Visible-light-promoted radical cross-coupling of: Para-quinone methides with N-substituted anilines: An efficient approach to 2,2-diarylethylamines

Article abstract of DOI:10.1039/c9ob02600b

An efficient protocol to access 2,2-diarylethylamines via visible-light-promoted radical reactions of para-quinone methides (p-QMs) with N-alkyl anilines has been disclosed. These reactions feature metal-free, redox-neutral, and mild reaction conditions with wide functional group compatibility.

Full text of DOI:10.1039/c9ob02600b

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DOI: 10.1039/C9OB02600B
Organic &
Biomolecular Chemistry
COMMUNICATION
Visible-light-promoted radical cross-coupling of para-quinone
methides with N-substituted anilines: An efficient approach to
Received 00th January 20xx,
Accepted 00th January 20xx
2
,2-diarylethylamines
DOI: 10.1039/x0xx00000x
Qiao-Lei Wu,† Jing Guo,† Gong-Bin Huang, Albert S. C. Chan, Jiang Weng* and Gui Lu*
rsc.li/obc
An efficient protocol to access 2,2-diarylethylamines via visible- that diarylmethyl radicals could be generated from p-QMs was first
1
2
light-promoted radical reactions of para-quinone methides (p- demonstrated by Kurreck in 1985. With the development of
QMs) with N-alkyl anilines has been disclosed. The reactions visible-light-promoted photoredox catalysis, a few photocatalytic
featured metal-free, redox-neutral, mild reaction conditions, and radical transformations of p-QMs have recently been realized. The
wide functional groups compatibility.
radical source is an important variable in these transformations. Up
to now, various carbon radicals including tri-/difluoroalkyl,
1
1a-b
Dopamine is a major neurotransmitter in the human brain. The
dopamine deficiency is associated with several health conditions,
including anxiety, depression and Parkinson's disease. However,
11c
11d
11e
benzyl, cyanoalkyl and alkyl radicals have been used in these
radical 1,6-addition reactions with p-QMs, which provide efficient
approaches to construct diverse diaryl compounds.
1
dopamine itself is too hydrophilic to cross the blood-brain barrier
and thus cannot be used for the treatment of central nervous
system diseases. Thus, the design and synthesis of dopamine
analogues has received considerable attention among medicinal
chemists. In particular, 2,2-diarylethylamine scaffold is a common
structural motif in numerous dopamine receptor agonists. For
example, SKF-38393 and its derivatives, which are dopamine D1
OH
HO
NH
HO
N
OH
SKF-38393
MCN-4187
NH2
H
N
Me
N
H
receptor agonists could be used for the treatment of
H
HO
HO
NH
H
2
neurodegenerative
disorders
and
cocaine
addiction.
HO
OH
Diethanolamine (MCN-4187) has shown potential antidepressant
3
Nomifensine
Dihydrexidine
Dinapsoline
activity (Fig. 1). Consequently, many methods have been
developed for the construction of the 2,2-diarylethylamine
skeleton, such as ring-opening arylation of 2-arylaziridines (Scheme
Fig. 1 Typical biologically active molecules with 2,2-diarylethylamine
motif.
4
5
1
a), hydrogenation of enamines (Scheme 1b), aminoarylation of
6
styrene (Scheme 1c), and arylation of β-nitroalkenes followed by
reduction (Scheme 1d). Despite these significant advances,
We have recently reported the photoredox-catalyzed
7
decarboxylative radical 1,6-addition of arylacetic acids to para-
alternative and straightforward methods are still highly desirable.
In recent years, para-quinone methides (p-QMs) have emerged
as versatile building blocks in organic synthesis. In particular, the
11c
quinone methides to access 1,1,2-triarylethanes. As part of our
continuing interest for the synthesis of diaryl compounds, we
envisioned that 2,2-diarylethylamines could be readily prepared by
the photoredox-catalyzed radical 1,6-addition reaction of p-QMs
1
,6-Michael addition of p-QMs with various nucleophiles has been
extensively developed for the synthesis of diverse diarylmethane
13
with α-aminoalkyl radicals generated from N-alkyl anilines.
8
-9
derivatives. However, in sharp contrast, the radical-type addition
Herein, we report a visible-light-promoted radical reactions of p-
QMs with N-alkyl anilines (Scheme 1e), providing a facile and
efficient access to a wide range of 2,2-diarylethylamines.
1
0-11
or coupling reaction of p-QMs has less been explored,
albeit
Initially, we carried out the model reaction of p-QM (1a) (Ered = -
Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery,
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.
R. China. E-mail: wengj2@mail.sysu.edu.cn, lugui@mail.sysu.edu.cn.
11a
0
[
.20 V vs. SCE) with N,N-dimethylaniline (2a) in the presence of
1
4
Ir{dF(CF
3
)
2
ppy}
2
(bpy)]PF
6
(Eox(Ir(IV/III*) = -1.00 V vs. SCE) and 1.2
†
These two authors contributed equally to this work.
equiv. of K
2
HPO
4
in DMF (2 mL) under nitrogen atmosphere at 25
Electronic Supplementary Information (ESI) available: Synthetic details, additional
spectroscopic data, and characterization of the new compounds.
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Organic & Biomolecular Chemistry
a
°
C. As expected, the reaction did proceed under the irradiation of
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), VcieawtaAlyrtsictle(O0.n0li0n5e
DOI: 10.1039/C9OB02600B
two 12
mmol), base (1.2 equiv.), solvent (2 mL), under 12 W green LEDs for 24 h at
R2
N
5 °C. b Isolated yield. In dark. d Under air atmosphere.
c
2
R1
a)
b)
Ar1
Ar2
N
2 4
K HPO gave the highest yield (entry 4). Control experiments
have shown that photocatalyst, nitrogen atmosphere and light
irradiation are essential for the success of this transformation
Ar1
PG
R2
N
R1
Ar1
Ar2
(entries 12-14).
R
Ar
Ar1
NO2
c)
d)
Table 2 Scope of para-quinonesa,b
+
+
R1
e) This work
O
B(OH)2
N
Ar2
O
S
R'
O
OH
Ar'
t-Bu
t-Bu
O
R
R
t-Bu
t-Bu
Eosin Y (5 mol %)
K2HPO4 (1.2 equiv.)
Me
Me
N
+
N
+
R1
R2
Me
DMF, 25 o
24 h, N2
Me
N
C
R
Ar1
R
1
2a
3
Scheme 1 Synthetic approaches of 2,2-diarylethylamines.
OH
OH
OH
OH
W green LED bulbs, providing the desired product 3a in 45%
yield (Table 1 entry 1). Inspired by this result, we then
screened a series of photocatalysts with different redox
potentials, including Ir-based photocatalysts (A and B), 4-CzIPN
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
N
Me
N
Me
N
Me
N
Me
Me
OMe
Me
(
C) and eosin Y (D), and found that 92% yield of 3a was
3a: 92%
3b: 86%
3c: 83%
3d: 89%
OH
obtained when using Eosin Y (Eox(EY • /EY*) = -1.11 V vs.
+
OH
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
1
5,16
SCE)
(entry 4). Subsequently, different solvents were
Me
N
Me
N
Me
N
Me
N
examined (entries 5-7), confirming that DMF was the optimal
choice. Further investigation on the effect of bases was
conducted, the yield was dramatically decreased to 53% in the
absence of base (entry 8), which indicated that base played a
considerable role in promoting the reaction. Among the bases
screened,
MeO
Cl
OMe
3e: 83%
OH
3f: 78%
OH
3g: 82%
3h: 88%
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
N
Me
N
Me
N
Me
N
Cl
R
NC
F3C
Table 1 Optimization of the reaction conditionsa
Cl
3i: R = Cl, 81%
3k: 82%
3l: 75%
3m: 66%
O
3j: R = Br, 92%
OH
t-Bu
t-Bu
t-Bu
t-Bu
Me
N
cat. (5 mol%)
base (1.2 equiv)
a
Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), Eosin Y (0.005 mmol),
Me
Me
N
+
solvent, 25 o
C
(1.2 equiv.), DMF (2 mL), under 12 W green LEDs for 24 h at 25 °C. b
K
HPO
2 4
N2
Me
Me
Isolated yield.
1
a
2a
3a
CF3
CF3
Cz
F
F
NC
Cz
CN
With the optimal reaction conditions in hand (Table 1 entry
), the substrate scope of para-quinones was further examined
(Table 2). To our delight, a series of substituted p-QMs could
smoothly react in this transformation, giving the
corresponding products 3a-3m in moderate to excellent yields
tBu
tBu
O
N
N
4
N
N
N
Cz
F
F
F
F
Br
O
Br
Ir
Ir
Cz
N
N
N
C
z
N
NaO
O
ONa
Br
Br
F
F
CF3
CF3
=
A
B
C
D
(
66-92%). It was found that the reaction could produce the
Yield (%)b desired products in high yields when the substituents on the
Entry
Catalyst
Base
Solvent
DMF
DMF
DMF
DMF
DMSO
MeCN
2 2
CH Cl
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1
2
3
4
5
6
7
8
9
A
B
C
K
2
HPO
2
HPO
2
HPO
2
HPO
2
HPO
2
HPO
2
HPO
-
4
4
4
4
4
4
4
45
50
68
92
52
30
25
53
87
84
24
-
phenyl ring were electron-donating groups such as methyl (3a-
3c) and methoxyl (3d-3f). The yields could also be guaranteed
when the substituents were electronically neutral (3g) or
electron-withdrawing groups (3h-3l). The yield was slightly
reduced for 3,5-dichloro-substituted substrate (3m, 66%).
Moreover, the position of the substituents on the phenyl ring
had little effect on the reaction outcome.
We next set out to explore the scope of the tertiary amines,
and the results were summarized in Table 3. A series of N,N-
dialkylanilines with electron-donating or -withdrawing
substituents at the para-position of the benzene ring were
reacted with p-QM 1a, and the corresponding β,β-
diarylethylamines 3n-3r were generally afforded in moderate
to good yields (42-79% yields). Furthermore, introduction of a
K
K
K
K
K
K
D
D
D
D
D
D
D
D
D
-
2 4
Na HPO
1
1
0
1
NaHCO
3
.
K
3
PO
4
3H
2
O
c
1
2
K
K
K
2
HPO
2
HPO
2
HPO
4
1
3
4
4
-
-
d
1
4
D
2
| Org. Biomol. Chem., 2019, 00, 1-4
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Communication
methyl group at the ortho- or meta-position did not Scheme 3 De-tert-butylation of 2,2-diarylethylamine 3Vaiew Article Online
DOI: 10.1039/C9OB02600B
significantly affect the yield of 3 (3s: 78% yield; 3t: 63% yield).
N,N-Dimethylanilines with bi-substituted ortho-chloro and
para-methyl groups in the benzene ring was well tolerated and
delivered the desired product 3u in 43% yield after 48 hours.
Moreover, N-methyldiphenylamine and N-ethyl-N-methyl
aniline were also suitable substrates for this reaction,
furnishing the desired products 3v and 3w in 62% and 82%
yield, respectively.
O
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
N
standard conditions
TEMPO (2.0 equiv.)
+
Me
Me
N
N
O
2a
Me
Me
Me
1a
4a
3a
detected by ESI-MS
not observed
Scheme 4 Radical trapping experiment with TEMPO
Table 3 Scope of N,N-dialkylanilinesa,b
O
OH
t-Bu
t-Bu
Me
N
t-Bu
t-Bu
Eosin Y (5 mol%)
K2HPO4 (1.2 equiv.)
R2
+
R1
R2
N
DMF, 25 o
h, N2
C
3
6
2
R1
Me
Me
1a
3
OH
OH
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
N
Me
N
Me
N
Me
N
Fig. 2 Time profile for the reaction of 1a with 2a: light was switched
off during the “dark” periods
Me
Cl
Me
Br
Me
3p: 68%
Ph
Me
3q: 68%
Me
3n: 79%
3o: 67%
OH
OH
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
In order to gain mechanistic insight into this reaction,
several control experiments were performed. Radical trapping
experiment was conducted with TEMPO (2,2,6,6-tetramethyl-
Me
N
Me
N
Me
N
Me
N
Me
Me
OMe
Me Me
Me
3t: 63%
Me Cl
3u: 43%c
Me
3
r: 42%c
3s: 78%
1
-piperidinyloxy) as radical scavenger under standard reaction
OH
OH
t-Bu
t-Bu
t-Bu
t-Bu
Me
conditions. TEMPO adduct can be detected by ESI-MS, while
no product 3a was observed (Scheme 4), which implied the
involvement of a diarylmethyl radical. The Stern-Volmer
studies of photocatalyst were also conducted and the details
were shown in Supporting Information (Figs. S1-S4). This
fluorescence quenching studies demonstrated that the excited
photocatalyst Eosin Y* was quenched by p-QM 1a. Moreover,
Ph
N
N
Me
v: 62%
Me
3w: 82%
3
a
Reaction conditions: 1a (0.1 mmol), 2 (0.12 mmol), Eosin Y (0.005 mmol), in order to verify the effect of photo-irradiation, we
K
2
HPO
4
(1.2 equiv.), DMF (2 mL), under 12 W green LEDs for 36 h at 25 °C. b investigated an on/off visible light irradiation experiment (Fig.
c
Isolated yield. 48 h.
2). The graph showed that this reaction did not proceed during
the “dark” period.
This photoredox process was amenable to gram-scale
synthesis without significant yield loss (88% vs. 92%).
Compound 3a was synthesized on a 5 mmol scale without any
specialized equipment using the same loading of photocatalyst
Scheme 2). Moreover, the bulky tert-butyl group could be
successfully removed by AlCl
On the basis of our experimental results and
1
1a,13a
literatures,
a plausible mechanistic pathway was
illustrated in Fig. 3. The long-lived excited-stated EY* produced
by light irradiation could engage in single electron transfer
(
(
SET) with p-QM 1a followed by a protonation process to give
1
7
3
(60% yield, Scheme 3).
•
+
•+
radical intermediate A as well as the oxidized EY . EY could
convert the neutral amine 2a into the radical cation via a single
electron oxidation. Thereafter, because the C-H bonds
adjacent to the nitrogen atom are greatly acidified (pKa ca. 8),
it is easy to deprotonate and produce the α-aminoalkyl radical
O
OH
t-Bu
t-Bu
t-Bu
t-Bu
Me
N
Eosin Y (5 mol%)
K2HPO4 (1.2 equiv.)
Me
N
Me
+
DMF, 25 o
4 h, N2
2 W green LEDs
C
2
Me
Me
3a
1
1
8-19
B.
with α-aminoalkyl radical B gave the corresponding product
a.
Finally, the direct coupling of the radical intermediate A
1
a
2a
0.726 g, 6 mmol
1
.54 g, 5 mmol
1.89 g, 88% yield
3
Scheme 2 Gram-scale preparation of 3a
OH
OH
t-Bu
t-Bu
AlCl3, benzene
Me
N
Me
N
60 oC, 12 h
Me
Me
3aa 60% yield
3a
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem. 2019, 00, 1-4 | 3
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Organic & Biomolecular Chemistry
OH
O
t-Bu
t-Bu
resulted reaction mixture was stirred overnight at room
View Article Online
t-Bu
t-Bu
DOI: 10.1039/C9OB02600B
temperature and basified with 0.1 N NaOH (20 mL). Methanol was
evaporated and aqueous layer was extracted with ethyl acetate (3 ×
50 mL). The combined organic layer was washed with water and
brine, dried over anhydrous sodium sulfate. Further, the organic
layer was evaporated to dryness and subjected for silica gel column
chromatography using ethyl acetate/hexane as eluent. Yield of tert-
amines 2 were approx. 80-90%.
+
H
OH
SET
t-Bu
t-Bu
*
Y
A
E
1
a
Me
Visible
light
Me
N
Me
Y
E
Me
N
H
Me
Y
H
CH2
N
E
3a
Me
SET
N
Me
Me
2
a
B
Fig. 3 Proposed mechanism
Procedure for the synthesis of compound 3
In summary, we have developed a novel photocatalytic radical
cross-coupling reaction of para-quinone methides with N-alkyl
To a solution of 1a (30.8 mg, 0.1 mmol) and 2a (14.5 mg, 0.12
mmol) in DMF (2 mL), K HPO (20.9 mg, 0.12 mmol) and Eosin Y (3.4
2 4
mg, 0.005 mmol) were added. The reaction mixture was degassed
by bubbling nitrogen stream for 15 min and then stirred and
irradiated with two 12 W Green LED bulbs with a fan placed nearby
for cooling. After 24 hours, the mixture was extracted with ethyl
anilines.
A variety of 2,2-diarylethylamine derivatives with
pharmaceutical potential were obtained in high efficiency (23
examples, up to 92% yield). Metal-free, redox-neutral, high atom
economy, and mild conditions make this synthetic method a worthy
one.
2 4
acetate, and the combined organic layer was dried over Na SO and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography on silica gel to afford the
title compound 3a.
Experimental Section
General information
All the commercial reagents were used as such without further
purification. All solvents were used as commercial anhydrous grade Conflicts of interest
without further purification. The flash column chromatography was
The authors declare no competing financial interest.
1
13
carried out over silica gel (230-400 mesh). H and C NMR spectra
were recorded on a Bruker Avance-400 MHz spectrometer or
Acknowledgements
1
Bruker Avance-500 MHz spectrometer. Chemical shifts in H NMR
spectra were reported in parts per million (ppm, δ) downfield from This work was financially supported by the Natural Science
1
3
the internal standard Me
4
Si (TMS, δ = 0 ppm). Chemical shifts in
C
Foundation of China (Nos 81972824, 21502240), the Guangdong
NMR spectra were reported relative to the central line of the Provincial Key Laboratory of Chiral Molecule and Drug Discovery
chloroform signal (δ = 77.0 ppm). Peaks were labelled as singlet (s), (2019B030301005), National Engineering and Technology Research
doublet (d), triplet (t), quartet (q), and multiplet (m). High Center for New drug Druggability Evaluation (Seed Program of
resolution mass spectra were obtained with a Shimadzu LCMS-IT-
TOF mass spectrometer. Chemical yields refer to pure isolated
substances.
Guangdong Province, 2017B090903004) and the Science and
Technology Program of Guangzhou (No. 201607010118).
Procedure for the synthesis of p-QMs 19
References
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bottom flask, a solution of phenols (25.0 mmol) and the
corresponding aldehydes (25.0 mmol) in toluene (100 mL) was
heated to reflux. Piperidine (50.0 mmol, 4.95 mL) was dropwise
added within 1 h. The reaction mixture was continued to reflux for
1
2
3
4
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2
1
2-18 h. After cooling just below the boiling point of the reaction
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mixture, acetic anhydride (50.0 mmol, 2.55 g) was added and the
stirring was continued for 15 min. Then the reaction mixture was
cooled to room temperature, poured into water and extracted with
5
CH
Na
2
Cl
SO
2
. The combined organic phases were dried over anhydrous
4
and solvents were removed under reduced pressure. The
2
9
180; (c) W. Ieawsuwan, R. Pingaew, S. Kunkaewom, P.
crude products were purified by flash column chromatography and
further recrystallized from n-hexane, affording the desired p-QMs
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7
(a) T. M. Monos, R. C. McAtee and C. R. Stephenson, Science,
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a-1m.
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018, 361, 1369; (b) S. Hajra, B. Maji and D. Mal, Adv. Synth.
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M.-H. Xu and G.-Q. Lin, Angew. Chem., Int. Ed., 2010, 49,
All reactants 2 are known compounds. Amine (1.0 g) and aldehyde
(8.0 equiv.) was stirred in methanol (15 mL) to which pre-prepared
methanol (5 mL) solution of sodium cyanoborohydride (1.0 equiv.)
and zinc chloride (0.5 equiv.) was added at room temperature. The
5
780; (c) Q. He, F. Xie, G.-H. Fu, M. Quan, C.-R. Shen, G.-Q.
4
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Organic & Biomolecular Chemistry
Communication
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O
OH
DOI: 10.1039/C9OB02600B
R1
R1
N
+
N
Ar2 Me
Eosin Y
Ar1
Ar1
Ar2
metal-free
mild reaction conditions
redox-neutral
23 examples, up to 92% yield
gram-scale preparation
A series of 2,2-diarylethylamines were accessed via visible-light-promoted radical cross-coupling
of p-QMs with N-alkyl anilines