Synthesis of aryl-(E)-2-(azidomethyl)alkenoate and aryl-(Z)-2-(azidomethyl)acrylonitrile from aryl aldehydes and activated alkenes via one-pot way

Full text of DOI:10.1002/bkcs.10751

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DOI: 10.1002/bkcs.10751
BULLETIN OF THE
S.-J. Lee et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Aryl-(E)-2-(azidomethyl)alkenoate and Aryl-(Z)-2-
(azidomethyl)acrylonitrile from Aryl Aldehydes and Activated
Alkenes via One-Pot Way
*
Sang-Jin Lee, Hae-Won Yang, Tae-Hwi Han, and Cheol Min Yoon
Department of Advanced Material Chemistry, Korea University, Sejong-si, 339-770, South Korea.
*E-mail: cmyoon@korea.ac.kr
Received September 4, 2015, Accepted February 12, 2016, Published online April 27, 2016
Keywords: Baylis–Hillman reaction, One-pot reaction, Nucleophilic substitution,
Allyl azide, Solvent-free
One-pot and solvent-free reactions have attracted significant
attention in organic synthesis. One-pot synthesis is a strat-
egy to improve the efficiency of a chemical reaction
whereby a reactant is subjected to successive chemical reac-
tions in just one reactor. This is much desirable because
avoiding a purification step of the intermediates would save
time and resources.1 The development of the solvent-free
reaction is very important because of the economical and
environmental reasons in organic synthesis.2
The Baylis–Hillman reaction is an important carbon–
carbon bond-forming reaction affording substituted
alkenes.3 Baylis–Hillman adducts and their acetates are
important synthetic substrates for the synthesis of a variety
of heterocycles.4 They are also used as intermediates for
the preparation of tri-substituted alkenes bearing various
functional groups by nucleophilic substitution5 or a cross-
coupling reaction with organometallics6–8 using palladium
and rhodium as a catalyst or alkyl halides using zinc9 and
trialkylindium.10
Baylis–Hillman reactions of aryl aldehydes with acti-
vated alkenes,16 acetylations of Baylis–Hillman adducts17
and nucleophilic substitutions of Baylis–Hillman acetate
with azide anion15 have been reported in the literatures.
The success of the one-pot consecutive reaction of the
three-step reactions is depending on finding out appropriate
conditions among the plethora of the reaction conditions or
developing the new reaction conditions for each three-step.
Benzaldehyde and methyl acrylate were chosen as a model
substrates for the study of our one-pot procedure.
Among Baylis–Hillman reaction conditions considered,
solvent-free condition developed by Indian chemist18 was
found to be the best. However, 3 equiv of methyl acrylate
and 1 equiv of 1,4-diazabicyclo[2,2,2]octane (DABCO) rather
than a catalytic amount of DABCO and 1 equiv of acrylate
are necessary for the completion of the reaction within the
reasonable reaction time. After Baylis–Hillman reaction
(48 h), the reaction mixture was concentrated to remove
remaining methyl acrylate which react with the sodium azide
in the next step to give unidentified side products. In the fol-
lowing acetylation reaction of Baylis–Hillman adduct, acetic
anhydride (1.2 equiv) as acetylating agent and 4-dimethylami-
nopyridine (DMAP) (0.2 equiv) as a catalyst were found to
be a successful protocol. Baylis–Hillman reaction and acetyla-
tion were conducted under solvent-free condition.
Many solvent systems such as water, acetone–water, ace-
tone, tetrahydrofuran (THF), THF–water, ethanol, acetoni-
trile, and dimethylformamide (DMF) were investigated in
the final substitution reaction and DMF was found to be the
choice of best solvent. Therefore, DMF and sodium azide
(1.5 equiv) were added to the first two-step reaction mix-
ture and the resulting solution was stirred at room tempera-
ture for 6 h to give methyl-(E)-2-(azidomethyl)-3-phenyl-2-
propenoate 2a stereoselectively and regioselectively in 84%
isolated yield (Table 1, entry 1). The each step of the reac-
tion was monitored by thin layer chromatography (TLC)
and 1H NMR spectroscopy.
Organoazides11 are one of the most important synthetic
intermediates for the preparation of nitrogen-containing
organic compounds, for example, amines via reduction,
imines via rearrangement, and other nitrogen-containing
heterocycles via cycloaddition reactions. Because allyl
azides among them are versatile building skeletons for the
synthesis of biologically active nitrogen-containing
heterocycles,12 the synthesis of allyl azides have become an
attractive research area.13 Especially, aryl-(E)-2-(azido-
methyl)alkenoate and aryl-(Z)-2-(azidomethyl)acrylonitrile
prepared by nucleophilic substitution of Baylis–Hillman
14,15a
acetates with NaN3
and bromide of their adducts with
15b
NaN3 are key intermediates for synthesis. Therefore, the
development of simple and efficient synthetic methods for
these allyl azides is highly desirable.
Here, we are going to report our result on the three-step
one-pot synthesis of aryl-(E)-2-(azidomethyl)alkenoate and
aryl-(Z)-2-(azidomethyl)acrylonitrile from aryl aldehydes
and activated alkenes. (Scheme 1) The first two-step reac-
tions are conducted under solvent-free condition.
One-pot consecutive reaction under our optimum condi-
tion was conducted with a variety of benzaldehyde having
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O
O
1. DABCO, activated alkenes
R
2. concentration
H
N3
O
or
Y
Y
Y
CN
3. Ac2O, DMAP for 10 min
4. NaN3/DMF for 4~8 h
1
N3
3
2: R = Me or Et
Scheme 1. One-pot synthesis of allyl azides
electron-donating group (Table 1, entry 7) or electron-
withdrawing group (Table 1, entries 3–6 and 8–12) and
methyl (or ethyl) acrylate to afford the corresponding aryl-
(E)-2-(azidomethyl)alkenoate
stereoselectivity in good to high yield as shown in Table 1.
The reactions of 2-furaldehyde and 2-thiophene aldehyde
2
with excellent E-
Table 1. One-pot synthesisa of aryl-(E)-2-(azidomethyl)alkenoate.
O
1. DABCO, acrylate
COOR
2. concentration
H
Y
Y
3. Ac2O, DMAP for 10 min
4. NaN3 / DMF for 4~8 h
1
N3
R = Me or Et
2
Entry
1
Aldehyde
Productb
Yield (%)c
(E) 84, 6 he
Entry
Aldehyde
Productb
Yield (%)c
O
COOMe
NO
O
NO
2
8
(E) 80, 5 h
2
COOMe
H
H
H
H
N
3
N
2a
2b
48 hc
4 h
3
2h
Br
O
COOEt
Br
O
2
3
(E) 83, 6 h
(E) 67, 5 h
9
(E) 74, 6 h
(E) 77, 6 h
COOEt
H
N
3
N
3
48 h
12 h
2j
Cl
O
COOMe
Cl
O
10
COOMe
H
H
O N
N
3
2
O N
2
2c
N
3
12 h
4 h
2l
O
O
O
COOEt
O
COOMe
4
5
(E) 78, 5 h
(E) 77, 4 h
11
12
(E) 96, 6 h
(E) 83, 5 h
H
Cl
N
3
O N
N
3
2
O N
2
Cl
F
2n
2d
18 h
18 h
4 h
O N
COOMe
O
COOMe
2
O N
2
H
H
H
N
F
N
3
3
2e
2o
4 h
O N
COOEt
O
COOEt
6
7
(E) 82, 4 h
(E) 88, 8 h
13
14
O
(E) 85, 5 h
(E) 93, 5 h
2
O N
O
2
H
N
3
N
3
2p
2f
48 h
4 h
OMe O
OMe
O
COOEt
S
COOMe
S
H
H
N
3
N
3
2q
48 h
1 week
2g
a
Reaction conditions: 1st step: aryl aldehyde (1 equiv), methyl (or ethyl) acrylate (3 equiv) and DABCO (1 equiv); 2nd step: acetic anhydride
(1.2 equiv) and DMAP (0.2 equiv); 3rd step: NaN3 (1.5 equiv) and DMF.
All products are known and their spectral data are consistent with literature data.15,19
Isolated yield.
Baylis–Hillman reaction time.
Substitution reaction time.
b
c
d
e
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Table 2. One-pot synthesisa of aryl-(Z)-2-(azidomethyl)acrylonitrile.
O
1. DABCO, acrylonitrile
2. concentration
H
N3
Y
Y
CN
3. Ac2O, DMAP for 10 min
4. NaN3 / DMF for 5~6 h
1
3
Entry
1
Aldehyde
Productb
Yield (%)c
(Z) 83, 6 he
Entry
Aldehyde
Productb
Yield (%)c
O
O
3
(Z) 64, 6 h
N
N
3
3
CN
CN
H
H
F
3o
3q
3r
F
12 hd
48 h
48 h
O
2
(Z) 71, 6 h
4
(Z) 74, 5 h
N
O
3
CN
H
H
MeO
N
3
3p
CN
MeO
96 h
a
Reaction conditions: 1st step: aryl aldehyde (1 equiv), acrylonitrile (3 equiv) and DABCO (0.5 equiv). 2nd step: acetic anhydride (1.2 equiv)
and DMAP (0.2 equiv). 3rd step: NaN3 (1.5 equiv) and DMF.
All products are known and their spectral data are consistent with literature data.15a
Isolated yield.
Baylis–Hillman reaction time.
Substitution reaction time.
b
c
d
e
also gave the corresponding azido products 2p and 2q with
step one-pot processes: Baylis–Hillman reaction of aryl
aldehydes and activated alkenes using DABCO followed
by acetylation using acetic anhydride and a catalytic
amount of DMAP and nucleophilic substitution using
sodium azide in DMF at room temperature. Our one-pot
synthetic protocol is efficient and simple.
E-stereoselectivity in high yields (entries 13 and 14). The
stereochemistry of the products was established by compar-
ing 1H NMR parameters for the olefinic and methylene pro-
tons of the each product with literature values15,19 and by
two-dimensional nuclear Overhauser defect spectroscopy
(NOESY) of product 2a.15c The reaction times of Baylis–
Hillman and substitution reaction are depending on the sub-
strate and listed in Table 1. All acetylation reactions were
finished within 10 min.
Experimental
A Typical Experimental Procedure of Benzaldehyde
and Methyl Acrylate. A solution of benzaldehyde (200 μL,
1.96 mmol), methyl acrylate (536 μL, 3 equiv) and DABCO
(220 mg, 1 equiv) without solvent was stirred for 2 days.
The reaction was monitored by TLC using a solution of ethyl
acetate and hexane (1:4). After the reaction was completed,
the reaction mixture was concentrated to remove the remain-
ing methyl acrylate. To the concentrate (syrup), acetic anhy-
dride (228 μL, 1.2 equiv) and DMAP (48 mg, 0.2 equiv) was
added, and the resulting mixture was stirred at room tempera-
ture for 10 min. And then, to the solution, DMF (3 mL per
aldehyde 1 mmol) and sodium azide (258 mg, 2 equiv) was
added and the resulting solution was stirred at room tempera-
ture for 5 h. The reaction was diluted with ethyl acetate
(30 mL) and washed with water (20 mL × 3) and brine
(20 mL). The organic layer was dried with anhydrous magne-
sium sulfate, filtered, concentrated, and chromatographed on
silica gel using a solution of ethyl acetate and hexane (1:15)
to give a product in 84% isolated yield.
One-pot consecutive reaction of aryl aldehydes with
electron-donating group (Table 2, entry 2) or electron-
withdrawing group (Table 2, entry 3) and acrylonitrile
under our reaction condition was conducted to afford the
corresponding aryl-(Z)-2-(azidomethyl)acrylonitrile in good
to high yield with excellent Z-stereoselectivity as shown in
Table 2. The amount of DABCO used in the first step
Baylis–Hillman reaction is 0.5 equiv rather than 1 equiv
because the reaction of acrylonitrile is faster than that of
methyl acrylate. The stereochemistry of the products was
1
established by comparing H NMR parameters for the ole-
finic and methylene protons of the each product with litera-
ture values15a and by two-dimensional NOESY of product
3o.15c The reaction times of Baylis–Hillman and substitu-
tion reactions are depending on the substrate and listed in
Table 2. All acetylation reactions were finished within
10 min.
In summary, aryl-(E)-2-(azidomethyl)alkenoate and aryl-
(Z)-2-(azidomethyl)acrylonitrile from aryl aldehydes and
activated alkenes (acrylate and acrylonitrile) were synthe-
sized in one-pot consecutive way with excellent stereose-
lectivity in good to high yield. The method include a three-
Acknowledgment. This work was supported by Korea
University.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
Bull. Korean Chem. Soc. 2016, Vol. 37, 771–774
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Bull. Korean Chem. Soc. 2016, Vol. 37, 771–774
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