Iodine-Catalyzed Decarboxylative Amidation of β,γ-Unsaturated Carboxylic Acids with Chloramine Salts Leading to Allylic Amides

Article abstract of DOI:10.1002/chem.201503298

The iodine-catalyzed decarboxylative amidation of β,γ-unsaturated carboxylic acids with chloramine salts is described. This method enables the regioselective synthesis of allylic amides from various types of β,γ-unsaturated carboxylic acids containing sub

Full text of DOI:10.1002/chem.201503298

DOI: 10.1002/chem.201503298
Communication
&
Synthetic Methods
Iodine-Catalyzed Decarboxylative Amidation of b,g-Unsaturated
Carboxylic Acids with Chloramine Salts Leading to Allylic Amides
Kensuke Kiyokawa, Takumi Kojima, Yusuke Hishikawa, and Satoshi Minakata*[a]
rated carboxylic acids with imide ligands, affording allylic
Abstract: The iodine-catalyzed decarboxylative amidation
imides.[9] However, the substrate scope and regioselectivity
of b,g-unsaturated carboxylic acids with chloramine salts
was not ideal. Concurrently, our group continued to investi-
is described. This method enables the regioselective syn-
gate oxidative amination reactions, in particular aziridination of
thesis of allylic amides from various types of b,g-unsaturat-
alkenes, using inexpensive and readily available chloramine
ed carboxylic acids containing substituents at the a- and
salts in the presence of I2 as the catalyst.[10,11] In the system, N-
b-positions. In the reaction, N-iodo-N-chloroamides, gener-
iodo-N-chloroamide is generated in situ by the reaction of
ated by the reaction of a chloramine salt with I2, function
a chloramine salt with I2 and then activates a carbon–carbon
as a key active species. The reaction provides an attractive
double bond in the substrate through the formation of
alternative to existing methods for the synthesis of useful
a three-membered iodonium intermediate. As part of our on-
secondary allylic amine derivatives.
going research efforts in iodine-catalyzed oxidative amination
reactions, we herein report on the iodine-catalyzed decarboxy-
lative amidation of b,g-unsaturated carboxylic acids with chlor-
Allylic amines are a versatile building block for the synthesis of
nitrogen-containing organic molecules. Therefore, great efforts
have been devoted to the development of new synthetic
methodologies for their preparation in the past few decades.
The coupling of amine derivatives with an allylic component
represents the most straightforward approach for the synthesis
of allylic amines. In these reactions, the classical method in-
volves the nucleophilic substitution of an allylic halide by a ni-
trogen nucleophile.[1a,b] Although this approach is efficient and
reliable, it remains limited by a narrow substrate scope, owing
to difficulties associated with the regioselective synthesis of al-
lylic halides. In recent years, transition metal-catalyzed allylic
substitution of allylic alcohols or their derivatives with nitrogen
nucleophiles has emerged as a broadly applicable method and
has also been extended to the asymmetric synthesis of allylic
amines.[1,2] Most recently, the intra- and intermolecular oxida-
tive allylic CÀH aminations of alkenes under transition-metal-
catalyzed[3,4] or metal-free[5] conditions have been reported as
a novel method to enable direct allylic amination. Although
these elegant methods appear to be general and efficient, new
synthetic strategies, especially under mild and environmentally
benign conditions, are still desirable.[6] In this context, we envi-
sioned that b,g-unsaturated carboxylic acids[7] could be utilized
as a new class of efficient allylating reagents for the synthesis
of allylic amines under oxidative conditions, that is, by decar-
boxylative amination.[8]
amine salts that function as a nitrogen source as well as an ox-
idant (Scheme 1). The method was found to be applicable to
Scheme 1. Decarboxylative amidation of b,g-unsaturated carboxylic acids.
various types of b,g-unsaturated carboxylic acids containing
substituents at the a- and b-positions to afford synthetically
useful secondary allylic amides in a regioselective manner. It is
noteworthy that the regioselective synthesis of allylic amides
containing a tetrasubstituted alkene moiety, which are difficult
to access by conventional protocols, was also achieved.
Our investigation began with the decarboxylative amidation
of 3-phenylbut-3-enoic acid (1a) as a model substrate with
1.5 equivalents
of
N-chloro-N-sodio-p-toluenesulfonamide
(chloramine-T) in the presence of a catalytic amount of I2
(Table 1). On the basis of our previous work on chloramine-T/I2
systems,[10] the reaction was first conducted in MeCN for 2 h at
room temperature, and the allylic amide 2a was produced in
53% yield.[12] Although reactions in other common organic sol-
vents, such as toluene, diethyl ether, dimethoxyethane (DME),
and dimethylsulfoxide (DMSO), failed to improve the product
yield of 2a (Table 1, entries 2–5), the use of several polar sol-
vents including N-methylpyrrolidone (NMP), N,N-dimethylace-
toamide (DMA), and N,N-dimethylformamide (DMF) resulted in
increased yields of up to 82% (Table 1, entries 6–8). Finally,
DMF was identified as the best solvent for this transformation,
providing a high yield with high reproducibility (Table 1,
Recently, our group reported on the use of hypervalent
iodine reagents in the decarboxylative imidation of b,g-unsatu-
[a] Dr. K. Kiyokawa, T. Kojima, Y. Hishikawa, Prof. Dr. S. Minakata
Department of Applied Chemistry, Graduate School of Engineering
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871 (Japan)
E-mail: minakata@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503298.
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Table 1. Solvent screening.[a]
Entry
Solvent
Yield[b] [%]
1
2
3
MeCN
Toluene
Et2O
53
7
6
4
5
6
7
8
9[c]
DME
DMSO
NMP
DMA
DMF
DMF
17
34
82
79
82 (78)
55
[a] Reaction conditions: 1a (0.25 mmol), chloramine-T (0.375 mmol), sol-
vent (2 mL), RT, 2 h. [b] Determined by 1H NMR analysis of the crude prod-
uct using 1,1,2,2-tetrachloroethane as an internal standard. The value in
parenthesis is the yield of isolated product. [c] Chloramine-T (1 equiv)
was used. Ts =p-toluenesulfonyl; DME=dimethoxyethane; DMSO=dime-
thylsulfoxide; NMP=N-methylpyrrolidone; DMA=N,N-dimethylacetoa-
mide; DMF=N,N-dimethylformamide.
entry 8). Decreasing the amount of chloramine-T from 1.5 to
1 equivalent resulted in a lower yield of 2a (Table 1, entry 9).
With the optimized conditions in hand, we next investigated
the decarboxylative amidation of various b-substituted b,g-un-
saturated carboxylic acids 1 (Scheme 2). Substrates with elec-
tron-rich aryl substituents at the b-position effectively provided
the amides 2b–d at room temperature without the formation
of any overoxidation product. However, in cases with substitu-
ents at the meta or ortho position on the phenyl ring, it was
necessary to heat the reaction mixture to achieve satisfactory
yields (2e and 2 f). Halogen substituents, fluoro (2g), chloro
(2h), and bromo (2i) groups, were well tolerated. A highly
electron-deficient substrate with a trifluoromethyl group also
underwent decarboxylative amidation in good yield at 508C
(2j). Other b-aromatic substrates, including naphthyl (2k),
phenanthryl (2l), and thienyl (2m) groups, were efficiently con-
verted into the corresponding amides. In addition, the amida-
tion could also be expanded to substrates that contained b-ali-
phatic substituents. In those reactions, it is noteworthy that al-
lylic amides containing a terminal alkene moiety (2n and 2o)
were produced selectively, where neither the internal alkene
isomer nor the oxidation product of benzylic and allylic CÀH
bonds was observed. A b-unsubstituted substrate, but-3-enoic
acid, also underwent decarboxylative amidation to provide 2p,
albeit in low yield. Consequently, this decarboxylative amida-
tion approach was proven to be useful for the synthesis of al-
lylic amides with a substituent at the b-position.
Scheme 2. Scope of b-substituted b,g-unsaturated carboxylic acids. Unless
otherwise noted, the following reaction conditions were employed:
1 (0.25 mmol), chloramine-T (0.375 mmol), DMF (2 mL), RT, 2 h. Yields are for
the isolated product. [a] The reaction was conducted at 508C. [b] The reac-
tion was conducted at 1208C for 6 h. Yield was determined by H NMR anal-
ysis of the crude product.
1
Scheme 3. Deuterium-labeling experiment for the decarboxylative amida-
tion.
Encouraged by the results described in Scheme 3, we exam-
ined the reaction of acids with a-substituents for the regiose-
lective synthesis of allylic amides that contain tri- and tetrasub-
stituted alkene moieties, which are difficult to prepare in iso-
merically pure form by conventional methods (Scheme 4).
As expected, the decarboxylative amidation of a-methylated
1q proceeded with complete selectivity at the g-position, af-
fording the product 2r (E/Z=8:92) in high yield.[13] The bulkier
isopropyl substituent at the a-position resulted in a decreased
yield of 2s as well as a decrease in E/Z selectivity. Acids with
a,a-dimethyl substituents also underwent decarboxylative ami-
dation selectively to give the corresponding products that con-
tained a tetrasubstituted alkene moiety (2t–x). Moreover, the
In an attempt to confirm the site of incorporation of the
amide group (a- vs. g-position), the reaction of the a-mono-
deuterated carboxylic acid [D]-1a was examined. Under the
standard conditions, the reaction predominantly afforded [D]-
g-2a, which contained a deuterium atom at the vinylic posi-
tion, over the a-product [D]-a-2a (g/a=98:2; Scheme 3). This
result clearly indicates that the amidation proceeds selectively
at the g-position.
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Scheme 6. Reactions using various chloramine salts. Unless otherwise noted,
the following reaction conditions were employed: 1 (0.25 mmol), chloramine
salts (0.375 mmol), Na2CO3 (0.25 mmol), DMF (2 mL), RT, 2 h. Yields are for
the isolated product. [a] Na2CO3 was not added. The reaction was conducted
for 4 h. Ms=methanesulfonyl, Ns=nitrobenzenesulfonyl, Boc=tert-butoxy-
carbonyl, Cbz=carboxybenzyl.
indicating the in situ formation of an equilibrium mixture of
the sodium salt 8 (Scheme 7a).[15] In addition, the reaction was
run using a mixture of chloramine-T and 1a in the presence of
10 mol% of I2 in [D7]DMF and was monitored by NMR spec-
Scheme 4. Scope of b,g-unsaturated carboxylic acids with a- and b-substitu-
ents. Unless otherwise noted, the following reaction conditions were em-
ployed: 1 (0.25 mmol), chloramine-T (0.375 mmol), DMF (2 mL), 508C, 2 h.
Yields are for the isolated product. [a] Determined by H NMR analysis of the
crude product. [b] The reaction was conducted for 12 h.
1
1
troscopy. In the H NMR spectra of the mixture, characteristic
signals, indicating the generation of amide 2a as well as the al-
lylic chloride 2a’ and iodide 2a“, were observed immediate-
ly.[16] The reaction then reached completion within 1 h to
afford the amide 2a and the allylic chloride 2a’, whereas the
signals indicating allylic iodide 2a” disappeared. Indeed, when
(3-iodoprop-1-en-2-yl)benzene (2a“), which was separately pre-
pared, was treated with chloramine-T in DMF, the allylic amide
2a was produced in high yield.[16] These results strongly sug-
gest that an allylic iodide could be an intermediate in this reac-
tion. Based on the experimental results, the proposed catalytic
cycle is shown in Scheme 7b. Initially, chloramine-T reacts with
allylic amide 2y, containing an exocyclic double bond, could
be synthesized in high yield using this protocol. However, the
reaction of 1z, which has a methyl group at the g-position, re-
sulted in the generation of a mixture of regioisomers, g-2z and
a-2z (g/a=80:20; Scheme 5).[14]
Scheme 5. Reaction using a g-substituted substrate.
Other types of chloramine salts were employed in the decar-
boxylative amidation (Scheme 6). Instead of chloramine-T, N-
chloro-N-sodio-methanesulfonamide (chloramine-Ms) was also
applicable and gave the corresponding amide 3 in moderate
yield. Chloramine salts with a nitrobenzenesulfonyl group (Ns)
were also suitable nitrogen sources affording products 4 and 5
in acceptable yields in the presence of Na2CO3 as a base. In ad-
dition, carbamate-protected chloramine salts such as chlora-
mine-Boc and -Cbz could also participate in the decarboxyla-
tive amidation to provide 6 and 7, respectively, but the latter
was produced in low yield.
To obtain further insight into the reaction mechanism, we
conducted several additional experiments. When a reaction
mixture of 1a and chloramine-T in [D7]DMF was monitored by
1H NMR spectroscopy, the signal of the acidic OH disappeared
and the proton signals of 1a underwent a slight upfield shift,
Scheme 7. Plausible reaction mechanism.
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product 2 by its smooth conversion to more synthetically
useful compounds (Scheme 8). For example, the reaction of 2a
Scheme 8. Alkylation of product 2a.
with allyl bromide and 4-bromobut-1-ene afforded the corre-
sponding products 12a and 12b, respectively, which are im-
portant precursors for the synthesis of chiral nitrogen-contain-
ing heterocycles by ring-closing metathesis followed by asym-
metric hydrogenation.[18] Moreover, the enyne 12c was also
synthesized by the reaction using propargyl bromide.[19]
In conclusion, we have reported the development of the
iodine-catalyzed decarboxylative amidation of b,g-unsaturated
carboxylic acids with chloramine salts. The reaction enables
the efficient and selective synthesis of various secondary allylic
amides. Considering the low cost and the availability of iodine
and chloramine salts, this metal-free approach represents
a highly economical and environmentally benign procedure.
Further investigations focused on expanding the scope of this
method are currently in progress.
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Re-
search (Nos. 25288047 and 26105735) from the Ministry of
Education, Culture, Sports, Science, and Technology (MEXT),
Japan.
Keywords: amines
·
amidation
·
chloramine salt
·
decarboxylation · iodine
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Received: August 20, 2015
Published online on September 10, 2015
Chem. Eur. J. 2015, 21, 15548 – 15552
www.chemeurj.org
15552
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