Regioselective synthesis of α-bromo-α,β-unsaturated carbonyl compounds via photocatalytic α-bromination reactions

Article abstract of DOI:10.1007/s11426-015-5530-7

A visible light-mediated approach for the preparation of α-bromo-α,β-unsaturated ketones and aldehydes was developed. In comparison to traditional methods that generally take two steps to afford the above compounds, this protocol was highlighted by its op

Full text of DOI:10.1007/s11426-015-5530-7

SCIENCE CHINA
Chemistry
• ARTICLES •
· SPECIAL TOPIC · Organic Photochemistry
doi: 10.1007/s11426-015-5530-7
doi: 10.1007/s11426-015-5530-7
Regioselective synthesis of -bromo-,-unsaturated carbonyl
compounds via photocatalytic -bromination reactions
Dan Wang, Yating Zhao, Chao Yang & Wujiong Xia*
State Key Laboratory of Urban Water Resource and Environment; Shenzhen Graduate School, Harbin Institute of Technology,
Harbin 150080, China
Received August 18, 2015; accepted September 21, 2015
A visible light-mediated approach for the preparation of -bromo-,-unsaturated ketones and aldehydes was developed. In
comparison to traditional methods that generally take two steps to afford the above compounds, this protocol was highlighted
by its operational simplicity, avoiding using hazardous bromine and mild reaction conditions.
visible light, -bromination, -unsaturated ketones and aldehydes, operational simplicity
Citation:
Wang D, Zhao YT, Yang C, Xia WJ. Regioselective synthesis of -bromo-,-unsaturated carbonyl compounds via photocatalytic -bromination
reactions. Sci China Chem, doi: 10.1007/s11426-015-5530-7
1 Introduction
-Bromo--unsaturated ketones or aldehydes are im-
portant building blocks in synthesis of natural products and
pharmaceutical compounds. They also can be transformed
into many synthetically useful compounds (Scheme 1)
[1–7]. With respect to their synthesis, the traditional method
through direct dibromination of the double bond followed
by elimination of a molecule hydrogen bromide promoted
by base is undoubtedly one of the most practical pathways
(Scheme 2) [8,9]. In addition, they are also accessible by
treatment of aldehyde with brominated reagents [10,11].
However, the above methods suffered from the tough reac-
tion conditions and/or employment of hazardous reagents.
With this regard, the development of a novel method with
cleaner reagents and milder conditions seems to be appeal-
ing.
Scheme 1 Various transformation from α-bromo-α,β-unsaturated ketones
or aldehydes.
vate molecules and promote synthetic transformations
[12–17]. Studies have demonstrated that photocatalysts,
such as Ru(bpy)3Cl2 and fac-Ir(ppy)3, can initiate the single
electron transfer (SET) process under visible light irradia-
tion. In previous work, we have developed a highly efficient
method to prepare -bromo ketones and diketones by ring
opening of epoxides via photoredox catalysis [18]. However,
Recently, photoredox catalysis has emerged as an effec-
tive and versatile method for the use of visible light to acti-
*Corresponding author (email: xiawj@hit.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

2
Wang et al. Sci China Chem February (2016) Vol.59 No.2
light irradiation (blue LEDs, λmax=435 nm) in the presence
of Ru(bpy)3Cl2 (5.0 mol%), but no reaction occurred (Table
1, Entry 1). Then the photocatalyst Ru(bpy)3Cl2 was
changed to fac-Ir(ppy)3. To our delight, -bromo--
unsaturated aldehyde 1b was formed in 93% yield after re-
action for 76 h (Entry 2). Notably, the reaction did not hap-
pen in the absence of either visible light (Entry 3) or photo-
catalyst (Entry 4). It seems that light source plays a very
important role in this reaction, when changed to 5 W fluo-
rescence blub, only 37% desired product was obtained (En-
try 15). The screen on the solvents indicated that the yield
was dramatically decreased to 30% in dimethylformamide
(DMF, Entry 5), and no reaction was observed in Dimethyl
sulfoxide (DMSO), tetrahydrofuran (THF) or dichloro-
methane (DCM, Entries 6–8). In addition, additives were
not necessary for the reaction (Entries 9–13). It was worth
mentioning that the reaction was characterized by its high
regioselectivity that all the brominated products were Z
isomers [19] for the olefins, and no E isomers were detected.
We then investigated the scope of this photocatalytic re-
action by submitting a series of substituted -unsaturated
aldehydes to the optimized conditions. As shown in Scheme
3, it can be seen that different kinds of functional groups on
the -aryl substituent were tolerant with the reaction condi-
tions. Substrates with electron-donating group on benzyl
ring afforded the corresponding α-brominated products in
high yields (1b, 3b). When the substrates bear an elec-
tron-withdrawing group, such as NO2 (8b, 9b) or halogen
Scheme 2 Different approaches to α-bromo-α,β-unsaturated ketones or
aldehyde.
only saturated -bromo ketones can be formed, to get this
work further, we then tried to explore visible light-mediated
synthesis of -bromo--unsaturated ketones or aldehydes
(Scheme 2).
2 Experimental
2.1 General experimental section
All reagents were purchased from commercial sources un-
less otherwise noted. Solvents were dried according to the
standard procedures prior to use.
1
The chemical shifts in the H NMR (600 MHz or 400
MHz) and 13C NMR (150 MHz) spectra are reported in
parts per million, with tetramethylsilane (TMS) or solvent
resonance (e.g., CDCl3) as the internal standard. HR-MS
spectra were recorded on LC mass spectrometer using elec-
trospray ionization (ESI, TOF).
Table 1 Optimization of experimental parameters (I) a)
2.2 General procedure for the synthesis of -bromo-
-unsaturated aldehydes 1b
Entry
Light
on
Catalyst
Ru(bpy)3Cl2
fac-Ir(ppy)3
fac-Ir(ppy)3
null
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Additive
Yield b)
N.R.
93%
N.R.
N.R.
30%
N.R.
N.R.
1
2
3
4
5
6
7







A 10 mL Schlenk flask was equipped with a magnetic stir
bar and was charged with substrate 1a (33 mg, 0.20 mmol),
CBr4 (198.2 mg, 0.60 mmol), CH3CN (2.0 mL) and
fac-Ir(ppy)3 (6.6 mg, 0.01 mmol). The reaction mixture was
degassed three times by Freeze-Pump-Thaw cycles and then
irradiated by blue LEDs (1 W) for 76 h at room temperature
under N2 protection. After reaction, the solvent was concen-
trated in vacuo and the residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc=50:1)
to afford the desired product 1b (40.1 mg, 83% yield). The
characterizations of α-bromo-α,β-unsaturated ketones or
aldehydes listed in the Supporting Information online.
on
off
on
on
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
on
DMSO
THF
on
8
on
on
on
on
on
on
on
on
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
DCM
N.R.
27%
N.R.
19%
70%
N.R.
56%
37%

K2HPO4
AcONH4
Imidazole
DMP
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10
11
12
13
14
15 d)
Na2CO3

c)

3 Results and discussion
a) Reaction conditions: 1a (1.0 equiv.), CBr4 (3.0 equiv.), fac-Ir(ppy)3
(5 mol%), solvent (0.1 mol/L), blue LEDs (1 W), additive (3 equiv.); b)
yield: all detected by GC; c) fac-Ir(ppy)3=2 mol%; d) fluorescence bulb
(5 W).
We commenced our research on subjecting the electron-rich
-unsaturated aldehyde 1a and CBr4 in MeCN to visible

Wang et al. Sci China Chem February (2016) Vol.59 No.2
Table 2 Optimization of experimental parameters (II) a)
3
Entry
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
Additive
Oxidant
CBr4
Yield b)
56%
32%
N.R.
5%
1
2
3
4
5
6
7
8
9




CBr4
BrCH2COOEt
BrCH(CH2CO2Et)2
CBr4
K2HPO4
43%
68%
N.R.
N.R.
N.R.
Na2CO3
CBr4
CBr4



CBr4
THF
CBr4
a) Reaction conditions: 10a (1.0 equiv.), oxidative quencher (3.0
equiv.), fac-Ir(ppy)3 (5 mol%), solvent (0.1 mol/L), blue LEDs (1 W),
additive (3 equiv.); b) yield: all detected by GC.
Scheme 3 Substrate scope of α-bromination of aldehydes. Reaction con-
ditions: a (1.0 equiv.), CBr4 (3.0 equiv.), fac-Ir(ppy)3 (5 mol%), solvent
(0.1 mol/L), blue LEDs (1 W), no additive; yield: isolated yield at com-
plete conversions.
(4b, 5b, 6b) on the aromatic ring, the reaction proceeded
smoothly to yield the desired products in moderate yield,
but longer reaction time was needed. Additionally, steric
effect on the aryl group is also tolerant with the reaction
conditions (7b).
Our continuous investigation revealed that this protocol
was also suitable for α-bromination of -unsaturated ke-
tones. Therefore, the representative substrate 10a was sub-
jected to the standard reaction conditions, and anticipated
product 10b was obtained in 56% yield (Table 2, Entry 1).
To optimize the reaction conditions, alternative photocatal-
ysis, Ru(bpy)3Cl2 was tested under the same conditions,
however a lower yield was observed (Entry 2). Then we
tried to examine some other oxidative quenchers, which
provided little or no product (Entries 3 and 4). To our de-
light, the addition of Na2CO3 could improve the reaction
efficiency and yield when screening the influence of addi-
tives (Entry 6). However, no reaction was observed when
the reaction was conducted in other solvents such as
DMSO, DMF, and THF (Entries 7–9). Notably, control ex-
periment revealed that both visible light and photocatalyst
were essential to this α-bromination reaction.
Next, a variety of α,β-unsaturated ketones bearing dif-
ferent substituents were tested, and the results are summa-
rized in Scheme 4. It was found that both electron-
withdrawing and -donating functional groups such as –H
(11b), –Me (12b), –Br (13b), and –F (17b) were well toler-
ated, giving the corresponding products in good yields.
Moreover, some other substituents on different positions of
the aryl group were also tested to produce desired products
in good yields (Scheme 4, 14b–16b, 18b).
Scheme 4 Scope of α-bromination of ketones. Reaction conditions:
10a–18a (1.0 equiv.), CBr4 (3.0 equiv.), fac-Ir(ppy)3 (5 mol%), solvent (0.1
mol/L), blue LEDs (1 W), Na2CO3 (3.0 equiv.); yield: isolated yield at
complete conversions.
To elucidate the mechanism of the reaction, a number of
controlled experiments were carried out using 10a as the
substrate (Table 3). When TEMPO was added to the reac-
tion, 10b was obtained in high yield (Entry 10) which indi-
cated that the simple free radical pathway might be exclud-
ed. Interestingly, when Na2S2O8 served as the oxidant and
LiBr was employed as an additive, the desired product 10b
was formed in 78% yield, which implied that bromide ion
might be involved as nucleophilic reagent (Entry 9). In ad-
dition, the amount of CBr4 ranging from 0.5 to 4 equiv. was

4
Wang et al. Sci China Chem February (2016) Vol.59 No.2
accompanied by the yields changing from 12% to 83% (En-
tries 1–5). Furthermore, the addition of LiBr improved the
yield to 37% in the case of 0.5 equiv. of CBr4 (Entry 6). The
above results showed that CBr4 served as not only an oxi-
dant. Other oxidative quenchers gave no or little products
(Entries 7, 8).
from C. Based on the high regioselectivity of the reaction
that only the α-bromination product was obtained, we spec-
ulate that the stability of the cation intermediate C might
play an important role in the product distributions.
Finally, to demonstrate the utility of this protocol, a scale
of 500 mg of substrate 19a was subjected to the standard
reaction conditions and the corresponding product 19b, an
intermediate for synthesis of natural product (−)-Wodeshiol
[21], was successfully prepared in 71% yield (Eq. (1)).
It was documented that the resulting Br (E1/2red=1.087 V
vs. SCE, in CH3CN) [20] is more oxidizing than fac-
Ir(ppy)3 (E1/2IV/III=0.77 V vs. SCE, in CH3CN) [17], which
means that molecular bromine could not be generated in situ
from oxidation of Br by IrIV. To map out the reaction
mechanism, the oxidation potentials of two representative
substrates 1a and 10a were therefore tested and shown as
0.65 V vs. SCE, in CH3CN for 1a and 0.70 V vs. SCE, in
CH3CN for 10a which could be oxidized by fac-Ir(ppy)3
(E1/2IV/III=0.77 V vs. SCE, in CH3CN). Based on the above
results, a tentative reaction mechanism was proposed as
shown in Scheme 5.
As shown in Scheme 5, the photoexcited state of
fac-Ir(ppy)3 was oxidized by CBr4 to generate Br and IrIV
which then accepted one electron from the starting material
to form the radical cation intermediate A. Nucleophilic ad-
dition of Br to A led to a radical intermediate B which was
then oxidized by IrIV to form the cation C. The final prod-
ucts 1b–18b were formed after the elimination of a proton
(1)
4 Conclusions
In summary, we have developed a photocatalytic protocol
for the -bromination of different kinds of -unsaturated
ketones or aldehydes under mild reaction conditions. Com-
pared with previous procedures, this method is highlighted
by operational simplicity, high regioselectivity, and the em-
ployment of environmentally friendly brominating reagent.
Meanwhile, further experiments were conducted to provide
a clear understanding of the reaction mechanism.
Table 3 Controlled experiments a)
Entry
Oxidant
4 equiv. CBr4
Additive
Yield b)
81%
83%
65%
38%
12%
37%
5% b)
0%
Acknowledgments This work was supported by the National Natural
Science Foundation of China (21002018, 21072038, 21472030, 21302029),
the State Key Laboratory of Urban Water Resource and Environment
(2015DX01), the Fundamental Research Funds for the Central Universities
(HIT.BRETIV.201310).
1
2
–
3 equiv. CBr4
–
3
2 equiv. CBr4
–
4
1 equiv. CBr4
–
5
0.5 equiv. CBr4
0.5 equiv. CBr4
3 equiv. BrCH(CO2Et)2
3 equiv. BrCH2CO2Et
5 equiv. Na2S2O8
3 equiv. CBr4
–
Conflict of interest The authors declare that they have no conflict of
interest.
6
5 equiv. LiBr
7
–
8
–
Supporting information The supporting information is available online
at http://chem.scichina.com and http://link.springer.com/journal/11426.
The supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains
entirely with the authors.
9
5 equiv. LiBr
4.5 equiv. Tempo
78%
81%
10
a) fac-Ir(ppy)3 as catalyst; b) yield were detected by GC.
1
Cynthia BG, Matthew JB, Yoshihisa K. Org Lett, 2007, 9: 3631–
3634
2
3
Kim DS, Bolla K, Lee S, Hama J. Tetrahedron, 2011, 67: 1062–1070
Zhu PT, He Xing, Chen XQ, You Y, Yuan YF, Weng ZQ. Tetrahe-
dron, 2014, 70: 672–677
4
Bobileva O, Bokaldere R, Gailite V, Kaula I, Ikaunieks M, Duburs G,
Petrovska R, Mandrika I, Klovins J, Loza E. Bio Med Chem, 2014,
22: 3654–3669
5
6
7
Ingolf C, Klaus B, Rolf N. Acta Chem Scand B-Org Chem Biochem,
1985, 39: 7–13
Henry N, Sánchez A, Sabatié V, Bénéteau G, Guillaumet MD. Tet-
rahedron, 2006, 62: 2405–2412
Bonifácio VD, González BC, Henry S, Prabhakar S, Lobo AM. Syn-
lett, 2010, 1: 145–149
8
9
Wrobel J, Jane M. J Med Chem, 1991, 34: 2504–2520
Dai WM, Lee MK. Tetrahedron Lett, 1998, 39: 8149–8152
Scheme 5 Proposed mechanism.

Wang et al. Sci China Chem February (2016) Vol.59 No.2
5
10 Deb KB, Lu B, Rachid B, Charles M, Falck JR. Tetrahedron Lett,
102–113
17 Christopher KP, Danica AR, David WC. Chem Rev, 2013, 113:
5322–5363
18 Guo L, Yang C, Zheng LW, Xia WJ. Org Biomol Chem, 2013, 11:
5787–5892
19 Ireneusz N, Morris JR. J Org Chem, 2007, 72: 2678–2681
20 Zhao YT, Li Z, Yang C, Lin R, Xia WJ. Beilstein J Org Chem, 2014,
10: 622–627
2008, 49: 4359–4361
11 Kanchan M, Abhinandan S, Prakas R, Indrajit D. Chem Eur J, 2014,
20: 662–667
12 Shi L, Xia WJ. Chem Soc Rev, 2012, 41: 7687–7697
13 Xuan J, Xiao WJ. Angew Chem Int Ed, 2012, 51: 6828–6838
14 Zeitler K. Angew Chem Int Ed, 2009, 48: 9785–9789
15 Tucker JW, Stephenson CR. J Org Chem, 2012, 77: 1617–1622
16 Narayanam JMR, Stephenson CRJ. Chem Soc Rev, 2011, 40:
21 Xiao JH, Corey EJ. Org Lett, 1999, 1: 1871–1872