Intermolecular C-H Quaternary Alkylation of Aniline Derivatives Induced by Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.6b02179

The intermolecular direct C-H alkylation of aniline derivatives with α-bromo ketones to build a quaternary carbon center was reported with a visible-light catalysis procedure. The reaction covers a variety of functional groups with good to excellent yield

Full text of DOI:10.1021/acs.orglett.6b02179

Letter
pubs.acs.org/OrgLett
Intermolecular C−H Quaternary Alkylation of Aniline Derivatives
Induced by Visible-Light Photoredox Catalysis
Jie Cheng,† Xia Deng,† Guoqiang Wang,‡ Ying Li,† Xu Cheng,*,† and Guigen Li†,§
†Institute of Chemistry and Biomedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210023, China
‡Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210023, China
§Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, United States
S
* Supporting Information
ABSTRACT: The intermolecular direct C−H alkylation of aniline
derivatives with α-bromo ketones to build a quaternary carbon center
was reported with a visible-light catalysis procedure. The reaction covers a
variety of functional groups with good to excellent yields. A regioselectivity
favoring the ortho position for the amine group was observed and
investigated with Fukui indices and spectral methods.
he intermolecular construction of quaternary carbon
centers poses a challenge and has received considerable
Scheme 1. Intra-/Intermolecular C−H Quaternary
T
Alkylation of Arene
attention and synthetic effort from the synthetic community.
Direct alkylation of an aromatic compound with a tertiary
carbon center could give the corresponding quaternary carbon
centers. In comparison to the well-established intramolecular
tertiary alkylation of arenes with transition-metal catalysis,1
visible-light catalysis,2 and metal-free procedures,3 intermolec-
ular coupling is challenging because of the steric disadvantage
as well as the entropy penalty. The direct C−H alkylation of
aromatic compounds has been implemented via photoredox
catalysis with examples being provided by the difluoroalkyla-
tion,4 trifluoromethylation,5 oxoallylation,6 arylation,7 etc.8
Nevertheless, the visible-light photoredox-catalyzed intermo-
lecular alkylation of aromatic compounds with tertiary carbon
has not been reported.9
substrates to optimize the reaction parameters (Table 1). At
first, a variety of bases typically employed in photoredox
catalysis were evaluated, and sodium acetate was the optimal
choice (entries 1−6). It was noted that when the bases with
carbonate anion were used in the photoredox catalysis,
monodemethylation occurred as a side reaction due to the
water generated in situ (entries 1 and 2). In turn, a test of
solvents such as DCM and DMSO confirmed that acetonitrile
was the preferred medium (entries 7 and 8). Next, several
photocatalysts were screened, including common transition-
metal complexes and organic dyes in MeCN, to ensure
complete dissolution of the catalyst. The alkylation product 3aa
could be prepared with iridium complexes (entries 11−13).
The best result was achieved with ruthenium complex giving
rise to the 3aa in 72% isolated yield. When the catalyst loading
was decreased to 0.5 mol %, the yield remained at the 73%
mark (entries 14 and 15). On the other hand, an organic dye
such as eosin Y gave rise to inferior results (entry 16).
α,α-Dimethyldesoxybenzoin has a quaternary carbon center
and was applied as a key intermediate in the synthesis of an
estrogen receptor modulator (Figure 1).10 The synthetic
Figure 1. Compounds for estrogen receptor modulation.
strategy for preparation of the dimethyldesoxybenzoin focused
on the α-alkylation of less hindered ketones, which required the
generation of anionic carbon species with strong base. Herein,
we report our study on the syntheses of α,α-dialkyldesox-
ybenzoins using direct C−H alkylation of electron-rich aniline
derivatives with tertiary α-bromo carbonyl compounds induced
by visible-light photoredox catalysis (Scheme 1).
With the optimized conditions established (Table 1, entry
15), we turned to substrate scope exploration. Initially, a series
of aniline derivatives were evaluated with p-cyano-substituted
2b, which simplified the product characterization and gave
At the outset, an electron-rich aniline derivative 1a and α-
bromo isobutyrophenone 2a were chosen as standard
Received: July 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02179
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Letter
a
at the para position in the aniline substrate 1g. The products
3gb and 3hb were accessed with the standard reaction
conditions in excellent yields. Our screening of anilines 1i
with an N,N-dibenzyl substituent and 1j with an N-4-
(methoxyphenyl)-N-methyl substituent gave the corresponding
products 3ib and 3jb in greater than 80% yield. It was noted
that only monoalkylation of 1j occurred when 1 equiv of 2b
was applied. Substrate 1k with diamine functionality was
subjected to this photoredox alkylation reaction, and a single
product 3kb was generated in 71% yield as the only
regioisomer.
Table 1. Reaction Optimization
b
entry
catalyst
Ru(bpy)3Cl2
base
solvent
yield (%)
1
Cs2CO3
Na2CO3
HCOONa
KOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
60
40
62
43
38
67
10
42
8
2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
3
4
In turn, a series of α-bromo ketones 3 were subjected to the
alkylation reaction with dimethyl-p-anisidine 1g in the presence
of 0.5 mol % of Ru(bpy)3Cl2 (Scheme 3). It was observed that
5
K2HPO4
NaOAc
NaOAc
NaxOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
6
7
a
8
DMSO
MeCN
MeCN
Scheme 3. Scope of α-Bromo Ketones 2
9
c
10
11
12
13
Ru(bpy)3Cl2
0
d
fac-Ir(ppy)3
MeCN
MeCN
MeCN
80
74
42
d
d
Ir(ppy)2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy)
PF6
d
d
d
e
14
15
16
Ru(bpy)3Cl2
NaOAc
NaOAc
NaOAc
MeCN
MeCN
MeCN
81 (72)
f
e
Ru(bpy)3Cl2
80 (73)
eosin Y
trace
a
The reaction was carried out with 1a (0.10 mmol), 2a (0.12 mmol),
base (0.10 mmol), and photocatalyst (1.0 mol %) in MeCN (0.5 mL),
b
24 W blue LEDs, 1 h. NMR yield (DMAP as the internal standard).
c
d
e
f
No light. 1.5 mL. Isolated yield in parentheses. 0.5 mol %.
improved yields in comparison to 2a (Scheme 2, 3ab).
Compound 1b with a phenyl group at the para position
a
Scheme 2. Scope of Anilines 1
a
1g (0.20 mmol), 2 (0.24 mmol), NaOAc (0.20 mmol), and
Ru(bpy)3Cl2 (0.5 mol %) in MeCN (3.0 mL), 24 W blue LEDs, rt,
1 h, isolated yield after chromatography.
substrates with electron-donating groups provided the corre-
sponding products in >70% yield (3gc,gd). To our delight,
electron-withdrawing groups, such as fluoride, chloride, and
bromide, enhanced the yield to more than 80% (3ge−gg).
Here, the alkylation ortho to the amine group was confirmed by
X-ray analysis of a crystal of 3ge. By increasing the electronic
deficiency of ketones with a CF3 group, an excellent yield was
achieved in the case of product 3gh. Product 3gi with ester
substitution was obtained in 87% yield as well. The m-
nitroisobutyrophenone was also a valid substrate, giving 3gj
with 75% yield. An even better result was achieved for 3gk with
a p-nitro group. Compound 3gl bearing an unprotected amino
group could be prepared with the same protocol in 88% yield.
Products 3gm and 3gn with α-naphthalenyl and β-naphthalenyl
groups were also prepared in 81% and 75% yield, respectively.
In addition, heterocyclic ketones could be applied in the
alkylation reaction. To our delight, the thiophene-yl,
benzothiophene-yl, and furyl functionalities were all compatible
with this protocol and gave rise to the corresponding products
3go−gr in good to excellent yield. Consequently, more bulky
a
1 (0.20 mmol), 2b (0.24 mmol), NaOAc (0.2 mmol), and
Ru(bpy)3Cl2 (0.5 mol %) in MeCN (3.0 mL), 24 W blue LEDs, rt,
1 h, isolated yield after SiO2 chromatography.
could be converted to the desired 3bb in 83% yield. The O-silyl
group remained intact during the reaction to obtain 3cb; it was
obtained in 53% yield. Dimethylaniline with a conjugated
alkene at the para position was also compatible with this
protocol, affording 3db in 55% yield. Subsequently, other
anilines substituted with additional heteroatoms were evaluated.
Molecule 3eb with a TMS group was prepared in moderate
yield. 4-Acetamide-substituted aniline 1f gave the correspond-
ing product 3fb in almost quantitative yield. The same trend
was observed when electron-donating methoxy was presented
B
DOI: 10.1021/acs.orglett.6b02179
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Letter
ketones like 2s and 2t were prepared and evaluated in the
reaction with 1g under the same conditions. Again, a similar
reaction occurred in acceptable yield (3gs,gt).
Scheme 5. Proposed Mechanism
To test the robustness of this photoredox alkylation reaction,
we carried out the reaction to prepare 3gb and 3gj with
sunlight instead of LEDs. The reaction was finished within 1 h
with comparable yields of 90% and 84% (Scheme 4, a). To
Scheme 4. Applications of Quaternary Alkylation
TEMPO (see the SI). The addition of A to aniline 1 generates
the neutral radical species B that is oxidized with the excited
RuII with release of the cationic intermediate C. The final
deprotonation gives the desired molecule 3. Note that the
regioselectivity during the radical addition to the aniline favors
the carbon ortho to the amine group. To elucidate this
selectivity, a DFT calculation of Fukui indices on the aniline
ring of 1a and 1g was conducted using the B3LYP/6-311g+
+(d,p) level of theory (Scheme 5b). It was found that the
carbon ortho to the amine group is more reactive than that
ortho to the methyl or methoxy group. The interaction between
two substrates was observed in the UV−vis spectrum (Scheme
5c) and via NMR titration (Scheme 5d) where the amine group
was essential. This interaction might facilitate the substitution
adjacent to the nitrogen as well.
In summary, we have demonstrated the first visible-light
catalytic C−H quaternary alkylation using aniline derivatives
and the tertiary radical from α-bromo ketones. The reaction
works with a variety of functionalities as well as heterocycles.
The reaction could be run on gram scale and be accomplished
with sunlight directly. In this reaction, the regioselectivity favors
the ortho position to N substitution through a radical addition
mechanism.
discover the scalability of this catalytic reaction, a gram-scale
reaction was set up with the LEDs kept at 24 W. A complete
conversion ensured within 1 h, and the isolated yield of 3gb
was 91% (Scheme 4, b). This compound was subjected to
several transformations of its functionalities to give the phenol
4 and aldehyde 5 smoothly (Scheme 4, c). Another compound
3fe was converted to alcohol 6 with NaCNBH3 in 85% yield. A
two-step transformation of hydrolysis and bromination afforded
the aniline 7 in 71% of overall yield from 3fe (Scheme 4, d).
In order to gain insight into the mechanistic course of this
reaction, a fluorescent-quenching experiment was conducted
with 1a and 2a, respectively. A predominant reductive
quenching was detected (Figure 2), suggesting the reaction
proceeds via the RuI−RuII pathway. Therefore, a possible
mechanism is proposed in Scheme 5a. At the beginning of the
reaction, the excited ruthenium catalyst enters the catalytic
cycle. A single-electron transfer from the RuI to α-bromo
isobutyrophenone 2 results in the mesolytic cleavage to the
isobutyrophenone radical A, which could be captured with
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02179.
X-ray data for compound 3ge (CIF)
Procedure for the preparation of substrates and photo-
redox catalysis, characterization of new compounds,
spectra, experimental and computational study of the
mechanism (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 2. Fluorescent quenching of Ru(bpy)3Cl2.
*E-mail: chengxu@nju.edu.cn.
C
DOI: 10.1021/acs.orglett.6b02179
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Letter
Wang, H.-L.; Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed. 2013, 52,
3972−3976.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
of China (Nos. 21572099 and 21332005) and the Natural
Science Foundation of Jiangsu Province (No. BK20151379).
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