Room temperature cyclization of arylpropiolic acid anhydride: Synthesis of naphtho[2,3-c]furan-1,3-dione derivatives

Article abstract of DOI:10.1080/00397911.2017.1358369

Cyclic anhydrides such as naphtho[2,3-c]furan-1,3-dione derivatives were synthesized from the reaction of arylpropiolic acids and 2-chloro-4,6-dimethoxy-1,3,5-triazine in the presence of N-methylmorpholine at room temperature. This mild condition provided

Full text of DOI:10.1080/00397911.2017.1358369

Synthetic Communications
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Room temperature cyclization of arylpropiolic acid
anhydride: Synthesis of naphtho[2,3-c]furan-1,3-
dione derivatives
Jaerim Park, Ji Dang Kim, Gabriel Charles Edwin Raja, Hyun Chul Choi &
Sunwoo Lee
To cite this article: Jaerim Park, Ji Dang Kim, Gabriel Charles Edwin Raja, Hyun Chul
Choi & Sunwoo Lee (2017): Room temperature cyclization of arylpropiolic acid anhydride:
Synthesis of naphtho[2,3-c]furan-1,3-dione derivatives, Synthetic Communications, DOI:
10.1080/00397911.2017.1358369
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1358369
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Date: 28 July 2017, At: 18:16

Room temperature cyclization of arylpropiolic acid
anhydride: Synthesis of naphtho[2,3-c]furan-1,3-dione
derivatives
Jaerim Park†
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Ji Dang Kim†
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Gabriel Charles Edwin Raja
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Hyun Chul Choi*
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
Sunwoo Lee*
Department of Chemistry, Chonnam National University, Gwangju, Republic of Korea
*Address correspondence to Hyun Chul Choi. E-mail: chc12@chonnam.ac.kr
*Address correspondence to Sunwoo Lee. E-mail: sunwoo@chonnam.ac.kr
†These authors contributed equally.
ABSTRACT
1

Cyclic anhydrides such as naphtho[2,3-c]furan-1,3-dione derivatives were synthesized
from the reaction of arylpropiolic acids and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in the
presence of N-methylmorpholine (NMM) at room temperature. This mild condition provided the
naphtho[2,3-c]furan-1,3-dione derivatives in good yields. Spectroscopic analysis suggested that
the formation of arylpropiolate is the rate-determining step.
GRAPHICAL ABSTRACT
KEYWORDS:
Introduction
Cyclic anhydrides are useful building blocks and important intermediates in the synthesis
of biologically active compounds and functional materials.[1] This group can be readily
transformed into other functional groups such as lactones, imides, carboxylic acids, esters, and
amides. As one of cyclic anhydride moieties, naphtho[2,3-c]furan-1,3-dione derivatives have
received significant attention from pharmaceutical and material scientists owing to the fact that
they have contributed to the synthesis of some very useful functional compounds such as
helioxanthin,[2] fluorophores,[3] gas separation polyimides,[4] chiral ligands,[5] and lactone
lignans.[6] Therefore, various synthetic methods have been developed for the preparation of
naphtho[2,3-c]furan-1,3-dione derivatives. Haworth et al. have reported that the reaction of aryl
propiolic acids with acetic anhydride provided the desired product.[7] Since it was reported, this
method has been widely used and modified. The reaction with aryl propiolic acid at high
2

temperature gave low yields of the product because of thermal decarboxylation of propiolic acid.
In order to address this issue, the reaction with aryl propioloylchloride and aryl propiolic acid was
developed and found to provide the desired cyclic anhydride product.[8] However, the instability
of the acyl chloride reduced the yields of the product. Recently, Kawano et al. have reported the
microwave-assisted synthesis of naphtho[2,3-c]furan-1,3-dione derivatives and it was found that
the reaction was complete in three minutes under these conditions.[9] Nevertheless, this reaction
still requires a high reaction temperature. Another method involves the cyclization of benzylidene
succinic anhydride, but it is limited to only one example.[10] Therefore, a more efficient synthetic
method that can be performed under mild condition is required. In the study of the decarboxylative
coupling reaction of phenylpropiolic acid, we found that the reaction with 2-chloro-4,6-dimethoxy-
1,3,5-triazine (CDMT) provided 4-phenylnaphtho[2,3-c]furan-1,3-dione at room temperature. It is
known that CDMT is stable and inexpensive. This motivated us to develop a mild synthetic method
of naphtho[2,3-c]furan-1,3-dione derivatives.
Results and Discussion
In order to optimize the reaction conditions, a variety of bases were tested. The results are
summarized in Table 1. Use of Et3N and pyridine furnished the desired product with 27% and
29% yields, respectively (entries 1 and 2). Bicyclic amine bases such as DBU and DBN provided
only trace amounts of the product (entries 3 and 4). When the reaction was performed using N-
methylmorpholine (NMM) was conducted, the desired product was formed in 82% yield (entry 5).
Among the other reaction solvents that were tested, CH2Cl2 and Et2O provided the desired product
3a in 71% and 55% yields, respectively (entries 6 and 7). While THF showed 81% yield of product
(entry 8), no product was found in DMSO as the solvent (entry 9). When the amount of the base
3

was decreased to 0.5 equivalents, the yield of the product also decreased to 54% (entry 10). In the
absence of a base, the reaction did not take place (entry 11).
In order to evaluate this cyclization method at room temperature, several arylpropiolic acid
derivatives were employed as starting materials and the desired cyclized products were isolated
and characterized. The results are summarized in Scheme 1. As expected, phenylpropiolic acid
afforded 3a in 82% isolated yield. Arylpropiolic acids bearing alkyl groups such as methyl, ethyl,
and tert-butyl at the para-position of the phenyl ring provided the corresponding products 3b, 3c,
and 3d in 74%, 77%, and 81% yields, respectively. 4-Methoxyphenylpropiolic acid afforded the
desired product 3e in 77% yield. In addition, 4-chloro-substituted arylpropiolic acid yielded 3f in
65% yield.
The mechanism of the dehydro-Diels-Alder reaction of propiolic anhydride has been
previously reported. Although Kishan et al. have proposed a concerted mechanism, it does not
apply to the case of phenylpropiolic anhydride because their chosen model substrate was in the
solid state.[11] Recently, Wessig et al. have reported a stepwise mechanism involving 1,4-
biradicals.[12] Based on a previous report and our results, the reaction pathway shown in Scheme 1
has been proposed. It has been reported that CDMT reacted with NMM to provide 4-(4,6-
dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) which was used as an
efficient condensing agent in the formation of esters and amides.[13] Phenylpropiolic acid reacted
with DMTMM to give the corresponding ester as an intermediate A. Ester A then reacted with
phenylpropiolic acid to afford the symmetric anhydride intermediate B, which further underwent
a [4 + 2] cycloaddition reaction to give the cyclized anhydride intermediate C. The final product
was formed via secondary hydrogen shift from the allenic intermediate C.
4

In order to find support for the proposed reaction pathway, the reaction was monitored by
IR and 13C NMR spectroscopies (Figure 1 and Figure 2). Thus, phenylpropiolic acid, CDMT, and
NMM were mixed at room temperature and their IR and 13C NMR spectra were measured after 10
min, which are the points at the beginning of the reaction. In the IR spectrum, the five-membered
ring anhydrides showed two weak bands at 1860 cm−1 and 1840 cm−1 and one strong band at 1780
cm−1. The C-C triple bond stretching band of phenylpropiolic acid appeared at 2230 cm−1. In 13C
NMR, a strong carbonyl carbon peak appeared at 172.5 ppm, which is assigned to the intermediate
A and the two carbon peaks at 163.1 and 161.9 ppm are the chemical shifts of the anhydride carbon
atoms of the product. It is worth noting that the symmetric anhydride B were not detected because
the carbon peaks of the anhydride and alkyne groups in B were not present in the 13C NMR
spectrum. After 30 min, the bands and peaks of phenylpropiolic acid disappeared from both IR
and 13C NMR spectra. Based on these results, it is proposed that the formation of intermediate A
is the rate determining step and intermediate B is too unstable to be detected. To the best of our
knowledge, the symmetric anhydride B has never been isolated.
Conclusion
In summary, derivatives of naphtho[2,3-c]furan-1,3-dione were synthesized by reacting
arylpropiolic acid with CDMT. The reaction proceeded with N-methylmorpholine at room
temperature. Substituted arylpropiolic acid derivatives produced the corresponding cyclic
anhydrides in moderate to good yields. Based on FT-IR and 13C NMR spectroscopic analyses, it
has been proposed that the formation of arylpropiolate is the rate-determining step.
Experimental Details
5

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) using TLC plates were visualized by
shortwave (254 nm) UV light. Melting points were determined on a capillary melting point
apparatus and are uncorrected using electrothermal melting point apparatus.1H NMR (300 MHz
13
and 600 MHz) and C NMR (75 MHz and 151 MHz) 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). IR spectra were recorded on BRUKER EQIUINOX-55 spectrophotometer.
General procedure for the synthesis of cyclic anhydride derivatives
To a round bottom flask containing CHCl3 (20 mL), aryl propiolic acid (2.0 mmol), CDMT
(351 mg, 2.0 mmol), NMM (202 mg, 2 mmol) were added. The resulting mass was stirred
vigorously for 3 h at room temperature (25oC. After the reaction based on TLC, the reaction mass
was filtered and removed the solvent using rotary evaporator. The crude mass was diluted with
CH2Cl2, and washed with 10% citric acid, followed by 1N NaOH. The DCM layer was dried over
sodium sulphate and concentrated which was further purified by flash column chromatography.
Selected product
4-Phenylnaphtho[2,3-c]furan-1,3-dione (3a)[14]
3-Phenylpropiolic acid (292 mg, 2.0 mmol) afforded 4-phenylnaphtho[2,3-c]furan-1,3-
1
dione (3a) (225 mg, 0.82 mmol, 82%). M.p.: 261–263oC; lit[14]260–262oC; H NMR (CDCl3
6

500MHzꢀ): δ 8.57 (s, 1H), 8.18 (d, J = 8.2Hzꢀ, 1H), 7.92 (d, J = 8.7Hzꢀ, 1H), 7.82-7.78 (m, 1H),
7.73–7.69 (m, 1H), 7.59–7.58 (m, 3H), 7.43–7.41 (m, 2H) ppm. 13C NMR (CDCl3, 126 MHz): δ
163.1, 161.9, 143.5, 136.2, 135.9, 133.2, 130.6, 130.3, 130.1, 129.8, 129.2, 128.9, 128.5, 127.2,
125.9, 122.3. Anal. Calcd for C18H10O3: C, 78.82; H, 3.67. Found: C, 78.59; H, 3.71.
Supporting information
Supporting information for this article is available online at
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.
References
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8

Table 1. Optimization of the synthesis of 4-phenylnaphtho[2,3-c]furan-1,3-dione (3a).a
Entry
Base
Et3Nꢀ
Pyridine
DBU
Solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
Et2O
Yield (%)
27
1
2
29
3
3
4
DBN
trace
82
5
NMM
NMM
NMM
NMM
NMM
NMMc
–
6
71
7
55
8
THF
81
9
DMSO
THF
N.D.
54
10
11
THF
N.D.d
aReaction conditions: 1 (0.4 mmol), 2 (0.4 mmol), and base (0.44 mmol) were reacted in different solvents (1.5mLꢀ) at 25°C for
3h. bDetermined by 1H NMR analysis. c0.2 mmol of NMM was used. dN.D. = not detected.
9

Figure 1. IR spectra of the reaction mixture of 1a, CDMT, and NMM in CHCl3 at 25°C. (a) Pure
1a. (b) At the beginning of the reaction, (c) after 30 min, and (d) after 60 min. e) Pure 3a.
10

Figure 2. 13Cꢀ NMR spectra of the reaction mixture of 1a, CDMT, and NMM in CDCl3 at 25°C
(a) at the beginning of the reaction and (b) after 30minꢀ. c) Pure 3a.
11

Scheme 1. Synthesis of naphtho[2,3-c]furan-1,3-dione derivatives.a, aReaction conditions: 1 (2.0
mmol), 2 (2.0 mmol), and NMM (2.2 mmol) were reacted in CHCl3 at 25°C for 3h. The values in
parentheses are isolated yields.
12

Scheme 2. Proposed reaction pathway.[
13