Photoinduced Cascade Reaction of Tertiary Amines with Sulfonyl Azides: Synthesis of Amidine Derivatives

Article abstract of DOI:10.1002/adsc.201900359

A metal-free cascade reaction of tertiary amines with sulfonyl azides promoted by acridinium salts under blue light irradiation was developed and provided amidine derivatives in moderate to good yields. Enamine was generated from tertiary amine via single-electron transfer promoted by acridinium salts, and the following [3+2] cyclization with sulfonyl azide and CH₂N₂ release afforded the desired products. (Figure presented.).

Full text of DOI:10.1002/adsc.201900359

Title: Photoinduced Cascade Reaction of Tertiary Amines with Sulfonyl
Azides: Synthesis of Amidine Derivatives
Authors: Rui Ding, Hui Chen, Yanli Xu, Hai-Tao Tang, Yan-yan Chen,
and Ying-ming Pan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900359
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10.1002/adsc.201900359
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Photoinduced Cascade Reaction of Tertiary Amines with
Sulfonyl Azides: Synthesis of Amidine Derivatives
Rui Ding,a Hui Chen,b Yan-Li Xu,b Hai-Tao Tang,a Yan-Yan Chen,b,* Ying-Ming Pana,*
a
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and
Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China. E-mail:
panym@mailbox.gxnu.edu.cn.
Pharmacy School, Guilin Medical University, Guilin, 541004 People’s Republic of China. E-mail:
b
chenyy269614@163.com.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A metal-free cascade reaction of tertiary amines
with sulfonyl azides promoted by acridinium salts under
blue light irradiation was developed and provided amidine
derivatives in moderate to good yields. Enamine was
generated from tertiary amine via single-electron transfer
promoted by acridinium salts, and the following [3+2]
cyclization with sulfonyl azide and CH2N2 release afforded
the desired products.
Keywords: photocatalysis; enamination; [3+2] cyclization;
cascade reaction; amidine derivatives
Given their wide existence in natural products and
drugs, the functionalization of tertiary amines has
always been of great interest. Enamine is an
important intermediate to achieve the direct
functionalization of tertiary amines.[1] However, the
formation of enamine is difficult because of the
strong competition of iminium ion and amino radical
Scheme 1. The reported synthesis of amidine derivatives.
in the process. In traditional methods, enamines are
promoted by transition metals, such as Ru,[2] Pt,[3]
iridium photocatalyst.[8] Xu reported the [2+2]
cycloaddition of propiolic acid ester with enamine
from tertiary amine promoted by visible-light
photocatalysis.[9] Zeng reported the cross coupling of
sulfonyl azides with tertiary amines to synthesize
amidines in good yields, and the enamine generated
from the photoinduced dehydrogenation of tertiary
amines played an important role in this reaction.[10]
Therefore, studying the reaction of photoinduced
enamines is important.
Amidine is a fundamental unit in medicinal and
synthetic chemistry that is widely applied in
pharmaceutical science[11] and metal complexation
ligands.[12] In the past years, great efforts have been
focused on developing a new method to prepare
Pd,[4] and Co,[5] and undergo subsequent reactions
with different electrophilic reagents. In the above
methods, expensive catalysts are needed, and the
following reactions are very limited, which mainly
focus on nucleophilic addition with nitrostyrenes and
aldehydes. In recent years, visible-light photoredox
catalysis has attracted considerable attention as a
green technology.[6] Tertiary amines can be
functionalized rapidly through photocatalysis. Most
reported reactions involve iminium ion or α-
aminoalkyl radical pathway.[7] However, reports
about the photoinduced formation of enamines from
tertiary amines are very few. Rueping and co-workers
achieved the β-sulfonylation of pyrrolidines via a
dehydrogenative enamine pathway promoted by the
1
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10.1002/adsc.201900359
Advanced Synthesis & Catalysis
Table 2. Scope of the substrates. a)
amidines. Wan and co-workers found that the direct
condensation of amides and sulfonamides gave
amidines in good yields under the condition of
NaI/TBHP[13] or Zn(OTf)2/EDA (Scheme 1a).[14] The
coupling of tertiary amines with sulfonamides offered
amidines on the basis of the in situ generation of
TsNBr2 (Scheme 1b).[15] Recently, excellent strategies
were applied to prepare amidines through the cascade
reaction of tertiary amines with sulfonyl azides
promoted by CuCl/CCl4,[16] electrocatalysis,[17] diethyl
azodicarboxylation,[18] and FeCl3,[19] and the enamine
generated from oxidative dehydrogenation as a key
intermediate in these reactions (Scheme 1c). Excess
oxidants and dehydrogenating agents, which are
harmful to the environment, are needed in the above
reactions.
Entry Amine 1
Azide 2
Product 3 (%)
1
2
3
4
5
2a
2a
2a
2a
Acridinium salts are
a
class of organic
photocatalysts that are applied to initiate olefins and
electric-rich aromatics into radical cations.[20]
Previously, we reported the formation of thioamide
radicals promoted by acridinium salt under visible-
light irradiation, and the following intramolecular
cyclization with p-quinone methides provided 1,2,4-
6
7
2a
2a
8
9
1a
1a
Table 1. Optimization of the photoinduced cascade
reaction. a)
10
11
1a
1a
Entry Photocatalyst
Solvent
CH3CN
CH3CN
CH3CN
DCE
DCE
CH3CN
DCE
DCE
DCE
DCE
DCE
Yield(%)b)
12
13
14
1a
1a
1a
1
Ru(bpy)3Cl2
71
45
59
76
26
trace
64
53
55
60
0
2
Ir(ppy)3
3
4
5
Ir(bpy)(ppy)2PF6
Mes-Acr-Ph+BF4
TPT
6
Eosin Y
7c)
8d)
9e)
10f)
11g)
Mes-Acr-Ph+BF4
Mes-Acr-Ph+BF4
Mes-Acr-Ph+BF4
Mes-Acr-Ph+BF4
Mes-Acr-Ph+BF4
15b)
1a
16
17
18
19
1a
1a
1a
1a
1a
a) Conditions: 1a (0.3 mmol), 2a (0.9 mmol), photocatalyst
(5 mol %), and solvent (2 mL) were stirred in air
atmosphere under the irradiation of 12 W blue LEDs for 10
20
h at rt. b) Isolated yields. K2CO3 (0.3 mmol). d) Na2CO3
c)
a)
Reaction conditions: 1 (0.3 mmol), 2 (0.9 mmol), and
Mes-Acr-Ph+BF4 (5 mol %) in DCE (2 mL) were stirred in
air atmosphere under the irradiation of 12 W blue LEDs
for 10 h at rt. b) CH3CN was used as solvent.
(0.3 mmol). e) 2a (0.6 mmol) was used. f) Photocatalyst (2.5
mol %) was used. g) The reaction was carried out in dark.
2
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10.1002/adsc.201900359
Advanced Synthesis & Catalysis
dithiazoles.[21] We speculated that this organic
photocatalyst could also promote amines to form
radical cations and underwent subsequent reaction.
As a source of amide, the application of acyl azides in
the photoinduced amidations also received great
attention in recent years.[22] Herein, we would report a
photoinduced cascade reaction of tertiary amines and
sulfonyl azides to synthesize amidines.
First, we examined the cascade reaction of
triethylamine and sulfonyl azide in the catalysis of 5
mol % Ru(bpy)3Cl2 under blue light irradiation; 3aa
was obtained in 71% yield (entry 1, Table 1). Then
the reaction conditions were further explored, and
results are shown in Table 1. Other metal
photocatalysts such as Ir(ppy)3 and Ir(bpy)(ppy)2PF6
were unsuitable in this reaction as they reduced the
yield of 3aa to 45% and 59%, respectively (entries 2
and 3, Table 1). Then, organic photocatalysts such as
TPT, Eosin Y, and Acr-Mes-Ph+BF4 were examined,
and Acr-Mes-Ph+BF4 was found to be the best
catalyst, which gave 3aa in 76% yield (entries 4–6,
Table 1). Bases were used as additive, which
decreased the yield (entries 7 and 8, Table 1).
Decreasing the amount of Acr-Mes-Ph+BF4 and
sulfonyl azide resulted in lower product yields
(entries 9 and 10, Table 1). When the reaction was
carried out in dark, 3aa was not obtained (entry 11,
Table 1). Finally, the optimized reaction conditions
were 5 mol % Acr-Mes-Ph+BF4 in DCE under blue
light irradiation for 10 h.
Scheme 2. Investigation of other substrates and a larger-
scale reaction.
trace amount of 3al was observed. 2-Thienyl was
suitable and generated 3am in 52% yield. To our
delight, when camphorsulfonyl azide was used, 3an
was obtained in a good yield (73%).
We also studied the coupling of triethylamine
with benzoyl azide, azidobenzene, and diphenyl
phosphorazidate (Scheme 2). Unfortunately, only a
trace amount of 3ao was detected, and 3ap and 3aq
were not produced. We found that almost all 2o
converted into isocyanatobenzene 4ao. When 1h was
introduced, 3ha and 3ha′ were obtained in 26% and
Under the optimum conditions, the substrate scope
of amines and sulfonyl azides were investigated, as
20%
yields,
respectively.
The
different
chemoselectivities were attributed to the two
pathways of generating enamine. We also
investigated the large-scale reaction of 1a with 2a (4
mmol), and 3aa was obtained in 60% yield.
To study the mechanism, several control
experiments were performed as shown in Scheme 3.
Firstly, the reaction of 1i and 2a gave 3ia in 55%
yield under the catalysis of acridinium salt (eq 1,
Scheme 3). Without the addition of photocatalyst, 3ia
was also obtained in 60% yield, indicating that the
photoinduced enamine could be the key intermediate
in the cascade reaction of tertiary amine with sulfonyl
shown
in
Table
2.
Tripropylamine
and
triphenethylamine reacted smoothly and gave 3ba
and 3ca in 85% and 68% yields, respectively. When
N-ethyl-N-isopropylpropan-2-amine was used, 3da
was obtained in 40% yield, indicating that the large
steric hindrance reduced the product yield. Cyclic
tertiary amines were also studied, and N-
methylpiperidine, N-methylpyrrolidine, and 1-
phenylpyrrolidine were used as substrates. 3ea, 3fa,
and 3ga were obtained via the hydrogen abstraction
of cyclic α-carbon. In the sulfonyl azide moiety, when
benzenesulfonyl azide was used, 3ab was obtained in
70% yield. Other substituents such as halogen, tert-
butyl, and methoxy in benzene ring offered the
corresponding products in good yields (3ac–3ag).
Considering the effect of steric hindrance, 2,4,6-
triisopropyl-benzenesulfonyl azide was used, and 3ah
was obtained in 65% yield, indicating that the steric
hindrance did not exert considerable influence on the
reaction. Acetamido was tolerant and offered 3ai in
59% yield. 1-Naphthyl and 1,1′-biphenyl provided
3aj and 3ak in 80% and 62% yields, respectively.
Unfortunately, when pyridyl was introduced, only a
Scheme 3. Mechanism studies.
3
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10.1002/adsc.201900359
Advanced Synthesis & Catalysis
azide (eq 2, Scheme 3). Furthermore, benzaldehyde
and benzyl alcohol were detected by GC-MS in the
reaction of 1c and 2a (see Supporting Information for
details). We speculated that benzaldehyde and benzyl
alcohol were obtained from the reaction of
(diazomethyl)benzene with oxygen[23] and water,[24]
respectively. According to the above experiment
results and the reported literatures, [8, 9, 18] a possible
mechanism was proposed (Scheme 4). Firstly, the
photocatalyst was induced to an excited state under
blue light irradiation. Then, single-electron transfer to
the excited-state photocatalyst resulted in a tertiary
amine radical cation A, and the photocatalyst was
reduced. The reduced photocatalyst transferred an
electron to the oxygen, generating oxygen radical
anion and completing the photocatalyst recycle. The
oxygen radical anion abstracted a hydrogen radical
from the intermediate A and gave an ammonium
cation B, which underwent double bond shift and
does not require special substrates, and the green
oxidant oxygen was used.
Experimental Section
Typical experimental procedure for the synthesis
of 3.
A solution of 1a (0.3 mmol, 30 mg), 2a (0.9 mmol,
180 mg), and Mes-Acr-Ph+BF4 (0.015 mmol, 7 mg)
in DCE (2 mL) was stirred under the irradiation of
blue LEDs at rt for 10 h. The mixture was diluted
with DCM (10 mL), extracted with NaOH aqueous
solution (0.5 mol/L, 10 mL), and dried with Na2SO4.
Then, the organic layer was concentrated under
reduced pressure, and the residue was purified by
flash column chromatography to provide 3aa in 76%
yield.
resulted in the generation of enamine C. Finally, the Acknowledgements
enamine C underwent 1,3-dipolar addition with 2a,
This study was supported by the National Natural Science
and the following open-ring reaction and CH2N2
release provided the product 3aa. When the cyclic
tertiary amine 1f was used as the substrate, the
intermediate F was formed through the above
pathway. Then, the following open-ring reaction, N2
release, and 1,2-H shift gave the product 3fa.[25]
Foundation of China (21861006 and 21861015), Natural Science
Foundation of Guangxi (2018GXNSFBA138050), Special Fund
for Talents of Guangxi (AD18281028), The Youth Promotion
Fund of Guangxi (2017KY0475 and 2018KY0400), and the State
Key Laboratory for Chemistry and Molecular Engineering of
Medicinal
Resources
(Guangxi
Normal
University)
(CMEMR2018-B08).
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5
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10.1002/adsc.201900359
Advanced Synthesis & Catalysis
UPDATE
Photoinduced Cascade Reaction of Tertiary
Amines with Sulfonyl Azides: Synthesis of
Amidine Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Rui Ding,a Hui Chen,b Yan-Li Xu,b Hai-Tao Tang,a
Yan-Yan Chen,b,* Ying-Ming Pana,*
6
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