Additive-free decarboxylative coupling of cinnamic acid derivatives in water: Synthesis of allyl amines

Article abstract of DOI:10.1021/acs.orglett.5b00303

The first example of an additive-free decarboxylative coupling of cinnamic acid derivatives with formaldehyde and amines to afford the corresponding allyl amines is reported. This reaction is highly environmentally friendly because it was conducted in H₂O and without any additives, releasing only CO₂ and H₂O as byproducts. This reaction showed a broad substrate scope including cyclic and acyclic amines and high functional group tolerance. Moreover, phenyl dienoic acid participated in this type of decarboxylative coupling reaction.

Full text of DOI:10.1021/acs.orglett.5b00303

Letter
pubs.acs.org/OrgLett
Additive-Free Decarboxylative Coupling of Cinnamic Acid
Derivatives in Water: Synthesis of Allyl Amines
Kyungho Park and Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju 500-757, Republic of Korea
S
* Supporting Information
ABSTRACT: The first example of an additive-free decarbox-
ylative coupling of cinnamic acid derivatives with form-
aldehyde and amines to afford the corresponding allyl amines
is reported. This reaction is highly environmentally friendly
because it was conducted in H2O and without any additives,
releasing only CO2 and H2O as byproducts. This reaction
showed a broad substrate scope including cyclic and acyclic
amines and high functional group tolerance. Moreover, phenyl dienoic acid participated in this type of decarboxylative coupling
reaction.
evelopment of an environmentally friendly synthetic
D
method has received much attention in the pharmaceutical
and chemical industries because it is ultimately cost-effective.1
Although a number of green processes have been developed, the
disposal of solvent and contaminated water derived from workup
processes is still of significant concern.2 One ideal solution
involves developing a reaction that conducts in water-based
solvent and releases nontoxic waste.3 Water is the most
inexpensive, nonflammable, and nontoxic solvent.4 To reduce
waste, no additive reaction conditions are required.5 To meet this
demand, we report an extremely green and simple method for the
synthesis of allyl amines in water and additive-free conditions.
Allyl amine is one of the most important scaffolds in
pharmaceutical and natural products.6 For example, Naftifine,7
Cinnarizine,8 Triprolidine,9 and Abamine10 containing this
scaffold are used as antifungal, antihistamine, and calcium
channel blocker drugs (Figure 1). In addition, it is a preferable
Figure 2. Synthesis of allyl amines.
requirement of harsh conditions and low functional group
tolerance. To solve these problems, transition metals such as Pd-,
Ir-, Pt-, and Rh-catalyzed allyl aminations have been developed
(Figure 2b).16 Recently, coupling reaction by C−H activation
was also employed to construct ally amines.17 Although these
methods afforded an efficient synthetic tool under mild
conditions, they all need a metal catalyst. As metal-free
conditions, nucleophilic additions of vinyl boronic acid or
electrophilic substitution of vinyl silane to imine or iminium were
developed (Figure 2c).18 However, these methods still need
expensive vinyl boronic acid or silane as an alkene source. As a
part of our ongoing effort in decarboxylative coupling,5d,19 we
found that allyl amines were formed from the reaction with
cinnamic acid derivatives, formaldehyde, and amines in the
absence of any additives. This finding would address all previous
Figure 1. Bioactive compounds having allyl amine structure.
platform for the preparation of nitrogen containing molecules by
the isomerization to vinyl amines,11 intramolecular olefin cross-
metathesis to form N-heterocyclic compounds,12 and reduc-
tion13 or oxidation.14
A number of preparation methods of allyl amines has been
reported. As classical methods, the nucleophilic substitution of
allyl alcohol or halides with amines have been widely used
(Figure 2a).6,15 However, they have some drawbacks such as the
Received: January 30, 2015
Published: February 23, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00303
Org. Lett. 2015, 17, 1300−1303

Organic Letters
Letter
issues. Our reaction method has several advantages. Cinnamic
acid derivatives are an abundant and stable source of alkene. In
addition, they released only environmentally nontoxic CO2 after
completing reaction.20 Neither metal catalyst nor any additives
are needed. Moreover, this reaction proceeded in H2O. This is
the first report of metal-free decarboxylative coupling of sp2
carbon to construct carbon−carbon bonds.
To optimize additive-free conditions, cinnamic acid (1a) was
allowed to react with paraformaldehyde and morpholine (2a)
under a variety of solvent. As shown in Table 1, most organic
Table 2. Decarboxylative Coupling of 4-Methoxycinnamic
Acid with Formaldehyde and a Variety of Amines
a
Table 1. Decarboxylative Coupling of 4-Methoxy-cinnamic
a
Acid with Formaldehyde and a Variety of Amines
b
entry
1
R
solvent
temp (°C) product
yield (%)
c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1c
H
MeCN
DMF
DMSO
EtOH
H2O
80
3aa
3aa
3aa
3aa
3aa
3ba
3ca
3ca
0(96)
c
H
100
100
80
0(97)
c
H
0(97)
c
d
H
0(83) (11)
c
H
100
100
100
120
10(81)
c
Me
OMe
OMe
H2O
35(61)
c
H2O
86(13)
e
c
H2O
86(13)
a
Reaction conditions: 1 (0.36 mmol), (CH2O)n (0.36 mmol), and 2a
b
(0.3 mmol) were reacted in solvent (1.0 mL) at 100 °C for 12 h. GC
yields. Yields of the cinnamic acid derivatives recovered after reaction
complete. Yield of ethyl cinnamate. The reaction at the sealed tube
c
d
e
reactor.
solvents did not give the desired product (entries 1−4). Under
EtOH solvent, ethyl cinnamate was formed with 11% yield
without any formation of allyl amine 3aa (entry 4). Replace of
water as solvent afforded the allyl amine product 3aa with 10%
yield (entry 5). Reaction with 4-methylcinnamic acid (1b)
provided the corresponding product 3ba with 35% yield (entry
6). Surprisingly, 4-methoxycinnamic acid (1c) afforded the
corresponding allyl amine 3ca with 86% yield (entry 7). When
the reaction was carried out at 120 °C, the yield was 86% (entry
8)
To evaluate this metal-free coupling reaction in water, the
coupling reactions of 1c and formaldehyde with diverse amines
were investigated (Table 2). Cyclic amines such as morpholine
(2a), thiomorpholine (2b), 1,4-dioxa-8-azaspiro[4.5]decane
(2c), piperidine (2d), pyrrolidine (2e), and azepane (2f)
afforded the corresponding allyl amines in 53−86% yields
(entries 1−6). The reaction with 1-phenylpiperazine (2g)
afforded the corresponding product in poor yield (entry 7).
However, 1-acetylpiperazine (2h) and 1-formylpiperazine (2i)
resulted in good yields (entries 8 and 9). The reactions of acyclic
diamines such as N,N-diethyl and N,N-dipropyl amines also
afforded the corresponding products in 63% and 64% yields,
respectively (entries 10 and 11). However, N,N-dibutyl and N,N-
allyl amines resulted in slightly low yields (entries 12 and 13).
When 2l was reacted in the presence of phase transfer catalyst,
the yield was increased to 53% (entry 12). The reactions of N-
benzylmethylamine (2n) and 2-benzylaminoethanol (2o)
afforded the corresponding products in good yields (entries 14
and 15). In particular, 2o with an aliphatic hydroxyl group gave
a
Reaction conditions: 1c (3.6 mmol), (CH2O)n (3.6 mmol), and
amines (3.0 mmol) were reacted in H2O (10.0 mL) at 100 °C for 12 h.
b
c
Isolated yield. GC yield of the reaction using octadecyl
trimethylammonium chloride (0.3 wt % of H2O) as a PTC.
the desired product in good yield. No desired products were
formed when primary amines such as cyclohexylamine or aniline
were employed.
To expand the substrate scope of the reaction, diverse
cinnamic acid derivatives with electron-donating substituents
were employed in the coupling reaction with formaldehyde and
amines (Figure 3). The coupling reactions of trimethoxy-
substituted cinnamic acids 1e and 1f with formaldehyde and
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Letter
Figure 4. Stereochemistry of the decarboxylative coupling of (Z)-
cinnamic acid derivatives. Reaction conditions: (Z)-1 (3.6 mmol),
(CH2O)n (3.6 mmol), and 2 (3.0 mmol) were reacted in H2O (10.0 mL)
1
at 100 °C for 12 h. The ratio of (Z)-3/(E)-3 was determined by H
NMR.
Figure 3. Decarboxylative coupling of substituted cinnamic acids with
formaldehyde and amines. Reaction conditions: 1 (3.6 mmol), (CH2O)n
(3.6 mmol), and 2 (3.0 mmol) were reacted in H2O (10.0 mL) at 100 °C
for 12 h. (a) Reaction time is 3 h. (b) Yield of (E)-isomer.
amines such as 2a, 2h, and 2m afforded the corresponding allyl
amines 3ea, 3eh, and 3fm in 84%, 78%, and 51% yields,
respectively. Cinnamic acids with ethoxy, isopropoxy, and
allyloxy groups in the para position afforded the corresponding
products in good yields; however, propynyloxy and thiomethoxy
groups resulted in slightly lower yields. Caffeic acid derivatives
with alkoxy, alcohol, and cyano groups afforded the correspond-
ing allyl amines 3ld, 3md, and 3nd in 72%, 72%, and 70% yields,
respectively. The reaction of 4-dimethylamino cinnamic acid
(1o) for 3 h afforded the corresponding product in 82% yield.
However, 3-(2-furan-2-yl)acrylic acid resulted in 36% yield. In
contrast, 3,3-disubstituted acrylic acid 1q afforded the corre-
sponding allyl amine in 89% yield. The stereochemistry of
cinnamic acids was retained in the reactions. (E)-Cinnamic acids
afforded the corresponding (E)-allyl amines without the
formation of (Z)-isomers. The coupling of (Z)-phenylthioacrylic
acid with formaldehyde and amines such as 2h and 2p afforded
the corresponding stereo-retention products 3rh and 3rp,
respectively, as the major products with small amounts of (E)-
isomers.
To investigate the stereochemistry of this coupling reaction,
(Z)-cinnamic acid derivatives such as 1c and 1d were selected as
the coupling substrates and reacted with formaldehyde and
amines. As shown in Figure 4, the major stereochemistry of the
product was (Z) with high ratios (Z/E = 6.7:1−16.7:1). The
coupling reactions with (Z)-4-methoxycinnamic acid and amines
such as 2a, 2h, and 2n resulted in higher yields than those with
(Z)-2-methoxycinnamic acid, which is sterically demanding.
However, (Z)-2-methoxycinnamic acid afforded higher stereo-
selectivity.
Figure 5. Decarboxylative coupling of phenyl dienoic acid with
formaldehyde and amines. Reaction conditions: 4 (3.6 mmol),
(CH2O)n (3.6 mmol), and 2 (3.0 mmol) were reacted in H2O (10.0
mL) at 100 °C for 12 h.
piperazines resulted in slightly lower yields. Notably, all the
products contained 2−3% of stereoisomeric products.
The effect of electronic substituents on reaction intermediates
was evaluated using the Hammett equation (see Supporting
Information).21 The initial rate constants of the reaction with
different sets of para-substituted cinnamic acids were correlated
using the σp+ values of each substituent, p-NMe2, p-OEt, p-OMe,
p-SMe, and p-Me, in cinnamic acid. A linear relationship with a
negative slope of 1.64 was observed by plotting the rate constants
of each reaction, indicating that the rate-determining transition
state is more stabilized by electron-donating substituents.
On the basis of the results of the Hammett equation and the
retention of stereochemistry of the double bond, we propose a
reaction pathway,8 22 as shown in Figure 6. (1) Addition of the
b,
iminium ion, which is generated by the condensation of
paraformaldehyde and amines, to the C−C double bond of
cinnamate affords a benzyl carbocation. (2) The carboxylic
carbon lies in the same plane as the adjacent vacant p-orbital. (3)
The subsequent facile decarboxylation leads to C−C double
bond formation and affords the allyl amine as the expected
stereospecific product. However, we do not rule out the
possibility of forming a lactone as an intermediate in the
proposed mechanism.23
In summary, a new and simple method for the synthesis of allyl
amines was developed by the decarboxylative three-component
reaction of cinnamic acids, formaldehyde, and amines. Most
importantly, this method is environmentally friendly. This
decarboxylative coupling reaction proceeds in water without
Interestingly, phenyl dienoic acid 4, which has an additional
double bond in the cinnamic acid unit, participated in the
decarboxylative coupling reaction with formaldehyde and
amines, even though it does not have any substituent at the
phenyl group (Figure 5). The coupling reactions of 4 with
morpholine, thiomorpholine, and N-methyl-N-benzylamine
afforded the corresponding products in 63%, 55%, and 48%
yield, respectively. The coupling reactions with piperidine and
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Letter
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ASSOCIATED CONTENT
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Hammett correlation; general methods and experimental
procedures; and NMR spectra. This material is available free of
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AUTHOR INFORMATION
Corresponding Author
■
(17) (a) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2012, 14,
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*E-mail: sunwoo@chonnam.ac.kr.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(19) Lim, J.; Park, K.; Byeun, A.; Lee, S. Tetrahedron Lett. 2014, 55,
4875−4878.
This research was supported by the Nano.Material Technology
Development Program (2012M3A7B4049655) and Basic
Science Research Program (2014R1A2A1A11050018) through
the National Research Foundation of Korea (NRF), funded by
the Ministry of Education, Science and Technology, ICT, and
Future Planning. Spectral data were obtained from the Korea
Basic Science Institute, Gwangju branch.
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rich cinnamic acids have been reported. See (a) Yamashita, M.; Hirano,
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