Stereoselective Chlorination and Bromination of Enamides and Enamines via an Electrostatic Attraction Effect Using (1,1-Diacetoxyiodo)benzene and a Halide Source

Article abstract of DOI:10.1021/acs.joc.5b01603

The direct chlorination and bromination of (E)-enamines and (Z)-enamides to the corresponding (Z)-configurated α-chloroenamines, α-bromoenamines, and α-chloroenamides have been realized using NiCl₂·6H₂O or tetrabutyl ammonium bromide as a halide source and (1,1-diacetoxyiodo)benzene as an oxidant. The high stereoselective reactions which produce products with only (Z)-configurations can be attributed to the structure of the intermediates, the conformations of which are controlled by the electrostatic attractions between the positively charged nitrogen atoms and the oxygen atoms of the carbonyl group. This type of electrostatic effect has never been reported in olefin halogenations. For this reason, the three-membered bromonium ion is only a minor intermediate in the enamine bromination pathway. These methods open pathways to prepare α-chloroenamines and α-chloroenamides, which are not accessible via the currently used methods.

Full text of DOI:10.1021/acs.joc.5b01603

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Article
Stereoselective Chlorination and Bromination of Enamides
and Enamines via an Electrostatic Attraction Effect
Using (1,1-Diacetoxyiodo)benzene and a Halide Source
Linlin Xing, and Chunbao Li
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 Sep 2015
Downloaded from http://pubs.acs.org on October 5, 2015
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Stereoselective Chlorination and Bromination of Enamides and
Enamines via an Electrostatic Attraction Effect Using
(1,1-Diacetoxyiodo)benzene and a Halide Source
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Linlin Xing and Chunbao Li*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China.
Fax: (+86) 2227403475. Eꢀmail: lichunbao@tju.edu.cn
X
R1
N
R2 O
OR3
OR3
OAc
O
OR3
H
X
Z
E
H
OR3
O
N +
R1
N
R2
X
R1
O
R2
X
R1
N
R2
Z
electrostatic attractionꢀ
controlled conformations
ABSTRACT
The direct chlorination and bromination of (E)ꢀenamines and (Z)ꢀenamides to the corresponding
(Z)ꢀconfigurated αꢀchloroenamines, αꢀbromoenamines and αꢀchloroenamides have been realized
using NiCl2·6H2O or tetrabutyl ammonium bromide as
a
halide source and
(1,1ꢀdiacetoxyiodo)benzene as an oxidant. The high stereoselective reactions which produce
products with only (Z)ꢀconfigurations can be attributed to the structure of the intermediates, the
conformations of which are controlled by the electrostatic attractions between the positively
charged nitrogen atoms and the oxygen atoms of the carbonyl group. This type of electrostatic
effect has never been reported in olefin halogenations. For this reason, the threeꢀmembered
bromonium ion is only a minor intermediate in the enamine bromination pathway. These methods
open pathways to prepare αꢀchloroenamines and αꢀchloroenamides, which are not accessible via
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the currently used methods.
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Introduction
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Enamides1ꢀ4 and enamines5,6 have proved to be useful building blocks for complex
nitrogenꢀcontaining compounds and substrates of various synthetic reactions such as the Porarov
reaction, the DielsꢀAlder reaction, the Mannich reaction, metalꢀcatalyzed regioselective
functionalization and halogenation. Among these products, halogenated enamides and enamines
are important intermediates for the synthesis of heterocycles,7 αꢀhaloꢀβꢀamino acid derivatives8ꢀ10
and αꢀarylꢀβꢀamino acid derivatives,11ꢀ13 some of which are bioactive.7,14 However, only a few
procedures have been used in preparing αꢀchloroenamides.15ꢀ18 In the NBS/DABCO procedure,17
only succinimide substituted αꢀchloroenamide products were prepared. In the Pummerer reactions
of sulfoxides,18 the products were limited to tetraꢀsubstituted αꢀchloroenamides. Currently
enamides are available through the Wittig reaction19 and Pd catalyzed crossꢀcoupling reaction of
an amide and an acrylic ester.20 However, there have been no reports on transforming
diꢀsubstituted enamides to αꢀchlorinated triꢀsubstituted enamides. (1,1ꢀDiacetoxyiodo)benzene
(PIDA)21ꢀ25 is a commercially available and widely used oxidant in organic synthesis and capable
to oxidize halide, which could possibly halogenate enamides and enamines. Herein, we report
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such
a
transformation, which used NiCl2·6H2O as
a
chloride source and
(1,1ꢀdiacetoxyiodo)benzene (PIDA) as an oxidant. These reactions are highly stereoselective. The
direct transformations of enamines to αꢀchloroꢀ and αꢀbromoenamines are also reported.
Results And Discussion
Initially, enamine 1a was used as a model compound and treated with a series of oxidants and
NiCl2·6H2O in MeOH (Table 1). No reactions occurred with BQ, DDQ, K2S2O8, TBHP, H2O2 and
mꢀCPBA (Table 1, entries 2ꢀ7). The oxidation of 1a with PIDA and NiCl2·6H2O led to 2a in 30%
yield (Table 1, entry 1). Next a series of solvents including MeCN, toluene, THF, DMF, DCE,
dioxane were screened and MeCN offered the best result (Table 1, entry 8ꢀ13). The employment
of other solvents decreased the reaction yields to a large extent. The reaction conditions were
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further optimized by varying the amounts of PIDA between 0.5ꢀ1.3 equiv and NiCl2·6H2O
between 1.0ꢀ2.5 equiv (Table 1, entries 14ꢀ20). The optimized reaction conditions were 1.0 equiv
of enamine, 1.2 equiv of PIDA and 2.0 equiv of NiCl2·6H2O in acetonitrile which produce a yield
of 64% (Table 1, entry 19).
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Table 1. Optimization of Reaction Conditionsa
Cl
N
O
N
O
NiCl2—6H2O, oxidant
solvent, rt
O
O
—
1a
2a
entry NiCl2·6H2O (equiv)
oxidant (equiv)
PIDA (1.0)
BQ (1.0)
solvent (5 mL)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
toluene
THF
yield (%)b
30
1
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
2.5
2.0
2.0
2.0
2.0
NRc
NRc
NRc
NRc
NRc
trace
46
3
DDQ (1.0)
K2S2O8 (1.0)
TBHP (1.0)
H2O2 (1.0)
mꢀCPBA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (0.5)
PIDA (1.1)
PIDA (1.2)
PIDA (1.3)
4
5
6
7
8
9
trace
22
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14
15
16
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18
19
20
DMF
20
DCE
trace
34
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
52
55
55
23
61
64
60
aReaction conditions: rt, 15 min. bGC yield, except for entry 19 (isolated yield). cNR, no
reaction.
Fifteen enamines were then subjected to the optimized conditions to produce the corresponding
αꢀchloroenamines in good (Scheme 1, 2c, 2f), fair (Scheme 1, 2a, 2b, 2d, 2e, 2gꢀ2n) and low
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(Scheme 1, 2o) yields. Enamines 1aꢀ1n are all aryl enamines, which are stable towards Lewis
acid NiCl2. However, alkyl enamine 1o is not particularly stable towards NiCl2, causing the low
chlorination yield. All the chlorinations took 15 min regardless of the nature and position of the
substituents on the aryl groups. The chlorination worked equally well when the alkyl group on the
nitrogen atom was an ethyl group (Scheme 1, 2l). The (Z)ꢀconfiguration of the products were
confirmed by NOE experiments on 2i (SI, S38).
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Scheme 1. Chlorination of Enaminesa
R2
N
R2 Cl
N
O
O
NiCl2—6H2O
R1
R3
R1
R3
PIDA
MeCN, rt, 15 min
O
O
1
2
Cl
Cl
Cl
R
Cl
N
O
N
O
N
O
N
O
O
O
O
O
R
NO2
2j, 68%
2a, R=H, 64%
2f, R=Me, 80%
2g, R=OMe, 75%
2h, R=Cl, 63%
2i, 69%
2b, R=Me, 63%
2c, R=OMe, 81%
2d, R=F, 67%
2e, R=Br, 64%
Cl
N
Cl
Cl
Cl
O
N
O
N
O
N
O
O
O
O
O
2n, 52%
2m, 66%
2l, 69%
2k, 58%
Cl
N
O
O
2o, 27%
aReaction conditions: 1 (0.5 mmol), PIDA (0.6 mmol), NiCl2·6H2O (1 mmol), MeCN (5 mL), rt,
15 min, isolated yields.
Previously, chloroenamines have been prepared in high yields from the condensations of
2ꢀchloroacetoacetate with aniline26ꢀ28 or primary alkyl amines29 and from the condensations of
2ꢀformylꢀ2ꢀchloroacetate sodium salt with the corresponding amine hydrochloride salts.30
However, the products were only limited to primary amineꢀsubstituted olefins, which is different
from the secondary amineꢀsubstituted olefins that were obtained in this work. Thus, this is the
only viable method to prepare secondary amineꢀsubstituted αꢀchloroenamines.
Next, eleven (Z)ꢀenamides were successfully transformed into the corresponding
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(Z)ꢀαꢀchloroenamides using the same procedure (Scheme 2). The reactions were rapid (15 min)
with yields ranging from 23% to 70%. The nature of substituent on the aryl rings had only a minor
influence on the product yields, but the position of the substituent greatly affected the yield. All
the othoꢀsubstituted aromatic enamides gave lower yields of the products (Scheme 2, 4eꢀ4g and
4i). An Xꢀray analysis of 4b was performed to determine the stereochemistry of 4 (SI, S39ꢀS42).
This type of primary amideꢀsubstituted αꢀchloroenamides cannot be synthesized by other currently
available methods.
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Scheme 2. Chlorination of Enamidesa
O
O
O
NiCl2—6H2O
R2
R1
N
R1
N
H
O
PIDA
MeCN, rt, 15 min
H
R2
Cl
O
O
3
4
O
O
O
O
O
O
O
O
N
O
N
O
N
H
O
H
N
O
H
Cl
H
Cl
Cl
Cl
O
O
Cl
4a, 70%
4b, 52%
4c, 57%
4d, 30%
O
O
O
O
O
O
O
N
H
O
N
O
N
O
N
H
OBn
O
H
H
Cl
Cl
Cl
Cl
Cl
I
NO2
4e, 23%
4h, 71%
4g, 30%
4f, 46%
O
O
O
O
O
O
N
O
O
N
O
N
H
O
H
H
Cl
Cl
Cl
4j, 43%
4k, 60%
4i, 44%
aReaction conditions: 3 (0.5 mmol), PIDA (0.6 mmol), NiCl2·6H2O (1 mmol), MeCN (5 mL), rt,
15 min, isolated yields.
Bromination of enamines (Scheme 3, 1c, 1d, 1i, 1l, 1m, 1g) with TBAB, PIDA in MeCN
offered the corresponding αꢀbromoenamines. The effect of the nature and position of the phenyl
ring substituents on the reaction yields and rates were not obvious. All the yields were moderate
(50ꢀ68%) and the reactions were all complete in 15 min. With the exception of 5c, which bears a
strong electronꢀdonating paraꢀMeO group, all the products were prepared stereoselectively in the
(Z)ꢀconfigurations. The stereochemistry of the compounds was confirmed by comparing the NMR
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data with those of known compounds.11,31 The bromination of enamides using the same procedure
ended in failure.
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The current methods to construct brominated enamine skeletons include the reaction of 3,
4ꢀdihaloꢀ2(5H) furan with amines,32ꢀ34 the bromination of enamines with NBS,35 the photolysis of
isoxazolꢀ5(2H)ꢀones in the presence of a bromide source (BnEt3N+Brꢀ or Et3NHBr)36 and
palladiumꢀcatalyzed aminohalogenation of alkenes oxidized by molecular oxygen.11,31,37 The first
method is limited to the production of furan skeletons, the next two produces a mixture of the two
isomers and the palladiumꢀcatalyzed coupling reaction produces primary amineꢀsubstituted or
sulfoximineꢀsubstituted olefins. This method is stereoselective, convenient and complementary to
the known methods.
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Scheme 3. Bromination of Enaminesa
R3
N
R3 Br
N
O
O
R2
TBAB
R2
R1
R1
O
O
PIDA
MeCN, rt, 15 min
1
5
Br
Br
O
N
Br
N
O
N
O
O
O
O
O
O
O
F
5c, Z:E=7:3, 51%
5d, 59%
5g, 58%
Br
Br
N
Br
N
N
O
O
O
O
O
5m, 68%
5l, 58%
5i, 50%
aReaction conditions: 1 (0.5 mmol), PIDA (0.6 mmol), TBAB (1 mmol), MeCN (5 mL), rt, 15
min, isolated yields.
To gain insight into the halogenation mechanism, several control experiments were carried out
(Scheme 4). A radical scavenger TEMPO were added to a mixture of 1f, PIDA, NiCl2·6H2O in
MeCN. The addition of TEMPO did not affect the reaction, which excludes the radical pathway
(Scheme 4, reaction (1)).
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Scheme 4. Mechanism Studies through Varying the Reaction Conditions
5
6
Cl
7
8
9
N
O
N
O
NiCl2—6H2O (2 equiv)
(1)
(2)
O
O
PIDA (1.2 equiv)
TEMPO (4 equiv)
MeCN, rt, 15 min
2f, 80%
1f
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Cl
N
O
N
O
PIDA (1.2 equiv)
MeCN, rt
O
O
2n
1n
conditions:
a: ZnCl2 (2 equiv), 15 min
b: BnEt3N+Clꢀ (4 equiv), 8 h
c: BnEt3N+Clꢀ (4 equiv), Ni(OAc)2 (1.2 equiv), 8 h
d: BnEt3N+Clꢀ (4 equiv), HOAc (2.4 equiv), 8 h
e: BnEt3N+Clꢀ (4 equiv), NaOAc (2.4 equiv), 8 h
f : BnEt3N+Clꢀ (10 equiv), HOAc (2.4 equiv), 8 h
yielda
46%
15%
14%
33%
6%
34%
aGCMS yield, except for condition a (isolated yield).
Next, other chlorine sources were tested (Scheme 4, reaction (2)). Chlorination of 1n using
benzyltriethyl ammonium chloride instead of NiCl2·6H2O as a chloride source made the reaction
sluggish (reaction (2), condition b). Addition of Ni(OAc)2 (reaction (2), condition c), a weaker
Lewis acid than NiCl2·6H2O, to benzyltriethyl ammonium chloride, PIDA, and 1n in MeCN gave
a similar result to reaction (2), condition b. When NiCl2·6H2O was replaced with ZnCl2, the
reaction was also rapid (reaction (2), condition a). These results suggest that acidic conditions are
necessary to oxidize Clꢀ to Cl+ using PIDA.
Other variables were also tested. Raising the concentration of AcOꢀ by adding AcOH or
AcONa did not accelerate the reactions, indicating that an attack of AcOꢀ on an intermediate is not
a rateꢀdetermining step (reaction (2), conditions d, e). Increasing the amount of BnEt3N+Clꢀ to 10
equiv did not improve the reaction (reaction (2), conditions f vs d), which indicates that an attack
of Clꢀ on an intermediate is not a rateꢀdetermining step.
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Scheme 5. Mechanism Studies through Varying the Substrates
5
6
7
8
9
N
O
SO2Cl2, CCl4
(1)
(2)
a complicated mixture
O
1f
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NiCl2—6H2O (2 equiv)
PIDA (1.2 equiv)
O
O
O
O
MeCN, rt, 15 min
N
O
N
O
H
H
Cl
(E)ꢀ3i
(Z)ꢀ3i
4i, 44%
NiCl2—6H2O (2 equiv)
PIDA (1.2 equiv)
MeCN, rt, 15 min
(3)
(4)
4i, 44%
H
N
NiCl2—6H2O (2 equiv)
a complicated mixture
a complicated mixture
PIDA (1.2 equiv)
MeCN, rt, 15 min
O
6
O
O
TBAB (2 equiv)
PIDA (1.2 equiv)
MeCN, rt, 15 min
N
H
O
(5)
3a
Addition of SO2Cl2 to the double bond is regarded as a convenient method for preparing
dichlorides.38 However, the reaction between SO2Cl2 and 1f (Scheme 5, reaction (1)) yielded a
complicated mixture, which indicates that dichloride is not the intermediate that leads to the
desired (Z)ꢀαꢀhaloenamine. Another control experiment, the oxidation of (E)ꢀethyl
3ꢀ(1ꢀnaphthamido)acrylate ((E)ꢀ3i), produced the same product as that starting from the
(Z)ꢀisomer ((Z)ꢀ3i) (Scheme 5, reactions (2), (3)). This indicates that the same
configurationꢀcontrolling intermediate is involved in the chlorinations of both (E)ꢀ3i and (Z)ꢀ3i.
Probably for the same reason, oxidation of 6 and NiCl2·6H2O with PIDA (Scheme 5, reaction (4))
yielded a complicated mixture.
Based on these experiments, the following mechanism is proposed (Scheme 6). The oxidation
of chloride by PIDA generates a chloronium ion which adds to the double bond of 1a to form I
and II. Conformation II dominates the equilibrium due to the attraction between the positively
charged nitrogen atom and the electronꢀrich carbonyl oxygen atom. Addition of AcOꢀ from the less
hindered side leads to III. An antiꢀelimination of AcOH produces (Z)ꢀconfigurated
αꢀchloroenamides, αꢀchloroenamines and αꢀbromoenamines.
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Scheme 6. Proposed Mechanism for the Halogenation of Enamine and Enamide Represented
by the Chlorination of 1a
7
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9
N
O
O
Ph
H
N
O
H
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1a
PhI(OAc)2
O
Cl+
Cl
Ph
Cl
2AcO
PhI
I
AcO
H
H
H
N
H
Cl
AcO
Cl
Ph
N
O
Ph
O
O
O
III
II
AcO
H
COOMe
H
Cl
HOAc
2a
Ph
N
IV
It is wellꢀdocumented in literature39ꢀ42 and taught in both undergraduate43 and graduate44
courses that threeꢀmembered bromonium ion is involved in the addition of bromine to olefins.
However, this is not the primary mechanism here since all the products are (Z)ꢀstereoisomers
whether starting from (E)ꢀenamines or (Z)ꢀenamides. This is probably because the positive charge
generated from the addition of bromonium ion to C=C bond is better stabilized by delocalization
onto the nitrogen atom than in the threeꢀmember bromonium ion (Scheme 6, I and II). This allows
the stereoselective addition of acetate to the C=N bond from the direction opposite to the halogen
atom. However, in the case of 5c (Z: E= 7:3), paraꢀMeO group is feeding electrons into the
πꢀsystem that is formed after the addition of bromide. This increases the electron density on the
πꢀsystem, partially reducing the electrostatic attraction between oppositely charged groups and the
stereoselectivity. In the cases of 5d, 5i, 5l and 5m (without strong electronꢀdonating groups), the
stereoselectivities is high. In the case of 5g, the orthoꢀMeO group reduces the conjugation
between the ring and the enamine. In the mean time, the electronꢀrich anilino group of 5c may
stabilize the threeꢀmember bromonium ion to some extent. The latter may account for the fact that
the chlorination stereoselectivity for 2c was higher than the bromination stereoselectivity for 5c,
since it is documented that threeꢀmembered chloronium ion exists in a trace amount.39,40 In the 1H
NMR spectrum of crude 2a (SI, S38), no signals for (E)ꢀ2a were detected. This may exclude the
steric effectꢀdominated or threeꢀmembered chloronium ionꢀinvolved mechanism since
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halogenations via these two mechanisms would lead to stereoisomers in a detectable amount.
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9
When we attempted to make αꢀbromoenamides that were analogous to the αꢀbromoenamines,
only a complicated mixture was obtained (Scheme 5, reaction (5)). This is because the nitrogen
atom in enamine is more electronꢀrich than that in enamide (Scheme 3ꢀ5l vs Scheme 5, reaction
(5)) and so the former stabilizes the positive charge better than the latter. Thus in the case of
enamides, the positive charge is more likely to be partially stabilized through the threeꢀmembered
bromonium ion. Consequently, the lack of the electrostatic attraction led to the complicated
mixture. Relevant examples of electrostatic attraction or repulsion are known to occur in
substitution reactions involving multiꢀfunctionalized molecules45 and in olefin epoxidations.46 To
the best of our knowledge, there have been no such reports with olefin halogenations.47ꢀ50
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The stereoselective halogenation method was extended to the simplification of the synthesis of
4h and 4i (Scheme 7). In the case of 4h, the conventional multiꢀpot reaction required both workup
and purification of the Wittig products from 7 and ethyl triphenylphosphonoacetate to get (E)ꢀ and
(Z)ꢀ3h. It was not easy to separate triphenylphosphine oxide and the Wittig products by
chromatography. This was followed by chlorination of both (E)ꢀ and (Z)ꢀ3h separately, producing
4h in 62% combined overall yield. In the simplified procedure, the Wittig reaction and
chlorination were realized in oneꢀpot avoiding workup and purification of the Wittig products and
producing 4h in 70% overall yield. This simplified procedure had benefits of saving two workup
and two purification operations and improving the yield by 8%. A similar result was observed in
the comparison reaction from 8 to 4i (Scheme 7).
Scheme 7. Comparison of the Multi-pot and the One-pot Synthesis Reactions
(1) Oneꢀpot Wittig reaction and chlorination of 7
O
O
O
O
N
OEt
N
H
1) toluene, 90
OEt
H
H
Cl
Ph3P
2) NiCl2—6H2O
PIDA, MeCN
O
NO2
overall yield: 4h, 70%
NO2
7
(2) Multiꢀpot Wittig reaction and chlorination of 7
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overall yield: 4h, 41%
overall yield: 4h, 21%
(E)ꢀ3h, 58%
OEt
toluene, 90
NiCl2—6H2O
PIDA, MeCN
Ph3P
7
(Z)ꢀ3h, 29%
O
combined overall yield: 62%
(3) Oneꢀpot Wittig reaction and chlorination of 8
8
9
O
O
O
O
1) toluene, 90
OEt
N
H
Ph3P
N
OEt
2) NiCl2—6H2O
PIDA, MeCN
H
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H
O
Cl
8
overall yield: 4i, 32%
(4) Multiꢀpot Wittig reaction and chlorination of 8
overall yield: 4i, 20%
overall yield: 4i, 13%
(E)ꢀ3i, 46%
(Z)ꢀ3i, 30%
OEt
toluene, 90
NiCl2—6H2O
PIDA, MeCN
Ph3P
8
O
combined overall yield: 33%
To further explore the utility of this synthetic method, chlorinated and brominated enamines
(2m, 5m) were transformed into three βꢀaminoacid esters (Scheme 8). Reduction of chlorinated
enamine 2m with NaBH4 in AcOH leading to αꢀchloroꢀβꢀaminoacid ester 9 in 95% yield, which
was further transformed to αꢀmecaptoꢀβꢀaminoacid ester 10 in 83% yield. Brominated enamine
5m was reduced with NaBH4 and treated with sodium azide to produce αꢀazidoꢀβꢀaminoacid ester
11 in 74% overall yield. Although several methods are known to prepare these types of
compounds,51ꢀ57 these syntheses provide alternative methods, which compared favorably to most
of the current procedures in terms of yield and operational convenience.
Scheme 8. Selected Transformation of Enamines
Cl
Cl
NaBH4, AcOH
to rt, 2 h, 95%
N
O
N
O
15
(1)
O
O
2m
9
O
O
S
SH
N
NaHCO3, CH3CN
rt, overnight, 83%
10
Br
N
N3
1) NaBH4, AcOH
15 to rt, 2 h
2) NaN3, CH3CN
rt, overnight
O
N
O
(2)
O
O
5m
74%
11
In conclusion, three types of halogenation methods including the direct chlorination of
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(Z)ꢀenamides and the direct bromination and chlorination of (E)ꢀenamines have been developed.
The similar intermediates were deduced to exist in all three reactions and their configurations were
controlled by the electrostatic attraction effect, which is the primary mechanism of the
stereoselective synthesis. This conclusion is supported by the results from the control experiments.
The reactions were mild, fast, convenient and highly stereoselective with good to moderate yields
for most products. The αꢀchloroenamine and αꢀchloroenamide products are only accessible via the
procedures reported herein.
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Experimental Section
General Information. Commercially available reagents were used without further purification.
The starting materials 1a-1o,58 3a-3k,20 PIDA59 were prepared according to literature methods.
1H NMR, 13C NMR and NOE spectra were recorded with a 400, 500 or 600 MHz spectrometer
using TMS as an internal standard. Chemical shifts (δ
) are reported relative to TMS (1H) or CDCl3
(13C). Single crystal Xꢀray diffraction data for compound 4b were collected on a diffractometer,
using graphiteꢀmonochromatized MoꢀKα radiation (0.71073 Å). High resolution mass spectra
(HRMS) were recorded on a QTOF mass analyzer using electrospray ionization (ESI). Melting
points were recorded with a micro melting point apparatus.
General Procedure for Chlorination of (E)-Enamines and (Z)-Enamides Using the
Chlorination of 1a as an Example.
To a solution of 1a (0.5 mmol, 96 mg) in MeCN (5 mL) were added NiCl2·6H2O (1.0 mmol,
238 mg) and PIDA (0.6 mmol, 193 mg). The mixture was stirred at room temperature for 15 min
(monitored by TLC). After completion, the reaction mixture was quenched with water (10 mL)
and extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and evaporated under vacuum. The residue was purified by preparative TLC
(EtOAc:petroleum ether, 1:5) to yield 2a (72 mg, 64%).
General Procedure for Bromination of (E)-Enamines Using the Bromination of 1c as an
Example.
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To a solution of 1c (0.5 mmol, 111 mg) in MeCN (5 mL) were added TBAB (1.0 mmol, 322
mg) and PIDA (0.6 mmol, 193 mg). The mixture was stirred at room temperature for 15 min
(monitored by TLC). After completion, the reaction mixture was quenched with water (10 mL)
and extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried
over Na2SO4 and evaporated under vacuum. The residue was purified by preparative TLC (EtOAc:
petroleum ether, 1:5) to yield 5c (77 mg, 51%).
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(Z)-Methyl 2-chloro-3-(methyl(phenyl)amino)acrylate (2a): Enamine 1a (96 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
1
1:5), αꢀchloroenamine 2a was isolated as a yellow oil (72 mg, 64% yield); H NMR (600 MHz,
CDCl3): δ 7.90 (s, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.17 (t, J = 7.1 Hz, 1H), 7.13 (d, J = 7.4 Hz, 2H),
3.79 (s, 3H), 3.66 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 166.2, 147.0, 142.4, 129.3, 124.9,
121.0, 95.2, 52.4, 39.2; HRMS (ESI) m/z:[M + Na]+ Calcd for C11H12ClNO2Na 248.0449, Found
248.0449.
(Z)-Methyl 2-chloro-3-(methyl(p-tolyl)amino)acrylate (2b): Enamine 1b (103 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
1
1:5), αꢀchloroenamine 2b was isolated as yellow oil (75 mg, 63% yield); H NMR (400 MHz,
CDCl3): δ 7.88 (s, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.66 (s,
3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.2, 144.7, 142.7, 134.8, 129.8, 121.3, 94.2,
52.3, 39.6, 20.8; HRMS (ESI) m/z:[M + Na]+ Calcd for C12H14ClNO2Na 262.0605, Found
262.0607.
(Z)-Methyl 2-chloro-3-((4-methoxyphenyl)(methyl)amino)acrylate (2c): Enamine 1c (111 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀchloroenamine 2c was isolated as a yellow solid, (104 mg, 81%
yield); mp 69ꢀ70 oC; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.89 (d,
J = 8.9 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.62 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.3,
157.3, 143.1, 140.3, 123.6, 114.3, 93.2, 55.5, 52.3, 40.9; HRMS (ESI) m/z:[M + Na]+ Calcd for
C12H14ClNO3Na 278.0554, Found 278.0559.
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(Z)-Methyl 2-chloro-3-((4-fluorophenyl)(methyl)amino)acrylate (2d): Enamine 1d (105 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀchloroenamine 2d was isolated as a yellow solid, (82 mg, 67%
yield); mp 56ꢀ57 oC; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.19–6.99 (m, 4H), 3.80 (s, 3H),
3.62 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.1, 160.1 (d, JCF = 245.2 Hz), 142.9 (d, JCF = 2.9
Hz), 142.6, 123.6 (d, JCF = 8.3 Hz), 116.0 (d, JCF = 22.8 Hz), 94.8, 52.4, 40.6; HRMS (ESI)
m/z:[M + Na]+ Calcd for C11H11ClFNO2Na 266.0360, Found 266.0356.
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(Z)-Methyl 2-chloro-3-((4-bromophenyl)(methyl)amino)acrylate (2e): Enamine 1e (135 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀchloroenamine 2e was isolated as a yellow solid, (97 mg, 64%
o
1
yield); mp 58ꢀ60 C; H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.54–7.41 (m, 2H), 7.11–6.73
(m, 2H), 3.80 (s, 3H), 3.61 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 165.8, 145.7, 141.8, 132.2,
122.4, 117.7, 96.7, 52.5, 39.4; HRMS (ESI) m/z:[M + Na]+ Calcd for C11H11BrClNO2Na 325.9554,
Found 325.9551.
(Z)-Methyl 2-chloro-3-(methyl(o-tolyl)amino)acrylate (2f): Enamine 1f (103 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
1
1:5), αꢀchloroenamine 2f was isolated as a yellow oil (96 mg, 80% yield); H NMR (400 MHz,
CDCl3): δ 7.70 (s, 1H), 7.39–6.99 (m, 4H), 3.75 (s, 3H), 3.45 (s, 3H), 2.25 (s, 3H); 13C NMR (101
MHz, CDCl3): δ 166.4, 144.0, 135.0, 130.9, 127.8, 126.9, 126.8, 91.3, 52.1, 17.7; HRMS (ESI)
m/z:[M + Na]+ Calcd for C12H14ClNO2Na 262.0605, Found 262.0611.
(Z)-Methyl 2-chloro-3-((2-methoxyphenyl)(methyl)amino)acrylate (2g): Enamine 1g (111 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀchloroenamine 2g was isolated as a yellow oil (96 mg, 75%
yield); 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.27 (td, J = 8.1, 1.6 Hz, 1H), 7.19–7.10 (m,
1H), 6.94 (t, J = 7.4 Hz, 2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.46 (s, 3H); 13C NMR (101 MHz, CDCl3):
δ 166.5, 154.6, 144.5, 128.5, 127.6, 120.6, 111.8, 91.5, 55.7, 52.1, 43.4; HRMS (ESI) m/z:[M +
Na]+ Calcd for C12H14ClNO3Na 278.0554, Found 278.0560.
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(Z)-Methyl 2-chloro-3-((2-chlorophenyl)(methyl)amino)acrylate (2h): Enamine 1h (113 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀchloroenamine 2h was isolated as a yellow oil (82 mg, 63%); 1H
NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.52–7.36 (m, 1H), 7.36–7.13 (m, 3H), 3.76 (s, 3H),
3.46 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.1, 143.7, 132.2, 130.2, 128.9, 128.8, 127.5, 93.0,
77.4, 77.1, 76.7, 52.2, 44.1; HRMS (ESI) m/z:[M + Na]+ Calcd for C11H11Cl2NO2Na 282.0059,
Found 282.0059.
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(Z)-Methyl 2-chloro-3-((2,4-dimethylphenyl)(methyl)amino)acrylate (2i): Enamine 1i (110 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀchloroenamine 2i was isolated as a yellow solid, (88 mg, 69%
yield); mp 75ꢀ77 oC; 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H), 7.19–6.87 (m, 3H), 3.76 (s, 3H),
3.43 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.5, 144.2, 137.6, 134.7,
131.5, 127.4, 126.7, 91.0, 52.1, 21.0, 17.6; HRMS (ESI) m/z:[M + Na]+ Calcd for C13H16ClNO2Na
276.0762, Found 276.0765.
(Z)-Methyl 2-chloro-3-(methyl(4-nitrophenyl)amino)acrylate (2j): Enamine 1j (118 mg, 0.50
mmol) was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum
ether, 1:5), αꢀchloroenamine 2j was isolated as a yellow solid, (92 mg, 68% yield); mp 118ꢀ121 oC;
1H NMR (400 MHz, CDCl3): δ 7.98 (ddd, J = 8.1, 2.0, 0.8 Hz, 1H), 7.94 (t, J = 2.2 Hz, 1H), 7.88
(s, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.40 (ddd, J = 8.2, 2.4, 0.7 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H);
13C NMR (101 MHz, CDCl3): δ 165.3, 148.8, 147.0, 140.9, 130.0, 125.7, 118.6, 114.5, 100.2, 52.8,
39.4; HRMS (ESI) m/z:[M + Na]+ Calcd for C11H11ClN2O4Na 293.0300, Found 293.0295.
(Z)-Methyl 2-chloro-3-(methyl(naphthalen-1-yl)amino)acrylate (2k): Enamine 1k (121 mg, 0.50
mmol) was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum
1
ether, 1:5), αꢀchloroenamine 2k was isolated as a yellow oil (80 mg, 58% yield); H NMR (400
MHz, CDCl3): δ 7.89 (dt, J = 16.3, 8.5 Hz, 4H), 7.57 (dq, J = 6.7, 5.8 Hz, 2H), 7.48 (t, J = 7.7 Hz,
1H), 7.38 (d, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.66 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.4,
144.8, 134.4, 129.8, 128.6, 128.2, 127.1, 126.6, 125.5, 124.3, 122.6, 92.0, 52.2, 44.5; HRMS (ESI)
m/z:[M + Na]+ Calcd for C15H14ClNO2Na 298.0605, Found 298.0607.
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(Z)-Methyl 2-chloro-3-(ethyl(phenyl)amino)acrylate (2l): Enamine 1l (103 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
αꢀchloroenamine 2l was isolated as a yellow oil (83 mg, 69% yield); 1H NMR (400 MHz, CDCl3):
δ 7.86 (s, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 4.05 (q, J
= 7.1 Hz, 2H), 3.80 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 166.3, 145.2,
142.0, 129.2, 125.5, 123.0, 93.9, 524, 47.3, 14.8; HRMS (ESI) m/z:[M + Na]+ Calcd for
C12H14ClNO2Na 262.0605, Found 262.0609.
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(Z)-Ethyl 2-chloro-3-(methyl(phenyl)amino)acrylate (2m): Enamine 1m (103 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
1:5), αꢀchloroenamine 2m was isolated as a yellow oil (79 mg, 66% yield); 1H NMR (400 MHz,
CDCl3): δ 7.92 (s, 1H), 7.38 (dd, J = 8.3, 7.6 Hz, 2H), 7.19 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 7.7 Hz,
2H), 4.27 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 165.6, 147.0, 142.2, 129.3, 124.7, 120.9, 95.9, 61.3, 39.1, 14.5; HRMS (ESI) m/z:[M + Na]+
Calcd for C12H14ClNO2Na 262.0605, Found 262.0610.
(Z)-Butyl 2-chloro-3-(methyl(phenyl)amino)acrylate (2n): Enamine 1n (117 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
1
1:5), αꢀchloroenamine 2n was isolated as a yellow oil (69 mg, 52% yield); H NMR (400 MHz,
CDCl3): δ 7.91 (s, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H),
4.21 (t, J = 6.7 Hz, 2H), 3.67 (s, 3H), 1.75–1.60 (m, 2H), 1.55–1.36 (m, 2H), 0.97 (t, J = 7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3): δ 165.7, 147.0, 142.1, 129.3, 124.7, 120.8, 96.0, 65.2, 39.0,
30.9, 19.2, 13.8; HRMS (ESI) m/z:[M + Na]+ Calcd for C14H18ClNO2Na 290.0918, Found
290.0921.
(Z)-Methyl 2-chloro-3-(dimethylamino)acrylate (2o):60 Enamine 1o (72 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
αꢀchloroenamine 2o was isolated as a yellow oil (22 mg, 27% yield); 1H NMR (400 MHz, CDCl3):
δ 7.50 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.18 (s, 6H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3): δ 166.2, 145.3, 89.0, 60.7, 42.8, 14.5.
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(Z)-Methyl 3-benzamido-2-chloroacrylate (4a): Enamide 3a (103 mg, 0.50 mmol) was reacted
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according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
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αꢀchloroenamide 4a was isolated as a white solid (84 mg, 70% yield); mp 117ꢀ119 C; 1H NMR
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(400 MHz, CDCl3): δ 8.55 (d, J = 11.7 Hz, 1H), 8.34 (d, J = 11.2 Hz, 1H), 7.91 (d, J = 7.3 Hz,
2H), 7.66 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 3.89 (s, 3H); 13C NMR (101 MHz, CDCl3):
δ 164.0, 163.0, 133.3, 132.0, 131.8, 129.1, 127.6, 106.2, 52.9; HRMS (ESI) m/z:[M + Na]+ Calcd
for C11H10ClNO3Na 262.0241, Found 262.0243.
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(Z)-Methyl 2-chloro-3-(4-methylbenzamido)acrylate (4b): Enamide 3b (110 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
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1:5), αꢀchloroenamide 4b was isolated as a white solid (66 mg, 52% yield); mp 127ꢀ128 C; H
NMR (400 MHz, CDCl3): δ 8.55 (d, J = 11.8 Hz, 1H), 8.31 (d, J = 11.4 Hz, 1H), 7.81 (d, J = 8.2
Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.89 (s, 3H), 2.47 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
163.9, 163.1, 144.3, 132.2, 129.8, 128.9, 127.6, 105.9, 52.9, 21.7; HRMS (ESI) m/z:[M + Na]+
Calcd for C12H12ClNO3Na 276.0398, Found 276.0401.
(Z)-Methyl 2-chloro-3-(4-methoxybenzamido)acrylate (4c): Enamide 3c (118 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
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1:5), αꢀchloroenamide 4c was isolated as a white solid (77 mg, 57% yield); mp 126ꢀ128 C; H
NMR (400 MHz, CDCl3): δ 8.55 (d, J = 11.8 Hz, 1H), 8.27 (d, J = 10.9 Hz, 1H), 7.88 (d, J = 8.8
Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H); 13C NMR (101 MHz, CDCl3): δ
163.7, 163.3, 163.2, 132.3, 129.7, 123.9, 114.3, 105.6, 55.6, 52.8; HRMS (ESI) m/z:[M + Na]+
Calcd for C12H12ClNO4Na 292.0347, Found 292.0349.
(Z)-Methyl 2-chloro-3-(4-chlorobenzamido)acrylate (4d): Enamide 3d (120 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
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αꢀchloroenamide 4d was isolated as a white solid (42 mg, 30% yield); mp 109ꢀ110 C;1H NMR
(400 MHz, CDCl3): δ 8.52 (d, J = 11.7 Hz, 1H), 8.27 (d, J = 10.9 Hz, 1H), 7.85 (d, J = 8.6 Hz,
2H), 7.53 (d, J = 8.6 Hz, 2H), 3.89 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 163.0, 162.9, 139.9,
131.8, 130.2, 129.5, 129.0, 106.7, 53.0; HRMS (ESI) m/z:[M + Na]+ Calcd for C11H9Cl2NO3Na
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295.9857, Found 295.9856.
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(Z)-Methyl 2-chloro-3-(2-chlorobenzamido)acrylate (4e): Enamide 3e (120 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
αꢀchloroenamide 4e was isolated as white solid (32 mg, 23% yield); mp 97ꢀ99 oC; 1H NMR (400
MHz, CDCl3): δ 8.86 (d, J = 10.5 Hz, 1H), 8.53 (d, J = 11.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H),
7.51 (d, J = 4.0 Hz, 2H), 7.48–7.38 (m, 1H), 3.88 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 163.1,
163.0, 133.2, 131.8, 131.6, 131.1, 131.0, 127.6, 107.0, 53.0; HRMS (ESI) m/z:[M + Na]+ Calcd for
C11H9Cl2NO3Na 295.9857, Found 295.9856.
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(Z)-Ethyl 2-chloro-3-(2-iodobenzamido)acrylate (4f): Enamide 3f (173 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
αꢀchloroenamide 4f was isolated as white solid (87 mg, 46% yield); mp 97ꢀ98 oC; 1H NMR (400
MHz, CDCl3): δ 8.48 (d, J = 11.7 Hz, 1H), 8.12 (d, J = 10.9 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H),
7.55 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.23 (td, J = 7.9, 1.7 Hz, 1H), 4.33 (q, J = 7.1 Hz,
2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 165.8, 162.4, 140.7, 139.1, 132.7,
131.0, 129.2, 128.5, 107.7, 92.2, 62.2, 14.3; HRMS (ESI) m/z:[M + Na]+ Calcd for
C12H11ClINO3Na 401.9364, Found 401.9375.
(Z)-Ethyl 3-(2-(benzyloxy)benzamido)-2-chloroacrylate (4g): Enamide 3g (163 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
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1:5), αꢀchloroenamide 4g was isolated as white solid (54 mg, 30% yield); mp 143ꢀ144 C; H
NMR (400 MHz, CDCl3): δ 10.26 (d, J = 11.3 Hz, 1H), 8.52 (d, J = 11.6 Hz, 1H), 8.31 (dd, J =
8.0, 1.7 Hz, 1H), 7.62–7.54 (m, 1H), 7.54–7.47 (m, 2H), 7.47–7.42 (m, 3H), 7.17 (t, J = 7.6 Hz,
2H), 5.26 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3):
δ 163.0, 162.9, 157.5, 134.7, 134.4, 133.3, 132.3, 129.4, 129.2, 129.1, 121.9, 119.3, 112.8, 106.1,
72.0, 61.8, 14.3; HRMS (ESI) m/z:[M + Na]+ Calcd for C19H18ClNO4Na 382.0817, Found
382.0819.
(Z)-Ethyl 2-chloro-3-(3-nitrobenzamido)acrylate (4h): Enamide 3h (132 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
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αꢀchloroenamide 4h was isolated as white solid (106 mg, 71% yield); mp 142ꢀ145 C; H NMR
(400 MHz, CDCl3): δ 8.73 (s, 1H), 8.47 (s, 3H), 8.25 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H),
4.32 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 162.3, 162.1,
148.5, 133.6, 133.3, 131.1, 130.4, 127.6, 122.7, 108.1, 77.4, 77.1, 76.8, 62.4, 14.3; HRMS (ESI)
m/z:[M + Na]+ Calcd for C12H11ClN2O5Na 321.0249, Found 321.0228.
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(Z)-Ethyl 2-chloro-3-(1-naphthamido)acrylate (4i): Enamide 3i (135 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
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αꢀchloroenamide 4i was isolated as white solid (67 mg, 44% yield); mp 93ꢀ96 C; H NMR (400
MHz, CDCl3): δ 8.62 (d, J = 11.5 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 11.6 Hz, 1H),
8.06 (d, J = 8.3 Hz, 1H), 8.01–7.86 (m, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.69–7.58 (m, 2H), 7.55 (dd,
J = 8.0, 7.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3): δ 166.0, 162.6, 133.9, 132.7, 131.6, 131.1, 130.2, 128.7, 128.0, 127.0, 126.1, 124.9, 124.6,
106.8, 62.1, 14.3; HRMS (ESI) m/z:[M + Na]+ Calcd for C16H14ClNO3Na 326.0554, Found
326.0575.
(Z)-Ethyl 2-chloro-3-((E)-3-phenylacrylamido)acrylate (4j): Enamide 3j (116 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
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1:5), αꢀchloroenamide 4j was isolated as white solid (60 mg, 43% yield); mp 82ꢀ84 C; 1H NMR
(400 MHz, CDCl3): δ 8.48 (d, J = 11.9 Hz, 1H), 7.95 (d, J = 11.9 Hz, 1H), 7.86 (d, J = 15.6 Hz,
1H), 7.57 (dd, J = 7.0, 2.2 Hz, 2H), 7.42 (dd, J = 5.1, 1.7 Hz, 3H), 6.62 (d, J = 15.6 Hz, 1H), 3.85
(s, 3H); 13C NMR (101 MHz, CDCl3): δ 163.2, 163.0, 145.9, 133.9, 132.0, 130.9, 129.1, 128.4,
117.9, 105.6, 52.9; HRMS (ESI) m/z:[M + Na]+ Calcd for C13H12ClNO3Na 288.0398, Found
288.0390.
(Z)-Methyl 3-(butoxycarbonylamino)-2-chloroacrylate (4k): Enamide 3k (101 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
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1:5), αꢀchloroenamide 4k was isolated as colorless oil (71 mg, 70% yield); H NMR (400 MHz,
CDCl3): δ 8.11 (d, J = 11.8 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 4.24 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H),
1.81–1.53 (m, 2H), 1.53–1.32 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ
163.1, 152.4, 133.7, 103.5, 66.9, 52.7, 30.7, 18.9, 13.6; HRMS (ESI) m/z:[M + Na]+ Calcd for
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C9H14ClNO4Na 258.0504, Found 258.0508.
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(Z,E)-Methyl 2-bromo-3-((4-methoxyphenyl)(methyl)amino)acrylate (5c): Enamine 1c (111 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀbromoenamine 5c was isolated as a yellow solid, (77 mg, 51%
yield); mp 56ꢀ57 oC; 1H NMR (400 MHz, CDCl3) (Z:E=7:3): δ 8.07 /7.81 (s, 1H), 7.09 (d, J = 8.9
Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.62/3.61 (s, 3H); 13C NMR
(Zꢀisomer) (101 MHz, CDCl3): δ 166.3, 157.5, 146.0, 143.1, 139.8, 124.3, 114.3, 80.7, 77.4, 77.1,
76.7, 55.5, 52.5, 41.7; HRMS (ESI) m/z:[M + Na]+ Calcd for C12H14BrNO3Na 322.0049, Found
322.0049.
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(Z)-Methyl 2-bromo-3-((4-fluorophenyl)(methyl)amino)acrylate (5d): Enamine 1d (105 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀbromoenamine 5d was isolated as a yellow solid, (85 mg, 59%
yield); mp 49ꢀ50 oC; 1H NMR (400 MHz, CDCl3): δ 8.07 (s, 1H), 7.10 (m, 4H), 3.78 (s, 3H), 3.61
(s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.0, 160.3 (d, JCF = 245.5 Hz), 145.5, 142.5 (d, JCF
=
2.8 Hz), 124.3 (d, JCF = 8.3 Hz), 116.0 (d, JCF = 22.8 Hz), 82.4, 52.7, 41.5; HRMS (ESI) m/z:[M +
Na]+ Calcd for C11H11BrFNO2Na 309.9849, Found 309.9854.
(Z)-Methyl 2-bromo-3-((2-methoxyphenyl)(methyl)amino)acrylate (5g): Enamine 1g (111 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀbromoenamine 5g was isolated as a yellow oil (87 mg, 58%
yield); 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.29 (ddd, J = 7.9, 6.1, 1.6 Hz, 1H), 7.16 (dd,
J = 7.6, 1.5 Hz, 1H), 6.95 (m, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.46 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 166.4, 155.0, 147.0, 128.7, 128.1, 120.6, 111.8, 78.9, 55.7, 52.3, 44.3; HRMS (ESI)
m/z:[M + Na]+ Calcd for C12H14BrNO3Na 322.0049, Found 322.0053.
(Z)-Methyl 2-bromo-3-((2,4-dimethylphenyl)(methyl)amino)acrylate (5i): Enamine 1i (110 mg,
0.50 mmol) was reacted according to the general procedure. After preparative TLC
(EtOAc:petroleum ether, 1:5), αꢀbromoenamine 5i was isolated as a yellow solid, (75 mg, 50%
yield); mp 68ꢀ70 oC; 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1H), 7.03 (m, 3H), 3.75 (s, 3H), 3.41
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(s, 3H), 2.34 (s, 3H), 2.19 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 166.4, 146.6, 137.8, 135.1,
131.4, 127.4, 127.1, 78.2, 52.3, 21.1, 17.7; HRMS (ESI) m/z:[M + Na]+ Calcd for C13H16BrNO2Na
320.0257, Found 320.0257.
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(Z)-Methyl 2-bromo-3-(ethyl(phenyl)amino)acrylate (5l): Enamine 1l (103 mg, 0.50 mmol) was
reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether, 1:5),
αꢀbromoenamine 5l was isolated as a yellow oil (82 mg, 58% yield); 1H NMR (400 MHz, CDCl3):
δ 8.12 (s, 1H), 7.37 (td, J = 7.6, 1.9 Hz, 2H), 7.23 (dd, J = 10.6, 4.2 Hz, 1H), 7.15 (dd, J = 8.4, 1.0
Hz, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3): δ 166.2, 144.9, 144.8, 129.2, 125.8, 123.9, 81.7, 52.6, 48.0, 14.7; HRMS (ESI) m/z:[M +
Na]+ Calcd for C12H14BrNO2Na 306.0100, Found 306.0107.
(Z)-Ethyl 2-bromo-3-(methyl(phenyl)amino)acrylate (5m): Enamine 1m (103 mg, 0.50 mmol)
was reacted according to the general procedure. After preparative TLC (EtOAc:petroleum ether,
1:5), αꢀbromoenamine 5m was isolated as a yellow oil (97 mg, 68% yield); 1H NMR (400 MHz,
CDCl3): δ 8.18 (s, 1H), 7.38 (m, 2H), 7.19 (t, J=7.4, 1H), 7.17–7.11 (m, 2H), 4.26 (q, J = 7.1 Hz,
2H), 3.67 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 165.5, 146.8, 145.1,
129.3, 124.9, 121.4, 83.9, 61.5, 39.7, 14.5; HRMS (ESI) m/z:[M + Na]+ Calcd for C12H14BrNO2Na
306.0100, Found 306.0104.
Preparation of Ethyl 2-chloro-3-(methyl(phenyl)amino)propionate (9)
To a solution of 2m (0.5 mmol, 120 mg) in HOAc (2 mL) was added NaBH4 (1.5 mmol, 57 mg)
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portion wisely at 15 C. Then the mixture was stirred at room temperature for 2 h (monitored by
TLC). After completion, the reaction mixture was quenched with ice water (5 mL), neutralized
with saturated NaHCO3 (aq) and extracted with DCM (2×5 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated under vacuum to yield pure 9 as a
yellow oil (115 mg, 95%); 1H NMR (400 MHz, CDCl3): δ 7.35–7.25 (m, 2H), 6.96–6.69 (m, 3H),
4.53 (dd, J = 8.0, 6.2 Hz, 1H), 4.29–4.16 (m, 2H), 4.06 (dd, J = 15.1, 8.0 Hz, 1H), 3.77 (dd, J =
15.1, 6.1 Hz, 1H), 3.06 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 169.1,
148.0, 129.4, 117.5, 112.3, 62.3, 56.8, 53.3, 39.4, 14.0; HRMS (ESI) m/z:[M + H]+ Calcd for
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C12H17ClNO2 242.0942, Found 242.0943.
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Preparation of Ethyl 2-(4-isopropyl)phenylthio-3-(methyl(phenyl)amino)propionate (10)
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Ethyl 2ꢀchloroꢀ3ꢀ(methyl(phenyl)amino)propionate (9, 0.48 mmol, 115 mg) was dissolved in
CH3CN (2 mL), to which were added 4ꢀisopropylphenylthiol (1.16 mmol, 176 mg) and NaHCO3
(2.88 mmol, 242 mg). Then the mixture was stirred at room temperature overnight (monitored by
TLC). After completion, the reaction mixture was concentrated under vacuum. The residue was
purified by preparative TLC (EtOAc:petroleum ether, 1:25) to yield 10 as a colorless oil (142 mg,
83%); 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.2 Hz, 2H), 7.23 (dt, J = 7.3, 3.9 Hz, 4H), 6.75
(t, J = 7.3 Hz, 1H), 6.64 (d, J = 8.1 Hz, 2H), 4.18–4.06 (m, 2H), 3.97–3.82 (m, 2H), 3.74 (dd, J =
14.4, 4.2 Hz, 1H), 3.02–2.82 (m, 4H), 1.29 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3): δ 171.6, 149.6, 148.4, 134.1, 129.2, 127.3, 116.9, 112.3, 61.4, 54.9, 48.9, 39.1,
33.9, 23.91, 23.89, 14.0; HRMS (ESI) m/z:[M + Na]+ Calcd for C21H27NO2SNa 380.1655, Found
380.1658.
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Preparation of Ethyl 2-azido-3-(methyl(phenyl)amino)propionate (11)
To a solution of 5m (0.5 mmol, 142 mg) in HOAc (2 mL) was added NaBH4 (1.5 mmol, 57 mg)
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portion wisely at 15 C. Then the mixture was stirred at room temperature for 2 h (monitored by
TLC). After completion, the reaction mixture was quenched with ice water (5 mL), neutralized
with saturated NaHCO3 (aq) and extracted with DCM (2×5 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was
dissolved in CH3CN (2 mL), to which was added NaN3 (1.0 mmol, 65 mg). Then the mixture was
stirred at room temperature overnight (monitored by TLC). After completion, the reaction mixture
was concentrated under vacuum. The residue was purified by preparative TLC (EtOAc:petroleum
ether, 1:30) to yield 11 as a colorless oil (92 mg, 74%); 1H NMR (400 MHz, CDCl3): δ 7.34–7.26
(m, 2H), 6.88–6.74 (m, 3H), 4.40–4.17 (m, 2H), 3.98 (dd, J = 15.2, 4.8 Hz, 1H), 3.58 (dd, J = 15.2,
8.2 Hz, 1H), 3.07 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 169.3, 148.1,
129.4, 117.4, 112.4, 62.1, 60.4, 54.4, 39.4, 14.2; HRMS (ESI) m/z:[M + H]+ Calcd for C12H17N4O2
249.1346, Found 249.1349.
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Acknowledgment
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Dedicated to Prof. Jun Zhou on the occasion of his 83rd birthday.
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Supporting Information
Copies of 1H NMR, 13C NMR spectra and NOE spectrum for 2i. XꢀRay crystallographic analysis
for 4b. This material is available free of charge via the Internet at http: //pubs.acs.org.
Author Information
Corresponding Author
*Fax: (+86) 2227403475. Eꢀmail: lichunbao@tju.edu.cn
Notes
The authors declare no competing financial interest.
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