
Ph
(E/Z = 45:55)
Scheme 4. Mechanistic experiments.
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To examine the role of a photocatalyst, Stern-Volmer quenching experiments were performed
(Figure 1). Although both Katritzky salts 3 and tertiary amines quenched the luminescence of
eosin Y, the significantly higher quenching constant for pyridinium salt 73 (kq = 3.8·1010 s-1·M-1)
compared with DIPEA (kq = 2.3·109 s-1·M-1) indicates that the oxidative quenching cycle is
favored. Additionally, a light on/off experiment proved the exclusive light-dependence of the
reaction (see SI).
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Figure 1. Stern-Volmer fluorescence quenching of eosin Y (c = 2.0 μM) in MeOH.
Based on the presented experimental evidences and reported results,7,17a,17c we propose the
reaction mechanism shown in Scheme 5. Photoexcited eosin Y (EY*) reduces pyridinium salt A
via single-electron transfer, followed by fragmentation of the resultant dihydropyridine radical B
generating alkyl radical C and rearomatized pyridine derivative D. Simultaneously, to maintain
the catalytic cycle, EY+· is reduced to the initial form by DIPEA. Subsequent α-addition of
radical C to acceptor E furnishes intermediate F that rapidly eliminates arylsulfonyl radical
giving product G. The E-selectivity of the alkenylation reaction arises during the β-elimination
step and is dictated by the thermodynamic and steric factors.26
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EY
h
DIPEA+
4
R2
R1
5
6
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8
EY*
RSO2
-
RSO2
R2
F
DIPEA
R1
EY+
G
R2
Ph
R1
Ph
Ph
Ph
E
RO2S
N+
9
Ph
Ph
N
A
R1
Ph
B
R1
C
+
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N
Ph
D
Ph
EY+
EY
Back-electron transfer dominates
for primary Katritzky salts
Scheme 5. Proposed reaction mechanism.
The intriguingly significant difference in the reactivity of secondary and primary alkyl
substituted Katritzky salts can be explained based on voltammetric (Figure 2) and kinetic (Figure
3) experiments. For primary alkylic (74), secondary alkylic (10) and benzylic (75) pyridinium
salts, fully-reversible, semi-reversible, and irreversible reduction waves are respectively
observed, illustrating the relative stability of the dihydropyridine radicals B. Similarly, the rates
of substrates conversion under optimized conditions follows the order benzyl > secondary >
primary. These results indicate that the fragmentation rate of dihydropyridine radical B strongly
depends on the stability of the resulting alkyl radical C. While benzyl- and secondary alkyl-
substituted pyridinium salts produce alkyl radicals at a sufficient rate, primary derivatives lead to
persistent dihydropyridine radicals, which preferentially undergo reoxidation to pyridinium salts
(Scheme 5).
Figure 2. Cyclic voltammograms of Katritzky salts 10, 74 and 75 (c = 10 mM) in dry MeOH.
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Figure 3. Kinetic study of the conversion of pyridinium salts 10, 74, and 75 under reaction
conditions.
CONCLUSIONS
In summary, a visible-light-mediated deaminative strategy for the construction of C(sp3)-C(sp)
bond has been developed. This reaction employs an environmentally benign “metal-free”
catalytic system. High chemoselectivity, mild conditions, and scalability of the title
transformation open new prospects for a straightforward access to complex molecules from
prevalent primary amines. Its applicability was demonstrated on the examples of diversification
of complex drug derivatives. Additionally, the developed approach proved to be also suitable for
synthesis of functionalized alkenes from vinyl sulfones.
ASSOCIATED CONTENT
Supporting Information. The following files are available free of charge.
Experimental procedures, optimization details and mechanistic studies (PDF file)
1H and 13C NMR spectra for all new compounds (PDF file)
AUTHOR INFORMATION
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Corresponding Author
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*E-mail: dorota.gryko@icho.edu.pl
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
Financial support for this work was provided by National Science Center (PL) Grant no.
2016/21/BST5/03169 OPUS.
REFERENCES
1. (a) Roughley, S. D.; Jordan, A. M. The Medicinal Chemist’s Toolbox: An Analysis of
Reactions Used in Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451-3479. (b)
Cushnie, T. P. T.; Cushnie, B.; Lamb, A. J. Alkaloids: An Overview of Their Antibacterial,
Antibiotic-Enhancing and Antivirulence Activities. Int. J. Antimicrob. Agents 2014, 44, 377-
386. (c) McGrath, M. A.; Brichaeck, M.; Njardarson, T. J. A Graphical Journey of
Innovative Organic Architectures That Have Improved Our Lives. J. Chem. Educ. 2010, 87,
1348-1349.
2. Sandmeyer, T. Ueber die Ersetzung Amidgruppe durch Chlor in den aromatischen
Substanzen. Ber. Dtsch. Chem. Ges. 1884, 17, 1633-1635.
3. (a) Hodgson, H. H. The Sandmeyer Reaction. Chem. Rev. 1947, 40, 251-277. (b) Ghosh, I.;
Marzo, L.; Das, A.; Shaikh, R.; König, B. Visible Light Mediated Photoredox Catalytic
Arylation Reactions. Acc. Chem. Res. 2016, 49, 1566-1577. (c) Mo, F.; Dong, G.; Zhang,
ACS Paragon Plus Environment
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Page 15 of 23
ACS Catalysis
1
2
3
4
5
6
Y.; Wang, J. Recent Applications of Arene Diazonium Salts in Organic Synthesis. Org.
Biomol. Chem. 2013, 11, 1582-1593.
7
8
9
4. (a) Qin, G.; Li, L.; Li, J.; Huang, H. Palladium-Catalyzed Formal Insertion of Carbenoids
into Aminals via C-N Bond Activation. J. Am. Chem. Soc. 2015, 137, 12490-12493. (b)
Huang, X.; Webster, R. D.; Harms, K.; Meggers E. Asymmetric Catalysis with Organic
Azides and Diazo Compound Initiated by Photoinduced Electron Transfer. J. Am. Chem.
Soc. 2016, 138, 12636-12642. (c) Rybicka-Jasińska, K.; Ciszewski, Ł. W.; Gryko, D.
Photocatalytic Reaction of Diazo Compounds with Aldehydes. Adv. Synth. Catal. 2016, 358,
1671-1678.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5. (a) Wu, G.; Deng, Y.; Wu, C.; Zhang, J.; Wang, J. Synthesis of α-Aryl Esters and Nitriles:
Deaminative Coupling of α-Aminoesters and α-Aminoacetonitirles with Arylboronic Acids.
Angew. Chem. Int. Ed. 2014, 53, 10510-10514. (b) Blakey, S. B.; MacMillan, D. W. C. The
First Suzuki Cross-Couplings of Aryltrimethylammonium Salts. J. Am. Chem. Soc. 2003,
125, 6046-6047. (c) Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.;
Watson, M. P. Nickel-Catalyzed Cross Couplings of Benzylic Ammonium Salts and Boronic
Acids: Stereospecific Formation of Diarylethanes via C-N Bond Activation. J. Am. Chem.
Soc. 2013, 135, 280-285.
6. (a) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P. Harnessing Alkyl Amines as
Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation. J. Am. Chem.
Soc. 2017, 139, 5313-5316. (b) Liao, J.; Guan, W.; Boscoe. B. P.; Tucker, J. W.; Tomlin, J.
W.; Garsney, M. R.; Watson, M. P. Transforming Benzylic Amines into Diarylmethanes:
Cross-Coupling of Benzylic Pyridinium Salts via C-N Bond Activation. Org. Lett. 2018, 20,
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1
2
3
4
3030-3033. (c) Guan, W.; Liao, J.; Watson, M. P. Vinylation of Benzylic Amines via C-N
5
6
Bond Functionalization of Benzylic Pyridinium Salts. Synthesis 2018, 50, 3231-3237.
7
8
9
7. Klauck, F. J. R.; James, M. J.; Glorius, F. Deaminative Strategy for the Visible-Light-
Mediated Generation of Alkyl Radicals. Angew. Chem. Int. Ed. 2017, 56, 12336-12339.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8. Jewett, J. C.; Bertozzi, C. Cu-Free Click Cycloaddition Reactions in Chemical Biology.
Chem. Soc. Rev. 2010, 39, 1272-1279.
9. Thirumurugan, P.; Matasiuk, D.; Jozwiak, K. Click Chemistry for Drug Development and
Diverse Chemical-Biology Applications. Chem. Rev. 2013, 113, 4905-4979.
10. Liu, Y.; Lam, J. W. Y.; Tang, B. Z. Conjugated Polymers Developed from Alkynes. Nat.
Sci. Rev. 2015, 2, 493-509.
11. (a) Modern Acetylene Chemistry; Stang, P. J.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
1995. (b) Acetylene Chemistry: Chemistry, Biology, and Material Science; Diederich, D.;
Stang, P. J.; Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005.
12. (a) Singh, M. S.; Chowdhury, S.; Koley, S. Progress in 1,3-Dipolar Cycloadditions in the
Recent Decade: An Update to Strategic Development Towards the Arsenal of Organic
Synthesis. Tetrahedron 2016, 72, 1603-1644. (b) Hein, C. D.; Liu, X.-M.; Wang, D. Click
Chemistry, A Powerful Tool for Pharmaceutical Sciences. Pharm. Res. 2008, 25, 2216-
2230.
13. Corey, E. J.; Fuchs, P. L. A Synthetic Method for Formyl→Ethynyl Conversion
(RCHO→RC≡CH or RC≡CR’). Tetrahedron Lett. 1972, 13, 3769-3722.
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1
2
3
4
5
6
7
8
9
14. Seyferth, D.; Marmor, R. S.; Gilbert, J. Reactions of Dimethylphosphito-Substituted
Diazoalkanes. (MeO)2P(O)CR Transfer to Olefins and 1,3-Dipolar Additions of
(MeO)2P(O)C(N2)R. J. Org. Chem. 1971, 36, 1379-1386.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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34
35
36
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15. Smith, J. M.; Qin, T.; Merchant, R. R.; Edwards, J. T.; Malins, L. R.; Liu, Z.; Che, G.; Shen,
Z.; Shaw, S. A.; Eastgate, M. D.; Baran, P. S. Decarboxylative Alkynylation. Angew. Chem.
Int. Ed. 2017, 56, 11906-11910.
16. Huang, L.; Olivares, A. M.; Weix, D. J. Reductive Decarboxylative Alkynylation of N-
Hydroxyphthalimide Esters with Bromoalkynes. Angew. Chem. Int. Ed. 2017, 56, 11901-
11905.
17. (a) Yang, J.; Zhang, J.; Qi, L.; Hu, C.; Chen, Y. Visible-Light-Induced Chemoselective
Reductive Decarboxylative Alkynylation under Biomolecule-Compatible Conditions. Chem.
Commun. 2015, 51, 5275-5278. (b) Zhang, H.; Zhang, P.; Jiang, M.; Yang, H.; Fu, H.
Merging Photoredox with Copper Catalysis: Decarboxylative Alkynylation of α-Amino
Acid Derivatives. Org. Lett. 2017, 19, 1016-1019. (c) Gao, C.; Li, J.; Yu, J.; Yang, H.; Fu,
H. Visible-Light Photoredox Synthesis of Internal Alkynes Containing Quaternary Carbons.
Chem. Commun. 2016, 52, 7292-7294. (d) Le Vaillant, F.; Courant, T.; Waser, J. Room-
Temperature Decarboxylative Alkynylation of Carboxylic Acids Using Photoredox
Catalysis and EBX Reagent. Angew. Chem. Int. Ed. 2015, 54, 11200-11204.
18. Huang, H.; Zhang, G.; Gong, L.; Zhang, S.; Chen, Y. Visible-Light-Induced Chemoselective
Deboronative Alkynylation under Biomolecule-Compatible Conditions. J. Am. Chem. Soc.
2014, 136, 2280-2283.
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2
3
4
5
6
7
8
9
19. Katritzky, A. R.; Bapat, J. B.; Blade, R. J.; Leddy, B. P.; Nie, P.-L.; Ramsden, C. A.; Thind,
S. S. Heterocycles in Organic Synthesis. Part 6. Nucleophilic Displacements of Primary
Amino-Groups via 2,4,6-Triphenylpyridinium Salts. J. Chem. Soc., Perkin Trans. 1 1979,
418-425.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
35
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38
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20. (a) Ruano, J. L. G.; Alemán, J.; Parra, A.; Marzo, L. Sulfonyl Acetylenes as Alkynylating
Reagents under Radical or Anionic Conditions. Eur. J. Org. Chem. 2014, 8, 1577-1588. (b)
Amaoka, Y.; Nagatomo, M.; Watanabe, M.; Tao, K.; Kamijo, S.; Inoue, M. Photochemically
Induced Radical Alkenylation of C(sp3)-H Bonds. Chem. Sci. 2014, 5, 4339-4345. (c) Noble,
A.; MacMillan, D. W. C. Photoredox α-Vinylation of α-Amino Acids and N-Aryl Amines. J.
Am. Chem. Soc. 2014, 136, 11602-11605.
21. (a) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116,
10075-10166. (b) Ravelli, D.; Fagnoni, M,; Albini, A. Photoorganocatalysis. What for?
Chem. Soc. Rev. 2013, 42, 97-113. (c) Visible Light Catalysis in Organic Chemistry;
Stephenson, C.; Yoon, T.; MacMillan, D. W. C., Eds.; Wiley-VCH: Berlin, 2018.
22. (a) Johansson-Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Palladium-
Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize.
Angew. Chem. Int. Ed. 2012, 51, 5062-6174. (b) Ruiz-Castillo, P.; Buchwald, S. L.
Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem. Rev. 2016, 116,
12564-12649.
23. Sato, T.; Onuma, T.; Nakamura, I.; Terada, M. Platinum-Catalyzed Cycloisomerization of
1,4-Enynes via 1,2-Alkenyl Rearrangement. Org. Lett. 2011, 13, 4992-4995.
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2
3
4
5
6
24. Katritzky, A. R.; Rubio, O. Conversion of N-Vinylpyridinium Cations into Tricyclic Cage
Compounds. J. Org. Chem. 1984, 49, 448-454.
7
8
9
25. Chen, H.; Zhang, L. A Desulfonylative Approach in Oxidative Gold Catalysis:
Regiospecific Access to Donor-Substituted Acyl Gold Carbenes. Angew. Chem. Int. Ed.
2015, 54, 11775-11779.
10
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12
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41
42
43
44
45
46
47
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55
56
57
58
59
60
26. (a) Liu, J.-T.; Jang, Y.-J.; Shih, Y.-K.; Hu, S.-R.; Chu, C.-M.; Yao, C.-F. Novel Synthesis of
Alkenes via Triethylborane-Induced Free-Radical Reactions of Alkyl Iodides and β-
Nitrostyrenes. J. Org. Chem. 2001, 66, 6021-6028. (b) Chu, C.-M.; Liu, J.-T.; Lin, W.-W.;
Yao, C.-F. Free Radical Reactions to Generate Alkenes and/or Ionic Reactions to Generate
Hydroximoyl Chlorides when β-Nitrostyrenes React with Triethylaluminium or
Diethylaluminium Chloride. J. Chem. Soc., Perkin Trans. 1 1999, 47-52.
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