One-pot synthesis of cinnamic anhydrides from cinnamic acids and 6-chloro-2,4-dimethoxy-sec-triazine (CDMT) at room temperature

Article abstract of DOI:10.1080/00397911.2017.1382535

Symmetric cinnamic anhydrides were prepared by the reactions of cinnamic acid substrates with 6-chloro-2,4-dimethoxy-sec-triazine. The reactions were performed at room temperature for 15 h. Diverse cinnamic acid substrates bearing electron-withdrawing or -donating groups worked well, providing the corresponding cinnamic anhydrides in moderate-to-good yields.

Full text of DOI:10.1080/00397911.2017.1382535

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
One-pot synthesis of cinnamic anhydrides from
cinnamic acids and 6-chloro-2,4-dimethoxy-sec-
triazine (CDMT) at room-temperature
Gabriel Charles Edwin Raja, Yujeong Son, Myungjin Kim, Sunwoo Lee &
Jonghoon Oh
To cite this article: Gabriel Charles Edwin Raja, Yujeong Son, Myungjin Kim, Sunwoo Lee &
Jonghoon Oh (2017): One-pot synthesis of cinnamic anhydrides from cinnamic acids and 6-
chloro-2,4-dimethoxy-sec-triazine (CDMT) at room-temperature, Synthetic Communications, DOI:
10.1080/00397911.2017.1382535
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1382535
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Date: 26 October 2017, At: 09:04

One-pot synthesis of cinnamic anhydrides from cinnamic
acids and 6-chloro-2,4-dimethoxy-sec-triazine (CDMT) at
room-temperature
Gabriel Charles Edwin Raja
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Yujeong Son
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Myungjin Kim
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Sunwoo Lee
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Jonghoon Oh
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Address correspondence to Sunwoo Lee, Department of Chemistry, Chonnam National
University, Gwangju 61186, Republic of Korea. Tele: +82-62-530-3385. Fax: + 82-62-530-3389.
E-mail: sunwoo@chonnam.ac.kr
1

Address correspondence to Jonghoon Oh, Department of Chemistry, Chonnam National
University, Gwangju 61186, Republic of Korea. Tele: +82-62-530-3385. Fax: + 82-62-530-3389.
E-mail: jnoh@chonnam.ac.kr
Full experimental detail, 1H and 13C NMR spectra have been provided in supporting information.
This material can be found via the “Supplementary Content” section of this article’s webpage.
ABSTRACT
Symmetric cinnamic anhydrides were prepared by the reactions of cinnamic acid substrates
with 6-chloro-2,4-dimethoxy-sec-triazine (CDMT). The reactions were carried out at room
temperature for 15 h. Diverse cinnamic acid substrates bearing electron-withdrawing or -donating
groups worked well, providing the corresponding cinnamic anhydrides in moderate-to-good yields
GRAPHICAL ABSTRACT
KEYWORDS: 6-chloro-2,4-dimethoxy-sec-triazine, cinnamic acid, cinnamic anhydride, room
temperature
Introduction
Acid anhydrides are useful reagents for the introduction of a carbonyl moiety into the target
molecule.[1] Acid halides are the most common starting materials to synthesize acid anhydrides.[2]
Although acid halides are highly active reagents, they have some drawbacks. To avoid the use of
harmful and highly active acid halides, acid anhydrides have been widely used as acylating agents.
Several methods have been developed for the synthesis of acid anhydrides. Among them, the
2

reactions with carboxylic acids and dehydrative coupling reagents are one of the most popular
tools. This is because carboxylic acids are stable and readily accessible, and diverse dehydrative
coupling reagents, such as thionyl chloride,[3] phosgene,[4] triphosgene,[5] phosphorus pentoxide,[6]
dicyclohexylcarbodiimide,[7] isocyanate,[8] (trimethylsilyl)ethoxyacetylene,[9] Vilsmeier–Haack
reagent,[10] BrCCl3-PPh3,[11] and Cl3CCN-PPh3,[12] have been reported. However, they have some
drawbacks including toxic or unstable reagents, expensive or unavailable, tedious procedures,
harsh reaction conditions, and low yields. Efficient, easily handled, commercially available, and
stable reagents should be developed to solve these problems.
6-Chloro-2,4-dimethoxy-sec-triazine (CDMT) has been used to prepare esters and amides
from carboxylic acids.[13] CDMT has also been used as a source of 2,4-dimethoxy-sec-triazine for
the synthesis of 6-subsituted-2,4-dimethoxy-sec-triazine. CDMT can be used on kilogram scale
and has also been used as an acylating agent low temperature (0-5C), but scope of substrates are
limited to aromatic and aliphatic carboxylic acids, unsaturated acids were not studied.[14] During
the development of various decarboxylative coupling reactions in our group, we found that the
reaction of cinnamic acid with CDMT afforded a symmetric acid anhydride at room temperature.
Hence it is clear that the reactivity of CDMT with saturated and unsaturated carboxylic acid is
quite different. Cinnamic anhydride derivatives have been frequently used in the synthesis of
natural products and bioactive materials.[15] Herein, we report a mild and simple preparation
method for cinnamic acid derivatives from cinnamic acids and CDMT.
Results and Discussion
To optimize the reaction conditions, diverse bases were screened in the reaction of
cinnamic acid with CDMT at 25 C. N-methylmorpholine and triethylamine provided cinnamic
3

anhydride in 56% and 50% yields, respectively (entries 1 and 2). However, pyridine and DBU
provided cinnamic anhydride in very low yields (entries 3 and 4). No anhydride was formed when
morpholine, K2CO3, Na2CO3, DMAP or 1-methyl imidazole was used (entries 5–9). Next, solvents
were screened. Toluene, Et2O, and CH2Cl2 furnished the desired anhydride in 70%, 51%, and 50%
yields, respectively (entries 8–10). The yield of the product increased to 95% in 1,4-dioxane (entry
11). Theoretically, 0.5 equiv of CDMT is needed to obtain the desired cinnamic acid anhydride.
The equivalent of CDMT was examined. When the amount of CDMT was decreased to 0.5 and
0.7 equiv, the yields were 50% and 90%, respectively (entries 14 and 15). Reducing the reaction
time and increasing the amount of base also decreased the yield to 81% and 65% respectively
(entries 16 and 17).
With this optimized condition, diverse cinnamic acid substrates were tested for the
synthesis of symmetric cinnamic anhydrides. As expected, cinnamic acid provided cinnamic
anhydride (2a) in a good isolated yield. Cinnamic acid substrates bearing methyl, methoxy, and
ethoxy substituents at the para position of the phenyl ring afforded the corresponding cinnamic
anhydrides 2b, 2c, and 2d in 75%, 81%, and 84% yields, respectively. 3-Methoxyphenyl and 3,5-
dimethoxyphenyl acrylic acids gave 2e and 2f in good yields. 3-(Benzo[d][1,3]dioxol-5-yl)acrylic
acid also provided the corresponding anhydride 2g. Cinnamic acid substrates bearing halide groups
such as bromide and fluoride produced 2h and 2i in 74% and 72% yields, respectively. Furan-2-
ylacrylic acid afforded the product in a good yield. Interesting, an -methyl substituted acid such
as 2-methyl-3-phenylacrylic acid (1k) and a dienoic acid such as 5-phenylpenta-2,4-dienoic acid
(1l) afforded the corresponding anhydrides 2k and 2l in 76% and 80% yields, respectively. 3-(4-
cyanophenyl)acrylic acid and 3-(4-(methoxycarbonyl)phenyl)acrylic acid[16] were allowed to react
with CDMT/NMM to afford the desired product 2m and 2n in 65% and 68% respectively.
4

However, 3-(4-nitrophenyl)acrylic acid did not afford the product because of its poor solubility in
1,4-dioxane and THF. 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)acrylic acid and 3-(4-
(benzyloxy)phenyl)acrylic acid proceeded to form the product which was confirmed by TLC, but
unable to isolate the product after column purification. Unfortunately, no anyhydride formation
was observed in aliphatic acrylic acids and N-protected amino acids. Acid and base work-up did
not affect the stability of the product during isolation in the case of cinnamic acid substrates
whereas for aliphatic and aromatic acids, low temperature is needed to avoid the decomposition of
the product.
To understand the selective formation of cinnamic anhydride from cinnamic acid and
CDMT, several control reactions were investigated. It is known that CDMT reacts with NMM to
give DMTMM.[17] When cinnamic acid was reacted with DMTMM, cinnamic anhydride was
obtained in 87% yield (Scheme 3a). When benzoic acid was allowed to react under the optimized
condition, the expected anhydride 5 was not obtained, and only benzoate 4 was formed in 81%
yield (Scheme 3b).[18] Cinnamic acid did not react with benzoate 4 (Scheme 3c). When an equal
amount of cinnamic acid and benzoic acid was reacted with CDMT and NMM, cinnamic anhydride
was obtained in a higher yield than benzoate 4 (Scheme 3d). Cinnamic anhydride was the major
product even under the condition of 5 equiv of CDMT and NMM; however, cinnamate 6 was
obtained in 12% yield (Scheme 3e). When cinnamic acid 1c with an electron-donating substituent
and cinnamic acid 1i with an electron-withdrawing substituent were reacted in the same vessel,
symmetric anhydrides 2c and 2i were obtained in 32% and 27% yields, respectively, and
unsymmetrical anhydride 7 was obtained in 26% yield (Scheme 3f). Anhydride 7 was identified
by GCMS. These results indicate the following. 1) The reaction of CDMT with NMM afforded
DMTMM, which worked as a coupling reagent. 2) Benzoic acid is not a suitable substrate for the
5

synthesis of an anhydride from CDMT. 3) Cinnamic acid reacts rapidly with CDMT, providing
the corresponding cinnamate which further reacts with cinnamic acid to give the corresponding
anhydride. 4) The reaction rate of cinnamate 6 with cinnamic acid might be faster than that of
cinnamic acid with CDMT could be due to electronic nature of unsaturated carboxylic acids. 5)
The electronic nature of the substituent on the aryl ring of cinnamic acid does not affect the yield
of the product. 6) The reactivity of unsaturated carboxylic acid towards CDMT is different than
the aromatic and aliphatic carboxylic acids; however the rate of the reactivity of carboxylic acids
towards CDMT is can be defined as sp > sp2 > sp3 carboxylic acids for anhydride formation.[21]
Aromatic and aliphatic acids required low temperature and sequential addition of reagents.[16b]
Conclusion
In summary, cinnamic anhydride derivatives were easily obtained from cinnamic acid
substrates and CDMT in the presence of NMM. Diverse cinnamic acid substrates provided the
corresponding cinnamic anhydrides in good yields at room temperature. The reaction conditions
are mild, and the reaction showed a good functional group tolerance. Cinnamic acid showed a high
reactivity towards CDMT, producing the corresponding cinnamate. The cinnamate was found to
be more reactive than cinnamic acid, providing cinnamic anhydride.
Experimental Details
All reagents and solvents were purchased and used without further purification. Thin Layer
Chromatography (TLC) on precoated plated of silicagel was performed on TLC silica gel 60 F254
with ethyl acetate/n-hexane (2:8) systems. Preparative flash chromatography were performed by
elution from columns of silica gel (230-400 mesh size). The TLC plates were visualized by
shortwave (254nm) UV light. Melting points were determined on a capillary melting point
6

apparatus and are uncorrected using Electrothermal melting point apparatus. 1H NMR (500MHz)
and 13C NMR (125MHz) spectra were recorded in CDCl3 using VARIAN VnmrJ. Chemical shifts
are given in parts per million (ppm) downfield from tetramethylsilane (TMS) as an internal
reference and coupling constants (J-values) are in hertz (Hz).
General procedure for the SYNTHESIS of anhydride derivatives
To a round bottom flask, cinnamic acid substrates (3.0 mmol) and CDMT (3.0 mmol) in
dioxane (10 mL) were added, followed by NMM (3.0 mmol) was added to the reaction mixture.
The resulted solution was stirred at room temperature for 15 h. The resulting mixture was cooled
and then filtered using a syringe filter. Then the mass concentrated and further diluted with diethyl
ether. The organic layer was washed with 5% citric acid and followed by 5% sodium bicarbonate.
The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure,
and the resulting crude product was purified by simple column chromatography (eluent =
hexane/ethyl acetate).
Selected product
(E)-Cinnamic anhydride (2a)[19]
Cinnamic acid (444mg, 3.0 mmol) CDMT (527 mg, 3.0 mmol) and NMM (303 mg, 3.0
mmol) in dioxane afforded (E)-cinnamic anhydride (2a) as a white solid (355 mg, 85% yield);
o
1
M.p.: 135.2–136.4 C; lit[20] 135–137 °C; H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 15.95 Hz,
2H), 7.63 – 7.56 (m, 4H), 7.49 – 7.40 (m, 6H), 6.54 (d, J = 15.95 Hz, 2H). 13C NMR (125 MHz,
CDCl3) δ 162.48, 148.67, 133.71, 131.29, 129.08, 128.58, 116.73. MS (EI) m/z: 278. Anal. Calcd
for C18H14O3: C, 77.68; H, 5.07; Found: C, 77.77; H, 5.11.
7

Acknowledgment
This research was supported by the National Research Foundation of Korea (NRF) and
funded by the Korea government (MSIP) (NRF-2015R1A4A1041036). The spectral data were
obtained from the Korea Basic Science Institute, Gwangju branch.
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DOI: 10.1080/00397911.2017.1358369.
9

Table 1. Screening of bases, solvents, equivalent of CDMT, and reaction time for the synthesis
of cinnamic anhydride.a
Entry
CDMT
(equiv)
Base (1 equiv)
Solvent
Time, Yield (%)b
hrs
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
NMM
Et3N
THF
THF
15
15
15
15
15
15
15
15
15
15
15
15
15
56
50
4
3
Pyridine
DBU
THF
4
THF
8
5
Morpholine
K2CO3
THF
0
6
THF
0
7
Na2CO3
DMAPc
1-Methyl imidazole
NMM
THF
0
8
1,4-dioxane
1,4-dioxane
Toluene
Et2O
0
9
0
10
11
12
13
70
51
50
95
NMM
NMM
CH2Cl2
1,4-dioxane
NMM
10

14
15
16
17
0.5
0.7
1.0
1.0
NMM
NMM
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
15
15
3
50
90
81
65
NMM
NMM (2 equiv.)
15
a Reaction conditions: 1a (0.3 mmol), CDMT (0.3, 0.15, and 0.21 mmol), and base (0.3 mmol) reacted in a solvent (1 mL) at 25
C. b Determined by gas chromatography using an internal standard naphthalene. c 4-Dimethylaminopyridine.
11

Scheme 1. Synthesis of anhydrides.
12

Scheme 2. Synthesis of Cinnamic Anhydride.a
13

Scheme 3. Reactivity of CDMT.
14