Metal-Free Synthesis of Furocoumarins: An Approach via Iodine-Promoted One-Pot Cyclization between 4-Hydroxycoumarins and Acetophenones

Article abstract of DOI:10.1002/ejoc.201800983

A transition metal-free approach was developed to achieve substituted furocoumarins via an iodine-promoted one-pot cyclization between 4-hydroxycoumarins and acetophenones. High yields of furocoumarins were achieved in the presence of NH₄OAc as

Full text of DOI:10.1002/ejoc.201800983

A Journal of
Accepted Article
Title: Metal-free synthesis of furocoumarins: A new approach
via iodine-promoted one-pot cyclization between 4-
hydroxycoumarins and acetophenones
Authors: Nam Thanh Son Phan, Phuc Pham, Que Nguyen, Nhu Tran,
Vu Nguyen, Son Doan, Hiep Ha, and Thanh Truong
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800983
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800983
Supported by

10.1002/ejoc.201800983
European Journal of Organic Chemistry
COMMUNICATION
Metal-free synthesis of furocoumarins: A new approach via
iodine-promoted one-pot cyclization between 4-
hydroxycoumarins and acetophenones
Phuc H. Pham,[a] Que T. D. Nguyen,[a] Nhu K. Q. Tran, [a] Vu H. H. Nguyen,[a] Son. H. Doan,[a] Hiep Q.
Ha,[a] Thanh Truong,[a] and Nam T. S. Phan*[a]
Dedication ((optional))
Abstract: A new transition metal-free approach was developed to
achieve substituted furocoumarins via iodine-promoted one-pot
cyclization between 4-hydroxycoumarins and acetophenones. High
yields of furocoumarins were achieved in the presence of NH4OAc
as an additive, while neither acidic nor basic additives were effective.
The reaction would proceed via 5-exo-tet cyclization but not O-
alkylation. The fact that commercially available starting materials
could be used without the need of transition metal catalyst would be
of significant advantages.
to improve the yield of the furocoumarin (Table 1). The reaction
was conducted in chlorobenzene for 12 h, with 1 equivalent of
acetophenone, in the presence of 2 equivalents of I2 and 3
equivalents of NH4OAc. The influence of temperature was
explored (Entries 1-4, Table 1), and the result indicated the
reaction should be performed at 120 oC with 56% yield being
recorded (Entry 3, Table 1). The transformation was not favored
by using excess amount of acetophenone, while the yield was
significantly upgraded in the presence of excess 4-
hydroxycoumarin (Entries 5-10, Table 1). With 3 equivalents of
4-hydroxycoumarin, 72% yield of 3-phenyl-4H-furo[3,2-
c]chromen-4-one was achieved (Entry 10, Table 1). One crucial
factor for the reaction between 4-hydroxycoumarin and
acetophenone was the amount of I2 (Entries 11-16, Table 1).
Noted that no evidence of the desired product was detected in
the absence of I2, thus verifying the requirement of I2 for this
transformation (Entry 11, Table 1). Best yield was observed for
the reaction utilizing 2 equivalents of I2 (Entry 14, Table 1), and
increasing the amount of I2 did not result in higher yield.
Coumarins have emerged as one of the most recognizable
scaffolds, existing in many natural products and pharmaceuticals
1,
2
.
Among numerous heterocyclic fused coumarins,
furocoumarins have received significant attention owing to their
essential medicinal values 3, 4. Accordingly, a variety of protocols
have been explored to synthesize these bicyclic scaffolds.
Cheng et al. previously synthesized furocoumarins via a
Pd(OAc)2-catalyzed intramolecular cross dehydrogenative
5
coupling transformation . Bankar et al. Bankar et al. achieved
The one-pot cyclization reaction between 4-hydroxycoumarin
and acetophenone did not proceed in the absence of
NH4OAc as an additive. Therefore, several additives were tested
for the formation of the furocoumarin, including basic, acidic, and
neutral candidates (Entries 17-23). Indeed, neither acidic nor
basic additives were appropriate for this reaction, generating the
furocoumarin in very low yield. Among these additives, NH4OAc
and NH4HCO3 were effective for the one-pot cyclization,
affording the expected product in 72% and 71% yields,
respectively (Entries 21-22, Table 1). Additionally, the amount of
NH4OAc displayed a noticeable impact on the formation of 3-
phenyl-4H-furo[3,2-c]chromen-4-one (Entries 24-28, Table 1).
Noted that only 3% yield was detected in the absence of
NH4OAc (Entry 24, Table 1), while expanding the amount of
NH4OAc to 5 equivalents improved the yield to 80% (Entry 28,
Table 1). One important factor to be considered for the one-pot
cyclization reaction was the reaction
furocoumarins by utilizing a cascade transacetalisation, Fries-
type rearrangement followed by Michael addition and ring-
opening aromatization 6. Yang et al. demonstrated a useful one-
pot protocol for the synthesis of furocoumarins via an acylation
of phosphorus zwitterions and a successive intramolecular Wittig
reaction 7. Ghosh and Hajra obtained furocoumarins via a
DABCO-promoted
cyclization
transformation
of
4-
hydroxycoumarins and nitrostyrenes 8. Iodine has recently
emerged as a promising alternative for many transition metals
due to its ability to promote a variety of organic transformations
9-12. In this communication, we would like to report a new iodine-
promoted
acetophenones
corresponding furocoumarins.
one-pot
cyclization
transformation
to
between
achieve
and
4-hydroxycoumarins
The reaction between 4-hydroxycoumarin and acetophenone
was investigated (Scheme 1). It was noted that 3-phenyl-4H-
furo[3,2-c]chromen-4-one was detected in the presence of I2 and
NH4OAc. Initial studies focused on screening reaction conditions
[a]
Phuc H. Pham, Que T. D. Nguyen, Nhu K. Q. Tran, Vu H. H.
Nguyen, Son. H. Doan, Hiep Q. Ha, Thanh Truong, Nam T. S. Phan
Faculty of Chemical Engineering
HCMC University of Technology, VNU-HCM
Scheme 1. Iodine-mediated one-pot synthesis of 3-phenyl-4H-furo[3,2-
268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
E-mail: ptsnam@hcmut.edu.vn
c]chromen-4-one.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Table 1. Screening of reaction conditionsa.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800983
European Journal of Organic Chemistry
COMMUNICATION
Reactant I2
(equiv.)
Additive
(equiv.)
Entry
Solvent
Yieldc
ratiob
1:1
1:1
1:1
1:1
1:2
1:3
1:4
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
0
1
1.5
2
2.5
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
NH4OAc (3) PhCl
8d
33e
54
56f
44
11
7
60
72
0
30
59
72
72
71
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Et3N (3)
PhCl
PhCl
PhCl
PhCl
DMAP (3)
K2CO3 (3)
NaOAc (3)
NH4OAc (3) PhCl
NH4HCO3(3) PhCl
8
9
2
72
71
0
HOAc (3)
PhCl
NH4OAc (0) PhCl
NH4OAc (2) PhCl
NH4OAc (3) PhCl
NH4OAc (4) PhCl
NH4OAc (5) PhCl
NH4OAc (5) n-BuOH
NH4OAc (5) DMF
3
46
72
76
80
8
3
Scheme 2. Control experiments.
NH4OAc (5) dioxane 26
NH4OAc (5) toluene
NH4OAc (5) xylene
NH4OAc (5) DCB
NH4OAc (5) PhCl
NH4OAc (5) PhCl
62
73
34
80
83g
fluorophenyl)-4H-furo[3,2-c]chromen-4-one (Entry 2), 3-(4-
chlorophenyl)-4H-furo[3,2-c]chromen-4-one (Entry 3), and 3-(4-
bromophenyl)-4H-furo[3,2-c]chromen-4-one (Entry 4) were
achieved in 90%, 88%, and 84% yields, respectively. Similarly,
3-(p-tolyl)-4H-furo[3,2-c]chromen-4-one was generated in 92%
yield (Entry 5). However, methoxy-substituted acetophenones
were noted to be less reactive towards the cyclization reaction
(Entries 6-8). The transformation of 1-(thiophen-2-yl)ethan-1-one
afforded the desired furocoumarin in 68% yield (Entry 9, Table
2). Propiophenone was also reactive towards the reaction,
producing 2-methyl-3-phenyl-4H-furo[3,2-c]chromen-4-one in
84% yield (Entry 10, Table 2). Several substituted
propiophenones and 4-hydroxycoumarins were utilized, and
corresponding furocoumarins were obtained in high yields
(Entries 11-17, Table 2). Propiophenone bearing strong
electron-withdrawing group was also well tolerated, and 2-
a) Reaction conditions: 4-hydroxycoumarin (0.3 mmol); solvent (0.5 mL); argon
atmosphere; 120 h; Et3N: triethylamine; DMAP: 4-
oC; 12
dimethylaminopyridine; PhCl: chlorobenzene; DMF: N,N-dimethylformamide;
c)
DCB: 1,2-dichlorobenzene. b) 4-hydroxycoumarin:acetophenone molar ratio.
GC yield. d) 80 oC. e) 100 oC. f) 140 oC. g) 0.4 mL PhCl.
solvent. A variety of solvents were tested for the transformation
(Entries 29-35, Table 1), and chorobenzene emerged as the
best solvent with 80% yield being noted (Entry 35, Table 1).
Furthermore, changing the solvent amount from 0.5 mL to 0.4
mL also upgraded the yield of 3-phenyl-4H-furo[3,2-c]chromen-
4-one to 83% (Entry 36, Table 1).
Following this protocol, several substituted furocoumarins
were then synthesized (Table 2). ). The reaction was conducted
at 120 C in chlorobenzene for 12 h, with 3 equivalents of 4-
hydroxycoumarins, in the presence of 2 equivalents of I2 and 5
equivalents of NH4OAc. In the first series, the reaction between
4-hydroxycoumarin and several substituted acetophenones were
explored (Entries 1-8, Table 2). The iodine-promoted one-pot
cyclization between 4-hydroxycoumarin and acetophenone
afforded 3-phenyl-4H-furo[3,2-c]chromen-4-one in 79% isolated
yield (Entry 1). Moving to halo-substituted acetophenones, 3-(4-
methyl-3-(3-nitrophenyl)-4H-furo[3,2-c]chromen-4-one
was
isolated in 87% yield (Entry 18, Table 2). This protocol was also
effective for cyclohexanone, forming 7,8,9,10-tetrahydro-6H-
benzofuro[3,2-c]chromen-6-one in 80% yield (Entry 19, Table 2).
Interestingly, when α-tetralone was used as a sterically hindered
substrate, subsequent aromatization occurred to give 6H-
naphtho[1',2':4,5]furo[3,2-c]chromen-6-one in 26% yield (Entry
20, Table 2).
o
In order to achieve more information for the pathway of the
one-pot cyclization reaction between acetophenone (1) and 4-
hydroxycoumarin (2), necessary control experiments were then
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800983
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Iodine-promoted one-pot synthesis of substituted furocoumarinsa.
Table 2 (continue)
Yieldb
(%)
Entry Reactant 1
Reactant 2
Product
15
16
17
18
19
76
Yieldb
(%)
Entry Reactant 1
1
Reactant 2
Product
78
72
87
80
26
79
90
88
2
3
4
5
6
84
92
53
20
a)
Reaction conditions: 4-hydroxycoumarins (0.3 mmol); acetophenones (0.1
mmol); I2 (0.2 mmol); NH4OAc (0.5 mmol); chlorobenzene (0.4 mL); 120 oC;
12 h. b) Isolated yield.
7
28
performed (Scheme 2). (i) The reaction afforded 75% yield of 3-
phenyl-4H-furo[3,2-c]chromen-4-one (3) in the presence of 1
equivalent
(TEMPO) as
of
a
(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl
radical scavenger, suggesting that the
8
9
54
68
84
transformation did not follow a radical mechanism (Scheme 2 a).
(ii) Heating (1) without (2) under the standard conditions led to
the formation of 2-iodoacetophenone (4) with 96% conversion
(Scheme 2 b). (iii) The reaction between (2) and (4) produced
(3) in 82% yield in the presence of NH4OAc under the standard
conditions (Scheme 2 c). (iv) Utilizing similar conditions, the
reaction between (2) and 2-bromoacetophenone (5) afforded
70% yield of (3) (Scheme 2 d). (v) 4-(2-Oxo-2-phenylethoxy)-2H-
chromen-2-one (6) was prepared in 83% yield via the O-
alkylation reaction between (2) and 2-bromoacetophenone (5) in
the presence of K2CO3. However, upon heating (6) under the
standard conditions, the desired furocoumarin (3) was not
detected in the reaction mixture (Scheme 2 e), indicating that the
one-pot cyclization reaction between (1) and (2) to produce (3)
would not proceed via the formation of (6).
10
11
12
13
14
85
84
81
75
On the basis of above observations and the literature, a
possible reaction pathway was suggested for the iodine-
promoted one-pot cyclization between 4-hydroxycoumarin and
acetophenone (Scheme 3). Initially, (1) was converted to (4) via
its enol form (A) in the presence of an acid catalyst. Ammonia
and acetic acid were produced upon heating the reaction
mixture. Noted that neither acidic nor basic additives were
appropriate, while NH4OAc was effective due to the formation of
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800983
European Journal of Organic Chemistry
COMMUNICATION
both acidic and basic species during the transformation. GC-MS
analysis indicated the formation of (4) in the product mixture.
Indeed, this transformation was previously demonstrated by Rao
and Jadhav 13. In the presence of NH3 as a base, (2) was
transformed to its enolate (C) via its active diketone form (B).
Subsequently, nucleophilic addition of enolate (C) to (4) led to
remarkable advantages of this protocol are: (i) no transitional
metal is required; (ii) commercially available acetophenones and
4-hydroxycoumarins; (iii) high yields of furocoumarins; and (iv)
broad substrate scope. This protocol would attract attention from
the pharmaceutical and fine chemical industries.
the
formation
of
intermediate
3-(1-hydroxy-2-iodo-1-
phenylethyl)chromane-2,4-dione (D). The base-promoted 5-exo-
tet cyclization consequently occurred to form intermediate 3-
hydroxy-3-phenyl-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (E).
Finally, the desired furocoumarin (3) was generated via an acid-
catalyzed dehydration step. Indeed, Risitano et al. previously
synthesized furocoumarins from 4-hydroxycoumarins and α-
haloketones, and proposed that these tandem transformations
would proceed
Experimental Section
To a 8-mL screw-cap vial containing 0.4 mL chlorobenzene was added
acetophenone (12.0 mg, 0.1 mmol), 4-hydroxycoumarin (48.6 mg, 0.3
mmol), NH4OAc (38.5 mg, 0.5 mmol), molecular iodine (50.8 mg, 0.2
mmol) and diphenyl ether (17.0 mg, 0.1 mmol) as an internal standard.
The reaction tube was then stirred at 120 oC for 12 h. After that, the
mixture was slowly cooled to room temperature and washed with
Na2S2O3 solution (10% in water, 3×5 mL), the organic components was
subsequently extracted into dichloromethane (20 mL), dried over
anhydrous Na2SO4 and concentrated in vacuo. The crude product was
purified
by
column
chromatography
on
silica
gel
with
hexane/dichloromethane as eluent to give pure product. The product
identity was further confirmed by GC-MS, 1H NMR and 13C NMR.
Acknowledgements ((optional))
Keywords: furocoumarins • 4-hydroxycoumarins •
acetophenones • one-pot • tandem reaction
[1]
[2]
[3]
Zhang, R.-R.; Liu, J.; Zhang, Y.; Hou, M.-Q.; Zhang, M.-Z.; Zhou, F.;
Zhang, W.-H. Eur. J. Med. Chem. 2016, 116, 76.
Kawaai, K.; Yamaguchi, T.; Yamaguchi, E.; Endo, S.; Tada, N.; Ikari,
A.; Itoh, A. J. Org. Chem. 2018, 83, 1988.
Medina, F. G.; Marrero, J. G.; Macías-Alonso, M.; González, M. C.;
Córdova-Guerrero, I.; García, A. G. T.; Osegueda-Robles, S. Nat. Prod.
Rep. 2015, 32, 1472.
[4]
[5]
[6]
[7]
Melough, M. M.; Vance, T. M.; Lee, S. G.; Provatas, A. A.; Perkins, C.;
Qureshi, A.; Cho, E.; Chun, O. K. J. Agric. Food Chem. 2017, 65, 3006.
Cheng, C.; Chen, W.-W.; Xu, B.; Xu, M.-H. Org. Chem. Front. 2016, 3,
1111.
Scheme 3. Plausible reaction mechanism.
Bankar, S. K.; Mathew, J.; Ramasastry, S. S. V. Chem. Commun. 2016,
52, 5569.
Yang, S. M.; Wang, C. Y.; Lin, C. K.; Karanam, P.; Reddy, G. M.; Tsai,
Y. L.; Lin, W. Angew. Chem. Int. Ed. 2018, 57, 1668.
Ghosh, M.; Hajra, A. Eur. J. Org. Chem. 2015, 35, 7836.
Donthiboina, K.; Namballa, H. K.; Shaik, S. P.; Nanubolu, J. B.;
Shankaraiah, N.; Kamal, A. Org. Biomol. Chem. 2018, 16, 1720.
following two different pathways: (i) via O-alkylation, and (ii) via
5-exo-tet cyclization 14. Prakash et al. initially considered two
plausible pathways for similar reactions, and finally suggested
that the transformation did not proceed via O-alkylation step
However, in this work, the iodine-promoted one-pot cyclization
would not proceed via the O-alkylation (Scheme 2 e).
[8]
[9]
15
.
[10] Kour, D.; Gupta, A.; Kapoor, K. K.; Gupta, V. K.; Rajnikant; Singh, D.;
Das, P. Org. Biomol. Chem. 2018, 16, 1330.
[11] Yang, J.; Xie, D.; Zhou, H.; Chen, S.; Huo, C.; Li, Z. Org. Chem. Front.
2018, 5, 1325.
In conclusion, a new transition metal-free approach was
developed to achieve substituted furocoumarins via iodine-
promoted one-pot cyclization between 4-hydroxycoumarins and
acetophenones. The transformation proceeded readily to
produce furocoumarins in the presence of NH4OAc as an
additive, while neither acidic nor basic additives were effective.
The solvent displayed a noticeable impact on the reaction, and
chlorobenzene emerged as the best candidate. The reaction
would proceed via 5-exo-tet cyclization but not O-alkylation. The
[12] Xu, H.; Liu, H.-W.; Lin, H.-S.; Wang, G.-W. Chem. Commun. 2017, 53,
12477.
[13] Rao, M. L. N.; Jadhav, D. N. Tetrahedron Lett. 2006, 47, 6883.
[14] Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. Tetrahedron Lett. 2001, 42,
3503.
[15] Prakash, O.; Wadhwa, D.; Hussain, K.; Kumar, R. Synth. Commun.
2012, 42, 2947.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800983
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Phuc H. Pham, Que T. D. Nguyen, Nhu
K. Q. Tran, Vu H. H. Nguyen, Son. H.
Doan, Hiep Q. Ha, Thanh Truong, and
Nam T. S. Phan*
Page No. – Page No.
Metal-free synthesis of
furocoumarins: A new approach via
iodine-promoted one-pot cyclization
between 4-hydroxycoumarins and
acetophenones
Iodine-mediated one-pot synthesis of furocoumarins
This article is protected by copyright. All rights reserved.