Palladium-catalyzed oxidative C-N bond coupling involving a solvent-controlled regioselective bromination process

Article abstract of DOI:10.1021/jo501171c

Stereoselective palladium-catalyzed oxidative C-N bond coupling reactions between aromatic amines and alkenes involving a solvent-controlled regioselective bromination process under 1 atm of oxygen atmosphere are disclosed, providing easy access to two different brominated enamines. The addition of hydrogen peroxide (30% aq) as a co-oxidant in the system is crucial for the dehydrogenative aminohalogenation under molecular oxygen (1 atm), and in such a case, the C-N bond coupling/electrophilic bromination reaction cascade is proposed. Furthermore, the different reaction media leads to a switched regioselectivity of the process.

Full text of DOI:10.1021/jo501171c

Article
pubs.acs.org/joc
Palladium-Catalyzed Oxidative C−N Bond Coupling Involving a
Solvent-Controlled Regioselective Bromination Process
Xiaochen Ji,† Huawen Huang,† Wenfang Xiong,† Kunbo Huang,† Wanqing Wu,† and Huanfeng Jiang*,†,‡
†School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: Stereoselective palladium-catalyzed oxidative C−N bond coupling reactions between aromatic amines and alkenes
involving a solvent-controlled regioselective bromination process under 1 atm of oxygen atmosphere are disclosed, providing easy
access to two different brominated enamines. The addition of hydrogen peroxide (30% aq) as a co-oxidant in the system is crucial
for the dehydrogenative aminohalogenation under molecular oxygen (1 atm), and in such a case, the C−N bond coupling/
electrophilic bromination reaction cascade is proposed. Furthermore, the different reaction media leads to a switched
regioselectivity of the process.
Scheme 1. Palladium-Catalyzed Oxidative Transformations
Involving Aromatic Amines and Alkenes
INTRODUCTION
■
Palladium-catalyzed transformations are powerful tools to
efficiently construct complex molecules from easily available
starting materials under mild conditions, with high chemo-,
regio-, and stereoselectivity and great functional group
tolerance generally observed.1−4 Oxidants are usually involved
in these processes, such as CuII, PhI(OAc)2, BQ, DDQ, etc. In
view of sustainable and green chemistry, molecular oxygen and
hydrogen peroxide are undoubtedly ideal oxidants, with only
nontoxic water released after the reaction. Moreover, the
inexpensive and highly atom-efficient properties make these
environmentally friendly oxidants particularly attractive, with
broad academic and industrial application prospects.5−8
Therefore, palladium-catalyzed reactions with molecular oxygen
or hydrogen peroxide as the oxidant have received considerable
attention over the past few decades and continue to be one of
the research hotspots in organic synthesis.9−12
The enamine skeleton is ubiquitous in a wide range of
pharmaceuticals and natural products, and its derivatives are
also valuable and flexible precursors in synthetic chemistry,
particularly in building a variety of biologically and synthetically
important nitrogen-containing heterocycles, such as pyrroles,
pyridines, and indoles.13−26 Enamines could also be used for
the asymmetric synthesis of various secondary or tertiary chiral
amines.27−32 Consequently, varieties of methods have been
developed to construct diversified enamine compounds over
the past years.33−46
Recently, our group has reported the first example of
palladium-catalyzed dehydrogenative aminohalogenation of
alkenes with molecular oxygen as the sole oxidant, with simple
aromatic amines as the nitrogen source (Scheme 1a).47 This
approach leads to (Z)-brominated enamine products with
excellent regio- and stereoselectivity which are difficult to
prepare by traditional methods. However, high pressure (5
atm) of O2 as the oxidant is indispensible to achieve high
efficiency of this transformation. While this process hardly
occurred under 1 atm of O2, the direct oxidative C−N bond
coupling between aromatic amines and alkenes proceeded
smoothly to give (Z)-enamines in good to excellent yields with
exclusive stereoselectivity (Scheme 1b).48 Further studies
revealed that the dehydrogenative aminohalogenation of
alkenes could be achieved efficiently under 1 atm of O2 by
Received: May 26, 2014
Published: July 10, 2014
© 2014 American Chemical Society
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simply adding a co-oxidant into the catalytic system. As part of
our continuing interest in palladium-catalyzed aerobic reac-
tions,49−53 herein we disclose a solvent-controlled highly
selective palladium-catalyzed oxidative transformation involving
aromatic amines and alkenes under molecular oxygen (1 atm)
with hydrogen peroxide (30% aq) as the co-oxidant. With DMF
as the solvent, the dehydrogenative aminohalogenation of
alkenes selectively occurs (Scheme 1c), while in the THF
system, the reaction proceeds via selective bromination of
aromatic amines and subsequent oxidative C−N bond coupling
with alkenes (Scheme 1d).
our delight, the addition of 30% aqueous H2O2 (2 equiv) to the
catalytic system could greatly promote this transformation with
DMF as the solvent, providing 3a in 93% yield with good
stereoselectivity (dr >10:1) (entry 8). As for the solvents, DMF
was proved to be superior over DMSO, CH3CN, or toluene
(entry 8 versus entries 10−12).
Intriguingly, a switched selectivity was observed when using
THF as the solvent, and (Z)-enamine product (4a),
brominated at the para position of the aniline motif, was
given in 71% yield with excellent stereoselectivity, which was
further improved to 87% with an increased dosage (3 equiv) of
30% aqueous H2O2 (entries 13−14). It was noteworthy that
molecular oxygen was indispensible to the success of these
reactions, since only a very low yield of product (3a or 4a) was
obtained with 30% aqueous H2O2 as the sole oxidant under N2
atmosphere (entries 9 and 15), thus highlighting the
significance of the co-oxidants in the catalytic system.
RESULTS AND DISCUSSION
■
In our previous report, the requirement of high pressure (5
atm) of molecular oxygen limited the practical applications of
the dehydrogenative aminohalogenation of alkenes to some
extent.47 We hypothesized that it would be preferable to
develop an efficient catalytic system to facilitate this trans-
formation under 1 atm of O2. Thus, we started to optimize the
reaction conditions by investigating the Pd-catalyzed oxidative
transformations between aniline (1a) and methyl acrylate (2a)
in the presence of LiBr (4 equiv) under molecular oxygen (1
atm), as summarized in Table 1. Notably, the addition of a co-
Next, we evaluated the substrate scope of the Pd-catalyzed
dehydrogenative aminohalogenation of alkenes under 1 atm of
O2 with 30% aqueous H2O2 as the co-oxidant (Scheme 2). In
Scheme 2. Palladium-Catalyzed Dehydrogenative
Aminohalogenation of Alkenes under O2 (1 atm)
a
Table 1. Optimization of the Reaction Conditions under 1
a
atm of O2
b
entry
co-oxidant
Cu(OAc)2
solvent
yield (%)
3a:4a
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
CH3CN
toluene
THF
7
>10:1
trace
trace
trace
trace
trace
27
PhI(OAc)2
DDQ
Oxone
K2S2O8
BQ
>10:1
>10:1
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
H2O2 (30% aq)
93 (89)
8
c
9
10
11
12
13
23
>10:1
>10:1
19
a
Reaction conditions: aromatic amine 1 (0.5 mmol), alkene 2 (0.8
trace
71
mmol), Pd(OAc)2 (5 mol %), LiBr (4 equiv), 30% aqueous H2O2 (2
<1:10
<1:10
equiv), DMF (2 mL), with an O2 balloon, 50 °C for 12 h. dr > 10:1
d
14
c
THF
87 (81)
9
b
c
unless otherwise noted. The reaction time was prolonged to 20 h. dr
= 5:1.
15
THF
a
Reaction conditions: aniline 1a (0.5 mmol), methyl acrylate 2a (0.8
mmol), Pd(OAc)2 (5 mol %), LiBr (4 equiv), co-oxidant (2 equiv),
b
general, this catalytic system was more efficient than that with 5
atm of O2 as the sole oxidant in our previous report, and mostly
a complete consumption of the substrates was observed within
12 h, giving (Z)-brominated enamine products (3) with similar
yields and stereoselectivity. A series of aromatic amines, with
various substituents at the ortho, meta, and para positions of the
phenyl ring, reacted smoothly with methyl acrylate (2a) to give
the corresponding products (3a−j) in good to excellent yields.
Prolonged reaction time (20 h) was required for ortho-
substituted anilines, probably due to the steric interference in
the process. In addition, α-naphthylamine worked well to
solvent (2 mL), with an O2 balloon, at 50 °C for 12 h. GC yield.
c
d
Isolated yield is given in parentheses. Under N2 atmosphere. The
reaction was performed using 3 equiv of 30% aqueous H2O2 for 10 h.
oxidant appeared to have a strong impact on this trans-
formation, and several co-oxidants were examined. While the
employment of Cu(OAc)2, PhI(OAc)2, DDQ, Oxone, or
K2S2O8 as the co-oxidant did not afford the desired product
(entries 1−6), BQ could enhance the efficiency, giving (Z)-
brominated enamine product (3a) in 27% yield (entry 7). To
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furnish 3k in 81% yield. On the other hand, other acrylates
bearing diverse functional groups, such as phenyl, trifluor-
omethyl, cyclohexyl, tetrahydrofuran, and even free hydroxyl,
performed well in the present catalytic system, affording
respective products (3l−q) in good yields. Delightedly, diethyl
vinylphosphonate was also productive, leading to the desired
product (3r) in 75% yield.
Scheme 4. Control Experiments
When THF was used as the solvent, the reaction exclusively
led to (Z)-enamine products 4 with bromination at the benzene
ring of anilines (Scheme 3). Further examination of this
a
Scheme 3. Solvent-Switched Selectivity on the Reaction
into brominated enamine 3a in the presence of LiBr with 30%
aqueous H2O2 in DMF, while could hardly be transformed into
product 4a with THF as the solvent under similar conditions
(Scheme 4b). Then the radical scavenger 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added to the reaction of aniline
(1a) and methyl acrylate (2a) in the presence of LiBr under the
standard conditions of the dehydrogenative aminohalogenation
of alkenes, and product (3a) was obtained in 31% yield
(Scheme 4c). The switched regioselectivity in THF could be
clarified by the fact that the bromination of aniline (1a)
efficiently occurred in the presence of 30% aqueous H2O2
within 2 h, delivering 4-bromoaniline (1d) in 92% yield, while
only 16% yield of 1d was obtained with DMF as the solvent
(Scheme 4d).54,55
As for the Pd-catalyzed dehydrogenative aminohalogenation
of alkenes, the above results were inconsistent with those when
5 atm of O2 was used as the sole oxidant in our previous report,
illustrating that different mechanisms might be involved in
these two reaction systems. We speculated that (Z)-enamine
(5) might be a key intermediate of the transformation in this
co-oxidative catalytic system. A plausible mechanism is
proposed to illustrate the reaction process of the dehydrogen-
ative aminohalogenation of alkenes in the present catalytic
system (Scheme 5). Initially, the complex I, formed by the
coordination of methyl acrylate (2a) to Pd(II) catalyst,
underwent nucleophilic attack by aniline (1a) to give the σ-
alkylpalladium species II. Subsequent β-hydride elimination of
complex II afforded the enamine intermediate (5) in exclusive
Z stereoselectivity, probably due to the existence of the
intramolecular hydrogen bond either in complex II or in
enamine 5. The Pd(0) species was oxidized by molecular
oxygen to regenerate the active Pd(II) catalyst. Then the
electrophilic substitution of the (Z)-enamine intermediate (5)
with [Br+], arising from the oxidation of [Br−] with 30%
aqueous H2O2,56,57 resulted in the final product 3a.
a
Reaction conditions: aromatic amine 1 (0.5 mmol), alkene 2 (0.8
mmol), Pd(OAc)2 (5 mol %), LiBr (4 equiv), 30% aqueous H2O2 (3
equiv), 2 mL of THF, with an O2 balloon, 50 °C for 10 h. Exclusive Z
selectivities of the products were obtained.
transformation revealed that the electronic nature of the
substituents on the phenyl ring of aniline component could
greatly affect the efficiency of this reaction, since anilines
substituted with electron-withdrawing functional groups, such
as fluoro, chloro, or trifluoromethyl, afforded the corresponding
products in significantly decreased yields. Aniline and o-
toluidine reacted well with various acrylates in this catalytic
system, providing the corresponding 4-brominated enamine
products (4a,b,d−g) in good to excellent yields with complete
stereoselectivity. In addition, pent-1-en-3-one was also a
suitable substrate to undergo this transformation, albeit
affording the product (4c) in moderate yield (42%). When p-
toluidine was employed as the substrate, ortho-brominated
enamine products (4h,i) were obtained in good yields. It was
noteworthy that the vinyl amine and the aryl bromine
functionalities in the resultant products enabled them to
undergo various transformations, thus providing ample
opportunity for further derivatization to construct more
complicated organic architectures.
Mechanism Investigations. In order to gain insight into
the reaction mechanism of these co-oxidative catalytic systems,
several control experiments were conducted (Scheme 4). The
reaction of aniline (1a) and methyl acrylate (2a) using
molecular oxygen (1 atm) as the sole oxidant proceeded
smoothly with either DMF or THF as the solvent, giving (Z)-
enamine 5 in excellent yields (85% and 91%, respectively,
Scheme 4a). The (Z)-enamine 5 was successfully converted
When THF was used as the solvent, we found that the
efficiency of the reaction was highly dependent on the
electronic nature of the amine partner, and electron-deficient
amines could not efficiently converted into the desired
products. Combined with the results of the control experi-
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Scheme 5. Plausible Mechanism for These Transformations
mixture was heated at 50 °C under magnetic stirring for 12 h. The
reaction was then quenched with water, and the mixture was extracted
with ethyl acetate (15 mL × 3). The combined organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(petroleum ether/EtOAc) to afford the corresponding products 3.
(Z)-Methyl 2-bromo-3-(phenylamino)acrylate (3a).47 Light yellow
ments, it was suggested that the electrophilic substitution at the
para position of aniline 1a with [Br+], generated by the
oxidation of [Br−] with 30% aqueous H2O2, preferentially
occurred in this case to provide 4-bromoaniline (1d), which
underwent subsequent Pd-catalyzed oxidative C−N bond
coupling with methyl acrylate (2a) in THF to deliver the
final products 4a.
1
oil (0.114 g, 89%). H NMR (CDCl3, 400 MHz): δ 8.25 (d, J = 13.2
Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1H), 7.02 (d, J =
8.0 Hz, 2H), 6.87 (d, J = 13.2 Hz, 1H), 3.82 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 164.3, 139.6, 138.6, 129.8, 123.5, 116.0, 87.1,
52.5.
CONCLUSION
■
In summary, we have developed two regio- and stereoselective
palladium-catalyzed aerobic transformations involving aromatic
amines and alkenes in the co-oxidative catalytic system. The
reaction media played a crucial role in determining the
regioselectivity of these processes. With 30% aqueous H2O2
as the co-oxidant, the Pd-catalyzed dehydrogenative amino-
halogenation of alkenes was achieved in DMF under 1 atm of
O2, providing easy access to (Z)-brominated enamines. When
THF was employed as the solvent, the electrophilic
bromination of anilines and subsequent oxidative C−N bond
coupling with alkenes selectively occurred instead. The two
oxidants performed their respective duties in this system: the
role of molecular oxygen lies in the regeneration of Pd(II)
species in the process of oxidative C−N bond coupling,
whereas H2O2 (30% aq) served for the oxidation of [Br−] to
[Br+] in the bromination process. Moreover, the employment
of readily available starting materials as well as environmentally
friendly oxidants makes these atom-economical transformations
particularly attractive and practical.
(Z)-Methyl 2-Bromo-3-((4-fluorophenyl)amino)acrylate (3b).47
Light yellow solid (0.116 g, 85%). Mp: 68−70 °C. 1H NMR
(CDCl3, 400 MHz): δ 8.14 (dd, J = 13.2, 2.0 Hz, 1H), 7.05−6.97 (m,
4H), 6.83 (d, J = 12.0 Hz, 1H), 3.80 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 164.3, 159.1, 139.1, 136.0, 117.7, 116.5, 87.0, 52.5.
(Z)-Methyl 2-Bromo-3-((4-chlorophenyl)amino)acrylate (3c).47
Light yellow solid (0.118 g, 81%). Mp: 124−125 °C. 1H NMR
(CDCl3, 400 MHz): δ 8.17 (d, J = 13.2 Hz, 1H), 7.28 (d, J = 8.8 Hz,
2H), 6.96 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 12.8 Hz, 1H), 3.81 (s, 3H).
13C NMR (CDCl3, 100 MHz): δ 164.1, 138.3, 138.2, 129.8, 128.4,
117.2, 87.7, 52.5.
(Z)-Methyl 2-Bromo-3-((4-bromophenyl)amino)acrylate (3d).47
Light yellow solid (0.141 g, 84%). Mp: 137−138 °C. 1H NMR
(CDCl3, 400 MHz): δ 8.16 (d, J = 13.2 Hz, 1H), 7.42 (d, J = 8.8 Hz,
2H), 6.90 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 12.4 Hz, 1H), 3.81 (s, 3H).
13C NMR (CDCl3, 100 MHz): δ 164.1, 138.8, 138.0, 132.7, 117.5,
115.8, 88.0, 52.6.
(Z)-Methyl 2-Bromo-3-((3-methoxyphenyl)amino)acrylate (3e).47
Light yellow oil (0.124 g, 87%). 1H NMR (CDCl3, 400 MHz): δ 8.22
(d, J = 13.2 Hz, 1H), 7.22 (t, J = 8.2 Hz, 1H), 6.83 (d, J = 13.2 Hz,
1H), 6.61 (dd, J = 8.2, 2.2 Hz, 2H), 6.55 (t, J = 2.4 Hz, 1H), 3.82 (s,
3H), 3.81 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.3, 161.0,
140.9, 138.5, 130.7, 108.7, 108.5, 102.3, 87.2, 55.4, 52.5.
(Z)-Methyl 2-Bromo-3-((3-fluorophenyl)amino)acrylate (3f).47
Light yellow solid (0.115 g, 84%). Mp: 97−99 °C. 1H NMR
(CDCl3, 400 MHz): δ 8.18 (d, J = 13.2 Hz, 1H), 7.30−7.24 (m, 1H),
6.88 (d, J = 12.8 Hz, 1H), 6.80−6.73 (m, 3H), 3.82 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 164.1, 163.7, 141.3, 138.0, 131.2, 111.6, 110.1,
103.3, 88.3, 52.6.
EXPERIMENTAL SECTION
■
General Methods. All commercial materials and solvents were
used without further purification. 1H and 13C NMR spectra were
1
recorded on a 400 MHz NMR spectrometer (400 MHz for H, 100
MHz for 13C), and the broadband decoupling of carbon data was
proton-decoupled 13C{1H}. The chemical shifts were referenced to
signals at 7.26 and 77.0 ppm, respectively, and CDCl3 was used as the
solvent with TMS as the internal standard. Melting points were
uncorrected. High-resolution mass spectra were obtained with a maXis
impact (UHR-TOF) mass spectrometer.
(Z)-Methyl 2-Bromo-3-(o-tolylamino)acrylate (3g).47 Light yellow
Typical Procedure for Pd-Catalyzed Dehydrogenative
Aminohalogenation of Alkenes under O2 (1 atm). A 25 mL
Schlenk tube was charged with a solution of Pd(OAc)2 (0.025 mmol,
5.6 mg), LiBr (2 mmol, 174 mg), amine 1 (0.5 mmol), and alkene 2
(0.8 mmol) in DMF (2 mL), and then 30% aqueous H2O2 (2 equiv)
was added. The tube was equipped with an O2 balloon, and the
1
oil (0.108 g, 80%). H NMR (CDCl3, 400 MHz): δ 8.25 (d, J = 13.2
Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (t, J =
7.4 Hz, 1H), 6.80 (d, J = 12.8 Hz, 1H), 3.82 (s, 1H), 2.31 (s, 4H). 13C
NMR (CDCl3, 100 MHz): δ 164.3, 139.0, 138.0, 131.1, 127.5, 125.3,
123.4, 114.9, 87.6, 52.4, 17.1.
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(Z)-Methyl 2-Bromo-3-((2-methoxyphenyl)amino)acrylate (3h).47
Light yellow oil (0.117 g, 82%). 1H NMR (CDCl3, 400 MHz): δ 8.28
(d, J = 13.6 Hz, 1H), 7.48 (d, J = 13.2 Hz, 1H), 7.12 (dd, J = 7.8, 1.4
Hz, 1H), 7.00−6.94 (m, 2H), 6.90 (dd, J = 8.0, 1.2 Hz, 1H), 3.92 (s,
3H), 3.82 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.5, 147.7,
137.7, 129.2, 122.9, 121.3, 113.2, 110.9, 87.4, 55.8, 52.4.
3H), 6.85 (d, J = 13.2 Hz, 1H), 4.16−4.03 (m, 4H), 1.37−1.33 (m,
6H). 13C NMR (CDCl3, 100 MHz): δ 141.2, 140.9, 139.7, 129.7,
123.0, 115.7, 62.4, 62.3, 16.2, 16.2. HRMS (ESI) m/z: [M + H]+ calcd
for C12H18BrNO3P 334.0202, found 334.0198.
Typical Procedure for the Solvent-Switched Selectivity on
the Reaction. A 25 mL Schlenk tube was charged with a solution of
amine 1 (0.5 mmol), LiBr (2 mmol, 174 mg) in THF (2 mL), and
30% aqueous H2O2 (3 equiv), and the mixture was heated at 50 °C
under magnetic stirring for 2 h. Then Pd(OAc)2 (0.025 mmol, 5.6 mg)
and alkene 2 (0.8 mmol) were added. The tube was equipped with an
O2 balloon, and the mixture was heated at 50 °C under magnetic
stirring for another 8 h. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (petroleum ether/EtOAc/Et3N) to afford the corresponding
products 4.
(Z)-Methyl 2-Bromo-3-((2-chlorophenyl)amino)acrylate (3i).
1
Light yellow oil (0.106 g, 73%). H NMR (CDCl3, 400 MHz): δ
8.26 (d, J = 13.2 Hz, 1H), 7.45 (d, J = 12.4 Hz, 1H), 7.39 (dd, J = 8.0,
1.2 Hz, 1H), 7.28−7.25 (m, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.98 (td, J =
7.8, 1.4 Hz, 1H), 3.83 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.1,
137.2, 136.3, 130.0, 128.2, 123.4, 121.9, 114.7, 89.5, 52.6. HRMS (ESI)
m/z: [M + H]+ calcd for C10H10BrClNO2 289.9578, found 289.9586.
(Z)-Methyl 2-Bromo-3-((2-(trifluoromethoxy)phenyl)amino)-
acrylate (3j). Light yellow oil (0.131 g, 77%). 1H NMR (CDCl3,
400 MHz): δ 8.23 (d, J = 13.2 Hz, 1H), 7.29−7.22 (m, 4H), 7.04 (td, J
= 7.6, 1.6 Hz, 1H), 3.83 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
164.0, 137.6, 137.1, 132.6, 128.1, 123.0, 121.6, 120.6, 115.2, 89.7, 52.6.
HRMS (ESI) m/z: [M + Na]+ calcd for C11H9BrF3NNaO3 361.9610,
found 361.9606.
(Z)-Methyl 3-((4-Bromophenyl)amino)acrylate (4a). Light yellow
1
oil (0.104 g, 81%). H NMR (CDCl3, 400 MHz): δ 9.88 (d, J = 12.0
Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.17 (dd, J = 12.4, 8.4 Hz, 1H), 6.83
(d, J = 8.8 Hz, 2H), 4.88 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 170.6, 142.6, 139.8, 132.5, 116.9, 114.8, 87.9,
50.7.
(Z)-Phenyl 3-((4-Bromophenyl)amino)acrylate (4b). Light yellow
solid (0.135 g, 85%). Mp: 93−95 °C. 1H NMR (CDCl3, 400 MHz): δ
9.94 (d, J = 12.4 Hz, 1H), 7.43−7.39 (m, 4H), 7.33 (dd, J = 12.8, 8.0
Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 6.83 (d, J =
8.4 Hz, 2H), 5.12 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz):
δ 168.8, 150.7, 144.3, 139.3, 132.6, 129.3, 125.5, 121.8, 117.0, 115.4,
87.0. HRMS (ESI) m/z: [M + H]+ calcd for C15H13BrNO2 318.0124,
found 318.0125.
(Z)-1-((4-Bromophenyl)amino)pent-1-en-3-one (4c). Light yellow
solid (0.053 g, 42%). Mp: 90−92 °C. 1H NMR (CDCl3, 400 MHz): δ
11.57 (d, J = 10.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.15 (dd, J = 12.2,
7.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 5.32 (d, J = 7.6 Hz, 1H), 2.43
(q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100
MHz): δ 202.8, 142.3, 139.6, 132.6, 117.4, 115.5, 97.2, 35.5, 9.1.
HRMS (ESI) m/z: [M + H]+ calcd for C11H13BrNO 254.0175, found
254.0175.
(Z)-Butyl 3-((4-Bromo-2-methylphenyl)amino)acrylate (4d). Light
yellow oil (0.129 g, 83%). 1H NMR (CDCl3, 400 MHz): δ 9.97 (d, J =
12.0 Hz, 1H), 7.28−7.25 (m, 2H), 7.22 (dd, J = 12.2, 8.2 Hz, 1H),
6.88 (d, J = 8.4 Hz, 1H), 4.90 (d, J = 8.0 Hz, 1H), 4.13 (t, J = 6.6 Hz,
2H), 2.29 (s, 3H), 1.69−1.62 (m, 2H), 1.46−1.37 (m, 2H), 0.95 (t, J =
7.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 170.6, 142.6, 138.3,
133.6, 129.9, 127.3, 114.4, 114.2, 88.5, 63.4, 30.9, 19.2, 17.3, 13.7.
HRMS (ESI) m/z: [M + H]+ calcd for C14H19BrNO2 312.0594, found
312.0585.
(Z)-Cyclohexyl 3-((4-Bromo-2-methylphenyl)amino)acrylate (4e).
Light yellow oil (0.142 g, 84%). 1H NMR (CDCl3, 400 MHz): δ 9.97
(d, J = 12.0 Hz, 1H), 7.28−7.26 (m, 2H), 7.21 (dd, J = 12.4, 8.4 Hz,
1H), 6.87 (d, J = 8.8 Hz, 1H), 4.89 (d, J = 8.4 Hz, 1H), 4.85−4.81 (m,
1H), 2.29 (s, 3H), 1.92−1.90 (m, 2H), 1.77−1.74 (m, 2H), 1.58−1.55
(m, 1H), 1.47−1.37 (m, 4H), 1.29−1.24 (m, 1H). 13C NMR (CDCl3,
100 MHz): δ 170.0, 142.4, 138.4, 133.5, 129.9, 127.2, 114.3, 114.1,
89.2, 71.6, 31.9, 25.4, 23.9, 17.3. HRMS (ESI) m/z: [M + H]+ calcd
for C16H21BrNO2 338.0750, found 338.0741.
(Z)-Phenyl 3-((4-Bromo-2-methylphenyl)amino)acrylate (4f).
Light yellow solid (0.143 g, 86%). Mp: 105−106 °C. 1H NMR
(CDCl3, 400 MHz): δ 9.98 (d, J = 12.0 Hz, 1H), 7.47−7.42 (m, 3H),
7.37 (d, J = 15.2 Hz, 1H), 7.34 (s, 1H), 7.29 (d, J = 6.0 Hz, 1H), 7.20
(d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 1H), 5.19 (d, J = 8.0 Hz, 1H),
2.30 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 168.9, 150.7, 144.6,
137.9, 133.6, 130.0, 129.4, 127.8, 125.5, 121.9, 115.2, 114.7, 87.3, 17.2.
HRMS (ESI) m/z: [M + H]+ calcd for C16H15BrNO2 332.0281, found
332.0285.
(Z)-Methyl 2-Bromo-3-(naphthalen-1-ylamino)acrylate (3k).47
1
Light yellow oil (0.124 g, 81%). H NMR (CDCl3, 400 MHz): δ
8.37 (d, J = 13.2 Hz, 1H), 7.90 (dd, J = 12.6, 8.6 Hz, 2H), 7.64−7.53
(m, 4H), 7.44 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 3.85 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 164.3, 140.2, 135.4, 134.3,
128.8, 126.6, 126.6, 125.9, 125.0, 124.3, 119.8, 112.9, 88.3, 52.5.
(Z)-Phenyl 2-Bromo-3-(phenylamino)acrylate (3l). Light yellow
solid (0.132 g, 83%). Mp: 122−124 °C. 1H NMR (CDCl3, 400 MHz):
δ 8.42 (d, J = 13.6 Hz, 1H), 7.39−7.31 (m, 4H), 7.22 (t, J = 7.4 Hz,
1H), 7.15 (d, J = 7.6 Hz, 2H), 7.10−7.03 (m, 4H). 13C NMR (CDCl3,
100 MHz): δ 162.4, 151.1, 140.0, 139.3, 129.8, 129.3, 125.6, 123.8,
121.7, 116.3, 86.4. HRMS (ESI) m/z: [M + Na]+ calcd for
C15H12BrNNaO2 339.9944, found 339.9936.
(Z)-2,2,2-Trifluoroethyl 2-Bromo-3-(phenylamino)acrylate
(3m).47 Light yellow solid (0.133 g, 82%). Mp: 60−62 °C. H NMR
1
(CDCl3, 400 MHz): δ 8.30 (d, J = 13.6 Hz, 1H), 7.36 (dd, J = 8.4, 7.6
Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 7.05−7.00 (m, 3H), 4.60 (q, J = 8.4
Hz, 2H). 13C NMR (CDCl3, 100 MHz): δ 162.1, 140.3, 139.1, 129.9,
125.4, 124.1, 116.4, 85.1, 60.9.
(Z)-2-Ethylhexyl 2-Bromo-3-(phenylamino)acrylate (3n).47 Light
yellow oil (0.152 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.24 (d, J =
13.2 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01
(d, J = 8.0 Hz, 2H), 6.86 (d, J = 13.2 Hz, 1H), 4.14 (d, J = 5.6 Hz,
2H), 1.68−1.64 (m, 1H), 1.42 (t, J = 7.6 Hz, 2H), 1.36−1.32 (m, 6H),
0.95−0.89 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 164.0, 139.7,
138.2, 129.8, 123.3, 115.9, 87.7, 67.8, 38.9, 30.6, 29.0, 24.0, 23.0, 14.0,
11.1.
(Z)-Cyclohexyl 2-Bromo-3-(phenylamino)acrylate (3o).47 Light
yellow oil (0.138 g, 85%). 1H NMR (CDCl3, 400 MHz): δ 8.23 (d, J =
13.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.01
(d, J = 7.6 Hz, 2H), 6.84 (d, J = 13.2 Hz, 1H), 4.94−4.88 (m, 1H),
1.91−1.87 (m, 2H), 1.78−1.75 (m, 2H), 1.59−1.50 (m, 3H), 1.47−
1.36 (m, 3H). 13C NMR (CDCl3, 100 MHz): δ 163.2, 139.8, 138.0,
129.8, 123.3, 116.0, 88.4, 73.5, 31.7, 25.5, 23.6.
(Z)-(Tetrahydrofuran-2-yl)methyl 2-Bromo-3-(phenylamino)-
acrylate (3p).47 Light yellow oil (0.137 g, 84%). H NMR (CDCl3,
1
400 MHz): δ 8.23 (d, J = 13.2 Hz, 1H), 7.29 (t, J = 7.8 Hz, 2H), 7.05−
6.94 (m, 4H), 4.27−4.13 (m, 3H), 3.92−3.87 (m, 1H), 3.82−3.77 (m,
1H), 2.05−1.83 (m, 3H), 1.71−1.62 (m, 1H). 13C NMR (CDCl3, 100
MHz): δ 163.7, 139.5, 138.7, 129.6, 123.3, 116.0, 87.0, 76.5, 68.4, 67.2,
27.9, 25.6.
(Z)-2-Hydroxyethyl 2-Bromo-3-(phenylamino)acrylate (3q).47
1
Light yellow oil (0.113 g, 79%). H NMR (CDCl3, 400 MHz): δ
8.28 (d, J = 13.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.07 (t, J = 7.4 Hz,
1H), 7.03 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 13.6 Hz, 1H), 4.37−4.34
(m, 2H), 3.90−3.88 (m, 2H), 2.23 (s, 1H). 13C NMR (CDCl3, 100
MHz): δ 164.4, 139.4, 139.2, 129.8, 123.7, 116.2, 86.7, 67.1, 61.5.
(Z)-Diethyl (1-Bromo-2-(phenylamino)vinyl)phosphonate (3r).
(Z)-2-Hydroxyethyl 3-((4-Bromo-2-methylphenyl)amino)acrylate
(4g). Light yellow oil (0.119 g, 79%). 1H NMR (CDCl3, 400 MHz): δ
9.94 (d, J = 12.0 Hz, 1H), 7.29−7.23 (m, 3H), 6.89 (d, J = 8.8 Hz,
1H), 4.95 (d, J = 8.0 Hz, 1H), 4.29−4.27 (m, 2H), 3.87−3.85 (m,
2H), 2.29−2.22 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 170.7,
143.5, 138.1, 133.6, 130.0, 127.5, 114.8, 114.5, 87.7, 65.3, 61.6, 17.2.
1
Light yellow oil (0.125 g, 75%). H NMR (CDCl3, 400 MHz): δ
7.93 (dd, J = 13.0, 9.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.04−6.99 (m,
7009
dx.doi.org/10.1021/jo501171c | J. Org. Chem. 2014, 79, 7005−7011

The Journal of Organic Chemistry
Article
HRMS (ESI) m/z: [M + H]+ calcd for C12H15BrNO3 300.0230, found
300.0221.
(18) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem.,
Int. Ed. 2009, 48, 8078.
(Z)-Butyl 3-((2-Bromo-4-methylphenyl)amino)acrylate (4h). Light
yellow oil (0.125 g, 80%). 1H NMR (CDCl3, 400 MHz): δ 10.23 (d, J
= 12.0 Hz, 1H), 7.35 (s, 1H), 7.18 (dd, J = 12.4, 8.4 Hz, 1H), 7.05 (d, J
= 8.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 8.4 Hz, 1H), 4.16
(t, J = 6.6 Hz, 2H), 2.27 (s, 3H), 1.70−1.62 (m, 2H), 1.46−1.39 (m,
2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 170.0,
141.7, 136.3, 133.5, 132.8, 129.1, 113.5, 111.8, 89.0, 63.4, 30.9, 20.2,
19.2, 13.7. HRMS (ESI) m/z: [M + H]+ calcd for C14H19BrNO2
312.0594, found 312.0593.
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(Z)-Phenyl 3-((2-Bromo-4-methylphenyl)amino)acrylate (4i).
1
Light yellow oil (0.136 g, 82%). H NMR (CDCl3, 400 MHz): δ
10.18 (d, J = 12.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.33−7.28 (m,
2H), 7.20 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.4
Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.13 (d, J = 8.4 Hz, 1H), 2.26 (s,
3H). 13C NMR (CDCl3, 100 MHz): δ 168.2, 150.7, 143.6, 136.0,
133.5, 133.5, 129.3, 129.1, 125.4, 121.9, 114.0, 112.1, 87.7, 20.2.
HRMS (ESI) m/z: [M + H]+ calcd for C16H15BrNO2 332.0281, found
332.0282.
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ASSOCIATED CONTENT
́
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds. This
(31) Verendel, J. J.; Pam
Rev. 2014, 114, 2130.
̀ ́
ies, O.; Dieguez, M.; Andersson, P. G. Chem.
material is available free of charge via the Internet at http://
pubs.acs.org.
(32) Burk, M. J. Acc. Chem. Res. 2000, 33, 363.
(33) Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.; Fokin, V.
V. J. Am. Chem. Soc. 2014, 136, 195−202.
(34) Jin, X.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2014,
53, 455.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
Notes
■
(35) Liang, H.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem.Eur. J.
2013, 19, 9789.
(36) Yamagishi, M.; Nishigai, K.; Ishii, A.; Hata, T.; Urabe, H. Angew.
Chem., Int. Ed. 2012, 51, 6471.
The authors declare no competing financial interest.
(37) Li, M.; Yuan, H.; Zhao, B.; Liang, F.; Zhang, J. Chem. Commun.
2014, 50, 2360.
ACKNOWLEDGMENTS
■
This work was supported by the National Basic Research
Program of China (973 Program) (2011CB808600), the
National Nature Science Foundation of China (21172076
and 21202046), the Guangdong Natural Science Foundation
(10351064101000000 and S2012040007088), and the Funda-
mental Research Funds for the Central Universities
(2014ZP0004 and 2014ZZ0046).
(38) Evano, G.; Gaumont, A.-C.; Alayrac, C.; Wrona, I. E.; Giguere, J.
R.; Delacroix, O.; Bayle, A.; Jouvin, K.; Theunissen, C.; Gatignol, J.;
Silvanus, A. C. Tetrahedron 2014, 70, 1529.
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