Iodine-mediated formal [3 + 2] annulation for synthesis of furocoumarin from oxime esters

Article abstract of DOI:10.1039/d0ra07566c

A novel synthesis of furocoumarins was developed by a reaction between oxime esters and 4-hydroxycoumarins. The reaction was proposed to undergo radical mechanism mediated by iodine, a cheap and common laboratory reagent. Mechanistic studies showed the ke

Full text of DOI:10.1039/d0ra07566c

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Iodine-mediated formal [3 + 2] annulation for
synthesis of furocoumarin from oxime esters†
Cite this: RSC Adv., 2020, 10, 44332
a
b
c
*
Quyen T. Pham,
Phong Q. Le,
Ha V. Dang,a Hiep Q. Ha,
d
c
a
*
*
and Tri Minh Le
Huong T. D. Nguyen,
Thanh Truong
A novel synthesis of furocoumarins was developed by a reaction between oxime esters and 4-
hydroxycoumarins. The reaction was proposed to undergo radical mechanism mediated by iodine,
a cheap and common laboratory reagent. Mechanistic studies showed the key for the successful
transformation was the presence of a-iodoimine intermediate which facilitated the ring-closing step. The
developed conditions produced good functional group tolerance with a wide range of high-profile
furocoumarin product. The potential for this strategy to be applied in other syntheses of heterocyclic
compounds is highly achievable.
Received 3rd September 2020
Accepted 27th November 2020
DOI: 10.1039/d0ra07566c
rsc.li/rsc-advances
such as pyrazolinones,7 1,2-benzisoxazones,8 quinoline.9 For the
generation of furocoumarin, 4-hydroxycoumarin would
1. Introduction
frequently be under the catalysis of metal salts, for instance,
Ce(IV),10 Ru(II),11 Cu(II),12 multicopper oxidase13 or it could be in
a multi-components reaction, mostly with benzaldehyde and
isocyanide.14 The disadvantages of these methods are the
employment of toxic metals and increasing complexity of the
reaction that would be using multiple chemicals in a single
procedure. Therefore, a simpler, non-metal catalyzed protocol
to generate these valuable furocoumarins is much needed. With
that standpoint, we found out that oxime esters are well-
suitable reagents in developing a new synthetic methodology
which is metal-free, rapid and from universal starting materials.
The oxime ester compounds are widely employed in organic
synthesis because they are readily accessable from oximes and
acid chlorides or anhydrides.15 The N–O s bond of oxime esters
with an average energy of ꢀ57 kcal molÀ1 causes this bond quite
unstable. And because of the susceptible cleavage of the N–O
bond by active metals, the oxime esters are frequently utilized in
transition metal catalyzed transformation.16 However, there are
still elegant studies which can convert these hydroxy amine
Heterocyclic compounds play crucial roles in the pharmaceu-
tical industry because of their presence in substantial amount
of drugs.1 In addition to offering protein binding functional
groups, heterocycles also affect favorably drugs' solubility and
their pharmacokinetic properties. Among the important
heterocyclic compounds, furocoumarins have been commonly
targeted due to their remarkable potential biological activities
(Fig. 1).2,3 They have been demonstrating anti-bacteria, anti-
viruses (including HIV), anti-cancer, and inhibitory hyper-
plasia activities.4 Furthermore, furocoumarins also showed
potential applications in photosensitive medications, pesti-
cides and molecular biology.5 In this report, we described the
rst metal-free formal [3 + 2] annulation between two versatile
synthetic building blocks, oxime esters and 4-hydrox-
ylcoumarine, to synthesize these important heterocyclic
compounds.
Approaches for furocoumarin synthesis varied but exten-
sively were integrated with 4-hydroxycoumarin starting mate-
rials. These 4-hydroxycoumarin substrates are known as
adaptable synthons in the synthesis of countless heterocycles,6
aSchool of Medicine, VNU-HCM, Linh Trung Ward, Thu Duc District, Ho Chi Minh City,
Vietnam. E-mail: leminhtri@ump.edu.vn
bSchool of Biotechnology, International University, VNU-HCM, Quarter 6, Linh Trung
Ward, Thu Duc District, Ho Chi Minh City, Vietnam. E-mail: lqphong@hcmiu.edu.vn
cDepartment of Chemical Engineering, HCMC University of Technology, VNU-HCM,
268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Vietnam. E-mail: tvthanh@
hcmut.edu.vn
dDepartment of Chemistry, HCMC University of Science, VNU-HCM, 227 Nguyen Van
Cu Street, District 5, Ho Chi Minh City, Vietnam
† Electronic supplementary information (ESI) available. CCDC 2026801. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0ra07566c
Fig. 1 Selected examples of furocoumarin derivatives.
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derivatives into higher value products in a transition metal-free added into the 8 mL vial containing a stirring bar. The reaction
fashion. For example, in 2016, Huang and coworkers reported mixture was tightly sealed and heated at 140 ꢁC in 12 hours.
the metal-free synthesis of polysubstituted pyridines from Aer completion, the reaction mixture was cooled down to
ketoximes and acroleins (Scheme 1a).17 In this dedicated room temperature and diphenylether (0.1 mmol, 17 mg) was
research, iodine and trimethylamine were used to facilitate the added as internal standard. Subsequently, the resulting mixture
[3 + 3] reaction to form pyridine products with high chemo- was extracted with DCM : H2O (3 : 1) and the organic layer was
selectivity and wide tolerance of functional groups. The reaction collected and dried by using anhydrous Na2SO4 and then
was suggested to undergo a radical pathway initiated by single recrystallized in ethylacetate to afford desired product.
electron transfer from iodine to oxime substrates. Huang
later found out that NH4I when incorporated with either Et3N
or Na2S2O4 could also be used to generate imine radical
3. Results and discussion
intermediates in the reactions with 1,3-diketone and
Our investigation of the heterocycles synthesis started with the
provided diversied polysubstituted pyridines (Scheme 1a
reaction of O-acetyl ketoxime 1 and 4-hydroxycoumarin 2a
and b).18,19 Besides, Gao developed I2-catalyzed condensation
(Table 1). To our surprise, furocoumarin 3a was obtained in
a small amount with DMSO as solvent at 120 ꢁC without the
need of any additives, giving very rst signal that our reaction
may follow different pathways rather than previous proposed
mechanism (Table 1, entry 1). The structure of furocoumarin 3a
was precisely conrmed by X-ray crystallography on its single
crystal (Fig. 2, CCDC number is 2026801). Furthermore, other
solvents, ranging from non-polar to polar, generated products
of ketoxime acetates with Et3N20a or aldehydes20b as the C1
source through formal [3 + 2 + 1] annulation to give struc-
turally symmetrical pyridines or 2,4-diarylpyridines (Scheme
1c). In another research based on the transamidation of
isatins, Gao and coworkers20c otherwise have demonstrated
an efficient quinoline-4-carboxamide formation using the
same substrate ketoxime acetates (Scheme 1d). Herein we
envisioned that the oxime esters will practically achieve the
formation of other heterocycles when cooperated with
with different results (Table 1, entries 1–8). Generally, solvents
such as DMF DMSO which are known to consume a big portion
different organic moieties and with specically 4-hydrox-
of the iodine radical via radical-mediated reactions provided the
ycoumarin to potentially form furocoumarin products.
desired product in low yields.21 Ethereal solvents were also
tested and only moderate yields were achieved presumably due
to the a-hydrogen abstraction of these solvents with radicals.22
2. Experimental
Non-polar aromatic solvents which are quite inert to radical
In a general procedure, 4-hydroxycoumarin (0.1 mmol, 16.2 reagents afforded higher efficiency and optimal results, 58%,
mg), iodine (0.05 mmol, 12.7 mg) and mesitylene (2.0 mL) were were obtained in mesitylene. Other sources of iodine were also
Scheme 1 Previous works of oxime esters with iodine and furocoumarin synthesis from 4-hydroxycoumarin.
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Table 1 Optimization of reaction conditionsa
with 67% and 46% yield, accordingly. Apparently, other gases,
especially oxygen, and moisture have momentous effects on the
product formation.
The reason of diminished product formation under air or
oxygen may be due to the presence of radicals over the course of
the reaction. Based on previously known iodine mediated
reaction with oxime esters, a plausible mechanism was outlined
in Scheme 2. The reaction started with the reduction of acetyl
oxime ester 1a by iodine to form the imino-radical A which
could be in resonance with a-carbon radical imine B. Aer
incorporated with another iodine radical, B was converted to a-
iodoimine intermediate C which could be detected by mass
spectroscopy (path a). The nucleophilic attack of the enol-
carbon on 4-hydroxycoumarin 2a to the imino carbon of C
then generated iodoamine D. Upon electrophilic O-alkylation
attack of ketone group on the iodocarbon with the IOAc to I2
promoter recovery, the dihydrofuranocoumarine E was formed
and accomplished the formal [3 + 2] annulation step. The
intermediate E under acidic catalysis would then undergo olen
formation via elimination of the ammonium group to furnish
nal furocoumarin product. In addition, the intermediate E
could be formed through the intramolecular nucleophilic
cyclization of H which was provided by the radical coupling
reaction of B and G (path b). The enolic oxygen radical G was
generated from 2a with [I+] species as the oxidant via a single-
electron-transfer (SET) process.
Entry
Catalyst
Solvent
Temp. (ꢁC)
Yieldb (%)
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
I2
KI
NH4I
I2O5
—
I2
I2
I2
I2
I2
DMSO
DMF
1,4-Dioxane
Dibutyl ether
PhCl
120
120
120
120
120
120
120
120
120
120
120
120
80
8
14
21
26
39
32
53
58
26
30
Trace
ND
44
87
67
46
86
Toluene
Xylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
9
10
11
12
13
14
15c
16d
17
140
140
140
160
a
Reaction condition: 1a (0.15 mmol), 2a (0.3 mmol), I2 promoter
b
(50 mol%) in solvent (1.5 mL) at T ꢁC under Ar for 2 h. GC yield.
c
d
The reaction was run under O2. Open air conditions.
Our discovery was highly interesting because the nitrogen of
oxime normally participates in the ring formation to generate N-
containing heteocycles and the a-keto carbon of the oxime
esters oen plays as a nucleophile in nucleophilic attacks;
however, this has not been observed in our case. To evaluate the
feasibility of our proposed mechanism, we conducted mecha-
nistic studies in which several control experiments were per-
formed. Firstly, TEMPO was introduced to the reaction mixtures
in addition to all other reagents to conrm a radical involment.
The reaction was indeed completely suppressed without any
trace of the furocoumarin 3a (Scheme 3a). This result supported
the proposed radical process via SET process. Secondly, no
formation of 3a was also observed when acetophenone was used
instead of O-acetyl ketoxime starting material (Scheme 3b). The
oxime undoubtedly played a key role as a radical component
and a strong electrophilic partner in the reaction condition. The
ketone, on the other hand, was unlikely to be electrophilic
enough for the nucleophilic attack from 4-hydroxycoumarin.
This turned out to be an appropriate rational when we used two
equivalents of ammonium acetate together with acetophenone
which could generate the imine in situ, 3a was isolated in 23%
yield (Scheme 3c). The last puzzle in our proposed mechanism
was C detected by mass spectroscopy. The iodoimine C may be
the key intermediate for this methodology since the iodo-
substitution has made the a-carbon of the amino group
become more electrophilic and facilitated the ring closure
approach from keto-oxygen of the coumarin ring.23 This was
consistent with the results of reactions in the absence of 4-
hydroxycoumarin (Scheme 3d). Interestingly, reaction path b is
likely to be not favorable as shown in Scheme 3e. Particularly,
reactions of 4-hydroxycoumarin in deuterated 1,4-dioxane
tested, with inorganic salts KI and NH4I gave comparably low
yield of product formation, 26% and 30% yield, respectively
(entries 9 and 10), while I2O5 provided only trace amount of the
product (entry 11). In absence of I2, no fucocoumarin was
observed, which showed the crucial role of the iodine promoter
in this reaction (entry 12).
We next turned our attention to the effects of temperature on
the reaction outcome (entries 13, 14, 17). The increase of
temperature greatly facilitated product formation by speeding
up the reaction rate. Among the examined temperatures, we
observed that the starting material was consumed quickly at
140 ꢁC and provided the product with highest yield, 87%.
Furthermore, running reaction in different atmospheres also
led to various results. In comparison with the reaction under
argon, only moderate amount of 3a was observed when the
reaction was carried out under pure oxygen or air atmosphere,
Fig. 2 Crystal structure of 3a.
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Scheme 2 Plausible mechanism of the reaction.
Scheme 3 Control experiments.
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resulted in less than 5% of H/D exchange. It was reported that the benzene ring is possible, the products were still generated
hydrogen abstraction of ethers by free radicals in liquid phase effectively, from 66% to 87% yield. The p-uorophenyl
was signicant.24 However, more further mechanistic experi- substrate, however, worked sluggishly with only 26% yield of the
ments are still needed to conrm the reaction path.
product formation (3i). Interestingly, cyclohexanone also toler-
Aer investigating the reaction mechanism, we directed our able in reaction conditions, afforded furocoumarin 3j in 73%
effort to explore the generality and scope of this versatile I2- yield. This showed that the method is not limited to only
triggered formal [3 + 2] annulation using optimized conditions. aromatic ketoximes. Moreover, the reaction surprisingly worked
To our expectation, the reaction had a very broad substrate well with more steric oxime esters. When different propiophe-
scope in regard to both substituted 4-hydroxycoumarin and none acetyloximes reacted with 4-hydroxycoumarin 1, disub-
oxime esters. Specically, the reaction of 4-hydroxycoumarin stituted furocoumarins (3k–3m) were produced from moderate
with a wide range of acetophenone oximes afforded aromatic- to high yields. In fact, steric hindrance did not expose any
substituted furocoumarins (3a–3h) in moderate to excellent barrier for the product formation, with diphenylfurocoumarin
yields. Both electron-donating and electron-withdrawing groups 3n could be obtained in very good yield (82%). With regard to 4-
were well tolerated. Changing the positions of substituents on hydroxycoumarin scope, it was realized that the electronic
Scheme 4 Substrates scope of the reaction.a aReaction condition: 1 (0.15 mmol), 2 (0.3 mmol), I2 (50 mol%) in mesitylene (1.5 mL) at 140 ꢁC
under Ar for 2 h.
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nature of substituents has a certain effect on the reaction
outcome. The halogenated electron-decient substrates tend to
give products with lower yield than the methoxy electron-rich
substrates (compared to 3o–3p and 3r–3s). Especially, when
both 4-hydroxycoumarin and acetophenone oxime bearing the
electron-withdrawing groups, the furocoumarin was obtained
with only 40% yield (product 3q). Similarly, product 3t with
a free-hydroxyl group was also isolated in 39% yield. Neverthe-
less, although obtained in low yield, this product shows that
a protected functional group was not necessary for a successful
product generation. This also indicates that the radical scav-
enging property of free hydroxy groups did not totally suppress
product formation in the current reaction conditions (Scheme
4).
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Finally, the heteroaromatic substrates were well-tolerated in
this I2-promoted formal [3 + 2] annulation. The furocoumarins
carrying thiophenyl groups (3u–3w) and pyridinyl groups (3x)
were obtained in high to excellent yields. Since heteroatoms
usually coordinate with metals and make the metal-catalyzed
reaction proceed sluggishly,25 these results demonstrate the
superior of our method compared to those with metal catalysts
and heterocyclic substrates.
6 For the review of 4-hydroxycoumarin chemistry,
see:M. M. Abdou, Recent advances in 4-hydroxycoumarin
chemistry.
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4. Conclusions
In conclusion, we have successfully developed an I2-mediated
formal [3 + 2] annulation between two highly versatile starting
materials, 4-hydroxycoumarin and acetyl oxime esters. The ob-
tained furocoumarin products were highly applicable due to
their potential biological activities. Our reaction was proposed
through a radical mechanism which was supported by control
experiments and observed intermediates. The ability of iodine
to activate the N–O bond of the oximes and form a a-iodoimine
intermediate was considered decisive for the ring-closing step
which established the furano moiety of furocoumarins. This
study also assisted our future protocols to employment of more
steric and functional groups tolerance. We are in the process of
exploring this efficient iodine catalyst system in the formation
of other bioactive heterocycles.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
Vietnam National Foundation for Science and Technology
Development (NAFOSTED) is acknowledged for nancial
support via grant no. 104.01-2018.326.
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