One-step synthesis of furan rings from α-isopropylidene ketones mediated by iodine/DMSO: An approach to potent bioactive terpenes

Article abstract of DOI:10.1021/acs.joc.9b00704

The system I₂/dimethyl sulfoxide mediates the one-step transformation of α-isopropylidene ketones into furan rings following a biomimetic approach. This methodology has been used for the synthesis of terpene furans such as mintfurane, curzerene, atractylon, and isoatractylon, all of them possessing interesting biological activities. The synthesis of linderazulene directly from 4,5-epoxygermacrone via a cascade reaction shows the potential of this protocol. Additionally, this compound proved to show significant ixodicidal activity.

Full text of DOI:10.1021/acs.joc.9b00704

Subscriber access provided by UNIV OF WISCONSIN - MADISON
Article
One-step Synthesis of Furan Rings from #-Isopropylidene Ketones
Mediated by Iodine/DMSO: An Approach to Potent Bioactive Terpenes.
Jonida Salihila, Lúcia Silva, Helena Pérez del Pulgar, Ana Quílez Molina, Azucena
González-Coloma, A. Sonia Olmeda, José F. Quilez del Moral, and Alejandro F. Barrero
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 14 May 2019
Downloaded from http://pubs.acs.org on May 14, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
a
One-step Synthesis of Furan Rings from -Isopropylidene
Ketones Mediated by Iodine/DMSO: An Approach to Potent
Bioactive Terpenes
Jonida Salihila,† Lúcia Silva,‡ Helena Pérez del Pulgar,† Ana Quílez Molina,† Azucena González-
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†,
†,
§
Coloma, A. Sonia Olmeda,∥ José F. Quílez del Moral, * and Alejandro F Barrero *
† Department of Organic Chemistry, Institute of Biotechnology, University of Granada, 18071 Granada,
Spain.
‡
FibEnTech-Materiais Fibrosos e Tecnologias Ambientais, Department of Chemistry, University of
Beira Interior, 6200 Covilhã, Portugal.
§
Institute of Agricultural Sciences, CSIC, 28006, Madrid, Spain
∥
Department of Animal Health, Faculty of Veterinary Medicine, Complutense University of Madrid,
28040, Madrid, Spain.
TOC GRAPHIC
ABSTRACT: The system I2/DMSO mediates the one-step transformation of a-isopropylidene ketones
into furan rings following a biomimetic approach. This methodology has been used for the synthesis of
terpene furans such as mintfurane, curzerene, atractylon and isoatractylon, all of them possessing
interesting biological activities. The synthesis of linderazulene directly from 4,5-epoxygermacrone via a
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 24
cascade reaction shows the potential of this protocol. Additionally, this compound proved to show
significant ixodicidal activity.
1
2
3
4
5
6
7
INTRODUCTION
8
9
Terpene furans encompass a number of structures ranging from monoterpenes to tri- or tetraterpenes
1
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(carotenes) possessing an interesting variety of biological activities.
Among them, menthofuran (mintfuran) 1 is an aromatic compound present in the essential oil of
2
different peppermint varieties including Mentha piperita and pennyroyal (Mentha pulegium). Recently,
menthofuran was found in red wines, where it is considered the precursor of p-menthane lactones,
3
which are an important group of aromatizers. This substance possesses, among other activities,
4
antifungal and hepatotoxic properties. Curzerene 2 was originally isolated from the “curcuma
5a
rhizomes”, a plant used in traditional Chinese medicine. It was also found in wild celery (Smyrnium
5b
olusatrum) and other Smyrnium species. This was reported to contribute to the antioxidant properties
5c
5b,5d
of the essentials oils of curcuma and to exhibit cytotoxic and antitumor activity. Atractylon 3 is an
6a
eudesmane derivative isolated from the rhizomes of species of Atractylodes. This furan sesquiterpene
presents a wide range of biological activities. Thus, atractylon is the major factor responsible of the
6a
anti-inflammatory and antinociceptive effects of Atractylodes japonica. It also shows anti-allergic,
6b
6c
anti-tumor, anti-viral, and insecticidal properties. Its isomer, isoatractylon (4), was isolated from the
6d
6e
Antarctic gorgonian Dasystenella acanthine and was reported to exhibit ichthyotoxicity against the
7
mosquito fish Gambusia affinis. Linderazulene (5) is a purple pigment isolated from Paramuricea
8a 8b-d
chamaeleon and other gorgonians This compound was reported to be a neoplasm inhibitor,
8e
immunomodulator and fungicide.
9
The synthesis of menthofuran (1) has been previously reported – including a cyclization from
9b
pulegone using an aqueous solution of Ba(OH)2 in the presence of a solution of I2/KI in MeOH.
2
ACS Paragon Plus Environment

Page 3 of 24
The Journal of Organic Chemistry
10
However, few synthetic efforts reporting the synthesis of 2-4 were described despite the wide range of
1
2
3
biological activities displayed by these compounds.
11
Molecular iodine is a versatile reagent in organic chemistry mediating a great number of synthetic
4
5
6
7
8
9
transformations including some dehydration and dehydrogenative processes. Additionally, the combined
use with DMSO not only has increased the range of transformations promoted by I2 but also made
12
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
possible its use in catalytic quantities.
It has been reported that in some living organisms terpene furans cooccur with the corresponding
derivatives possessing a a-isopropylidene ketone. This moiety was postulated as biogenetic precursor of
13
the furan ring through cytochrome P450 mediated oxidations. Bearing all this in mind, we described an
I2/DMSO mediated synthesis of furans from a-isopropylidene cyclohexanones (I), a structural moiety
present in different natural products and easily accessible by synthetic means (Scheme 1).
The process would imply the addition of the iodine reagent to enol II to produce the cyclic iodonium
ions III or V. Since in the intermediate II the two double bonds should be twisted, there should not
exist much conjugation between the isopropylidene group and the enol moiety, which would render the
intermediate V more likely to be formed. Then, intermediates III or V would evolve, likewise, via an
iodoetherification reaction to give the iododihydrofuranes IV or VI. Finally, an easy HI elimination
from intermediates IV or VI would generate the more stable aromatized structure, VIII. Alternatively,
intermediate V could also produce the a-iodo-b,g-unsaturated ketone VII before evolving to aromatic
14
VIII.
Finally, it should be noted that according to the proposed mechanism, the process of regeneration of I2
by DMSO generates DMS. This sulfide, in the presence of I2, could generate iododimethylsulfonium
15
iodide, which in turn may contribute to the furan ring synthesis.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 24
1
2
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Scheme 1. Working Hypothesis: A Simple Process Converting -Isopropylidene ketones into
Furans.
RESULTS AND DISCUSSION
To test the feasibility of this approach to synthesizing furans and explore its applicability to the
synthesis of natural bioactive products, we chose commercially available pulegone (6) as a model.
When pulegone (1 mmol) was exposed to 1 mmol of I2 and 5 mmol of DMSO in refluxing tert-butyl
12b
methyl ether (MTBE) for 6 h, menthofuran (1) was obtained in a 15% yield together with minor
proportions of dehydromintlactone (7) (Table 1, entry 1). The latter product was formed from 1 via an
iodation-Korblum oxidation tandem process. This result proved the feasibility of our approach to the
synthesis of furans via the cascade of transformations depicted in Scheme 1. If under the same
experimental conditions, the reaction time was prolonged to 25 h, only a 2% yield of 1 was obtained but
the production of 7 increased up to 35% (Table 1, entry 2). When solvents of medium-low polarity,
such as THF, DCM or CCl4, were tested (Table 1, entries 3-5), mainly degradation of the starting
material was obtained when performing the reaction with THF or DCM. However, when CCl4 was used,
noticeable proportions of lactone 7 and ketofuran 8 were obtained. The use of benzene or toluene as
solvent (Table 1, entries 6-9) also led to the formation of dehydromintlactone (7) as major reaction
4
ACS Paragon Plus Environment

Page 5 of 24
The Journal of Organic Chemistry
product, which implies that the conditions were too harsh to stop the process at the furan level. When
hexane was used as solvent, the transformation proceeded more smoothly (Table 1, entries 10-13), and
the best yield of 1 (68%) was obtained when the quantity of iodine was reduced to substoichiometric
proportions of I2, that is 0.2 mmol. Noticeably, the use of an excess of I2 led to a 55% yield of
dehydromintlactone 7 (Table 1, entry 13). Gratifyingly, the combined use of I2 (0.2 mmol) and DMSO
as solvent led to a 75% yield of furan 1 (Table 1, entry 14). Additionally, different reactions were
1
2
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
achieved using NIS as source of I (Table 1, entries 15-16). Thus, the reaction of 0.2 mmol of NIS with
pulegone in DMSO at 50 °C afforded target 1 in 65% yield after 24 h. When toluene was used as
solvent and no DMSO was added, the reaction of pulegone with NIS evolved to give the
16
isopropylbenzofurane 9 as the main reaction product, with only traces of 1 being obtained. The
formation of 9 implies a retro-Aldol condensation of 1 yielding acetone, which couples with an
16
appropriate furan intermediate.
It should be noted that compounds 7 and 8, found in some of the abovementioned tests, were also
natural products. Thus, dehydromintlactone 7 is claimed to be responsible for the coumarinic odor
17
indicating high-quality in the corresponding peppermint oils. Compound 8 is a minor constituent of
18
Mentha piperita.
Table 1. Optimization of the Furan Ring Synthesis of Pulegone
Source of
I (mmol)
Tim
e (h)
entry
Solvent
1
7
8
9
10
+
1a
2
3
4
5
6
1
1
1
1
1
1
MTBE
MTBE
THF
DCM
CCl4
6
25
2
2
3
15
t
3
-
18
35
15
5
34
32
14
3
32
15
4
5
Toluene
0.5
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 24
7
8
0.2
1
0.2
1
0.5
0.2
3
0.2
NIS 0.2
NIS 0.2
Toluene
Benzene
Benzene
Hexane
Hexane
Hexane
Hexane
DMSO
DMSO
0.2
3
1
6
9
12
3
6.5
24
0.2
14
26
3
44
29
2
4
20
1
2
3
4
5
6
7
8
19
9b
32
10
11
12
13
14c
15c
16d
14
15
9
14
14
68
55
16
4
75
65
2
3
Toluene
52
9
The reactions were performed at refluxing temperature and at [C] 0.1 M and using 5 mmol
of DMSO to regenerate iodine. 50% of pulegone was recovered. 24% of pulegone was
recovered. The reaction was conducted at 60 °C. No DMSO was added.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
c
d
Once we proved that menthofuran (1) can be efficiently synthesized from the corresponding a-
isopropylidene cyclohexanone, i.e., pulegone (6), we focused our efforts on checking if this
methodology is useful to other bioactive furanterpenes, such as natural compounds 2-5. All these
compounds were planned to be synthesized using germacrone (11) as common starting material.
Germacrone is a sustainable natural product, available in multigram scale from cultivated Geranium
19
macrorrhizum.
The synthesis of curzerene (2) was anticipated to proceed in only two steps from germacrone (Scheme
2). The first step involved the Pd(II)-mediated Cope rearrangement of germacrone to produce
20
elemenone (12) in 98% yield.
Scheme 2. Synthesis of Curzerene (2)
6
ACS Paragon Plus Environment

Page 7 of 24
1
2
3
The Journal of Organic Chemistry
When elemenone was treated with 0.2 mmol of I2 in DMSO (the best experimental conditions
obtained for menthofuran synthesis), curzerene (2) was produced in an excellent (83%) yield. The high
chemoselectivity of this transformation warrants mention, since elemenone (12) presents two additional
4
5
6
7
+
double bonds also susceptible of reacting with positive iodine ions (I ). It should also be noted that when
8
9
the reaction was performed in refluxing toluene and using 1 mmol of I2, variable quantities (up to 21%)
of the natural elemenolactone curzerenone (14) were produced together with minor proportions of the
ketocurzerene derivative 13. Both compounds were previously described from natural sources. Thus,
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21
ketone 13 was found in the essential oil of Asarum caulescens, whereas lactone 14 was isolated from
Commiphora molmol (Burseraceae) “Myrrha” and Curcuma wenyujin (Zingiberaceae). Compound 14
shows an important cytotoxic activity and anti-inflammatory action comparable to that of
22
hydrocortisone.
Three different synthetic routes to atractylon (3) and its isomer 4 were planned (Scheme 3). The first
one supposed the initial reaction of germacrone with catalytic Bi(OTf)3 to yield (70%) a mixture of
23
eudesmanes 15-17 in a 1:1:0.4 ratio. From this mixture, the exo isomer 16 was isolated and tested
reaction with the system of I2/DMSO in different solvents and conditions. Up to 80% yield of atractylon
was obtained after refluxing 16 in MTBE for 6 h. The reaction of 17 under the same experimental
conditions afforded 82% yield of isoatractylon (4).
Scheme 3. Three Routes toward Atractylon (3) and Isoatractylon (4) from Germacrone (11)
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 24
1
2
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the second route to atractylon, the eudesmane skeleton was generated via electrophilic bromination
of germacrone to give the bromoderivatives 18 and 19 in 19 and 53% yield, respectively. The reductive
bromination of 18 and 19 proceeded with yields higher that 95% to produce eudesmanes 16 and 17,
which were converted into 3 and 4 following our iodine-mediated protocol for the synthesis of furans.
For the third route, we anticipated that the I2/DMSO system could provoke in only one step the
iodocarbocyclization of germacrone to produce iodoeudesmanes that would evolve in the same reaction
media to the corresponding iodofurans 20 and 21. A reductive deiodination in a subsequent step would
lead to atractylon (3) and its isomer 4. Thus, when germacrone (11) was made to react with the
I2/DMSO system under different experimental conditions, it was found that a 74% of the mixture of
iodofurans 20 and 21 (5:1 ratio) were produced if 1 mmol of I2 and 5 mmol of DMSO were employed,
and the reaction was let to evolve for 48 h at rt in hexane. The radical-promoted hydrodeiodination of
20 using the system nBu3SnH-AIBN afforded a 54% of atractylon (3). The same transformation
produced a 56% of furan 4 from iododerivative 21.
At this point, we considered that the different reactivity of the olefin moieties in germacrone (11) and
elemenone (12) (Schemes 2 and 3) warranted rationalization. In this regard, some of us described the
23
two major conformations that germacrone (11) presents in solution. These studies revealed that no
appreciable conjugation exist between the carbonyl and the isopropylidene groups, thus-preventing the
easy formation of the corresponding enol and consequently the generation of the furan ring. Instead, the
8
ACS Paragon Plus Environment

Page 9 of 24
The Journal of Organic Chemistry
reaction took place at the 1,5-diene moiety of germacrone. Once the eudesmane skeleton is generated,
the high torsional strain existing in germacrone is released, which favors the formation of the
corresponding enols, and therefore, the production of eudesmane furans 20 and 21. The same reasoning
can be argued to rationalize the selective reactivity of elemenone (12).
1
2
3
4
5
6
7
8
12
Finally, bearing in mind the synthetic versatility of the I2/DMSO system, we wondered if I2/DMSO
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
could promote a cascade reaction to yield linderazulene in only one step from 4,5-epoxygermacrone
24
(22), a natural compound that is considered a biosynthetic precursor of guaianes. The process will
mimic the natural biosynthesis of linderazulene (5) and presents a remarkable synthetic challenge since
it would include, in only one step, a series of very different synthetic transformations such as
carbocyclization, dehydration, dehydrogenation, heterocyclization and furan aromatization (Scheme 4).
Scheme 4. Proposed Mechanism for the Direct Conversion of 4,5-Epoxygermacrone (22) into
Linderazulene (5).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 24
1
2
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Epoxygermacrone 22 is a natural product present in Geranium macrorrhizum and can also be
23
obtained after treatment of germacrone with MCPBA. Initially, 22 was treated with 0.4 mmol of I2 and
5 mmol of DMSO in refluxing MTBE for 90 min affording a mixture of four guaiane alcohols (23-26,
5.2:1.9:1.9:1 ratio) together with 2% of linderazulene (5) (Scheme 5). The formation of these guaianes
confirmed the capability of the I2/DMSO system of opening epoxides and carrying out carbocyclizations
efficiently. Compound 26 is described for the first time, whereas 23-25 are active principles of different
25
Curcuma species. With the ultimate idea of improving the efficiency in the generation of linderazulene,
10
ACS Paragon Plus Environment

Page 11 of 24
The Journal of Organic Chemistry
we found that the mixture of guaianes 23-25 could be converted into 5 with a 46% yield after treatment
with 0.5 mmol of I2 and 5 mmol of DMSO in refluxing toluene for 3 min. We next focused on
optimizing the conditions for the generation of linderazulene in only one step. After examining different
conditions, we found that a 21% yield of linderazulene (5) was obtained when 0.5 mmol of I2 and 30
mmol of DMSO were used in refluxing toluene after only 5 min. It should also be underlined that all
these transformations were promoted using substoichiometric quantities in iodine. Although the yield
obtained is undoubtedly modest, we should take into consideration that this transformation involved
seven synthetic steps.
1
2
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Conversion of 4,5-Epoxygermacrone (22) into Linderazulene (5).
To conclude, the insecticidal and acaricidal effects of linderazulene against the hard tick Hyalomma
lusitanicum Koch (Ixodida: Ixodidae) and the insect pests Spodoptera littoralis Boisd, Myzus persicae
Sulz, and Rhopalosiphum padi L. Although linderazulene did not present remarkable insecticide activity
(Table 2), it showed strong ixodicidal (anti-tick) effects (Table 3).
Table 2. Insecticidal Effects of Linderazulene (5).
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 24
Dosis
(µg /cm2)
50
S. littoralis
M. persicae
R. padi
1
2
3
4
62,48 ± 7,72 43,81 ± 9,67 62,15 ± 6,09
5
6
7
Table 3. Acaricidal Effects of Linderazulene (5).
8
9
mg/ml
2.5
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
5
1.25
0.62
0.31
Mortalitya,b
98.41±0.02
81.36±2.24 100 ± 0 100 ± 0 20.20 ± 3.79 3.33 ± 3.33
a
b
Corrected according to Scheider-Orelli’s formula. Values are means of three replicates. Doses needed to give 50 and 90%
mortality: LC50: 1.49 (1.13-1.86) and LC90: 4.80 (4.09-5.88). Values in parenthesis indicate 95% confidence limits: lower,
upper.
CONCLUSION
In conclusion, an I2/DMSO-mediated biomimetic protocol for the synthesis of furan rings from a-
isopropylidene ketones was developed. The utility of the method was demonstrated by the synthesis of
different bioactive furan terpenes 2-4 and specially the guaiazulene linderazulene (5), which was
revealed to be a potent garrapaticide. Furthermore, in some cases, the corresponding bioactive
dienelactone derivatives can also be generated in moderate yields in this transformation.
EXPERIMENTAL SECTION
General Remarks.
Silica gel SDS 60 (35-70 µm) was used for flash column chromatography. NMR spectra were
1
13
1
acquired with Varian Direct-Drive 600 ( H 600 MHz/ C 150 MHz), Varian Direct-Drive 500 ( H 500
13
MHz/ C 125 MHz), Varian Direct-Drive 400 ( H 400 MHz/ C 100 MHz) and Varian Inova Unity 300
1
13
1
13
( H 300 MHz/ C 75 MHz) spectrometers. Accurate mass determinations were achieved with a SYNAPT
G2-Si Quadrupole-time-of-flight mass spectrometer (Waters, Milford, MA, USA) equipped with high-
efficiency T-Wave ion mobility and an orthogonal Z–spray™ electrospray ionization (ESI) source was
used for mass analyses. MassLynx v.4.1 software was used for HRMS instrument control, peak
detection, and integration. The reactions were monitored by TLC, which were performed on 0.25-mm
E. Merck silica gel plates (60F-254) and involves the use of UV light for visualization and solutions of
phosphomolybdic acid in EtOH and heat as the developing agents. HPLC with UV light and RI
12
ACS Paragon Plus Environment

Page 13 of 24
The Journal of Organic Chemistry
detection was also used. Semipreparative HPLC separations were conducted on a silica column (5 µm,
1
2
3
4
5
6
7
10 x 250 mm) at a flow rate of 2.0 mL/min using an Agilent Series 1100 instrument. The reagents were
purchased at the highest quality that was commercially available and were used without further
purification.
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
General procedure for the I2/DMSO-mediated generation of furan rings from -isopropylidene
ketones
To a solution of the corresponding starting material (1 mmol) in the organic solvent (0.1 M) heated
under reflux was added iodine (0.2-3 mmol) and DMSO (5 mmol). The solution was stirred at reflux
and monitored by thin-layer chromatography analysis. Upon consumption of the starting material the
reaction was diluted in tert-butyl methyl ether (MTBE) (100 mL), washed with a saturated solution of
sodium thiosulfate (1 x 100 mL), and brine (1 x 100 mL). The organic layer was dried over sodium
sulfate and evaporated in vacuo. Purification was performed by silica gel chromatography to yield
chromatographically and spectroscopically pure product.
Reaction of pulegone (6) with the system I2/DMSO: Synthesis of menthofuran (1).
The standard procedure was followed using 1 mmol (152 mg) of 6, 0.2 mmol (51 mg) of iodine and
DMSO as solvent, the reaction was heated at 60 ºC with a reaction time of 6.5 h. The crude product was
purified by column chromatography over silica gel using mixture de hexanes (H) as eluent to obtain
menthofuran (1) (112 mg, 75%)
1
Menthofuran (1). H NMR (500 MHz, CDCl3) δ 7.07 (bs, 1H), 2.69 (dd, J = 16.0, 5.3 Hz, 1H), 2.46-
2.31 (m, 2H), 2.20 (dd, J = 16.0, 9.5 Hz, 1H), 2.00-1.90 (m, 1H), 1.96 (d, J = 1.0 Hz, 3H), 1.91-1.83
13
(m, 1H), 1.39 (dddd, J = 13.2, 10.9, 10.1, 5.8 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H); C{ H} NMR (125
1
MHz, CDCl3): δ 150.7, 136.8, 119.6, 117.4, 31.5, 31.4, 29.6, 21.5, 19.9, 8.1. The spectroscopic data
9a
found for this compound matched those reported in the literature.
Reaction of pulegone (6) with the system I2/DMSO: Synthesis of mintlactone (7) and compounds 8
and 10.
The standard procedure was followed using 1 mmol (152 mg) of 6, 1 mmol (254 mg) of iodine,
MTBE as solvent heated at a reflux temperature and with a reaction time of 25 h. The crude product
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 24
was purified by column chromatography over silica gel using mixtures of H and MTBE of increasing
polarity as eluent to obtain 57 mg (35%) of compound 7 (H/MTBE 4:1), 29 mg (18%) of compound 8
(H/MTBE 4:1) and 25 mg (14%) of compound 10 (H/MTBE 2:1).
1
2
3
4
5
6
7
1
(R)-3,6-Dimethyl-5,6-dihydrobenzofuran-2(4H)-one (7). H NMR (500 MHz, CDCl3) δ 5.61 (d, J =
8
9
3.3 Hz, 1H), 2.74 (dt, J = 17.1, 5.0 Hz, 1H), 2.63–2.55 (m, 1H), 2.48 (dddq, J = 17.6, 11.1, 4.8, 1.6 Hz,
1H), 1.98 (dq, J = 13.3, 4.9 Hz, 1H), 1.87 (bs, 3H), 1.46 (dddd, J = 13.4, 11.3, 8.9, 4.7 Hz, 1H), 1.15 (d,
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1
J = 7.1 Hz, 3H); C{ H} NMR (125 MHz, CDCl3): δ 171.5, 149.1, 148,1, 119.7, 114.0, 30.9, 29.7, 21.6,
21.1, 8.3. The spectroscopic data found for this compound were identical to those reported in the
26
literature.
1
(R)-3,6-dimethyl-5,6-dihydrobenzofuran-7(4H)-one (8). H NMR (600 MHz, CDCl3) δ 7.36 (q, J =
1.2 Hz, 1H), 2.73–2.61 (m, 2H), 2.61–2.54 (m, 1H), 2.22 (dq, J = 13.7, 4.6 Hz, 1H), 2.00 (d, J = 1.0 Hz,
13
1
3H), 1.91 (dddd, J = 13.5, 10.6, 9.3, 5.5 Hz, 1H), 1.25 (d, J = 6.9 Hz, 3H); C{ H} NMR (125 MHz,
1
CDCl3): δ 189.1, 147.4, 144,5, 139.7, 120.6, 41.8, 32.2, 20.1, 14.9, 7.8. The H NMR data found for this
18
compound were identical to those reported in the literature.
1
(R,Z)-2-(4-Methyl-2-oxocyclohexylidene)propanoic acid (10). H NMR (500 MHz, CDCl3) δ 2.66 (bd,
J = 13.9 Hz, 1H), 2.40–2.31 (m, J = 11.4, 3.2 Hz, 2H), 2.04–1.92 (m, 2H), 1.78 (bs, 3H), 1.24 (t, J =
13
1
12.8 Hz, 1H), 1.00 (dq, J = 13.0, 4.2 Hz, 1H), 0.96 (d, J = 6.5 Hz, 3H); C{ H} NMR (125 MHz,
CDCl3): δ 172.6, 160.7, 121.2, 103.7, 45.9, 35.0, 29.1, 24.4, 21.0, 8.1. The spectroscopic data found for
27
this compound were identical to those reported in the literature.
Reaction of pulegone (6) with NIS/ Toluene: Synthesis of compound 9.
The standard procedure was followed using 1 mmol (152 mg) of 6, 0.2 mmol (45 mg) of NIS and
toluene as solvent heated at 60º C with a reaction time of 0.2 h. The crude product was purified by
column chromatography over silica gel using H as eluent to obtain a compound 9 (49 mg, 52%).
1
2-Isopropyl-3,6-dimethylbenzofuran (9). Colorless oil; H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.9
Hz, 1H), 7.22 (bs, 1H), 7.03 (bd, J = 7.9 Hz, 1H), 3.17 (hept, J = 7.0 Hz, 1H), 2.47 (s, 3H), 2.17 (s,
13
3H), 1.33 (d, J = 7.0 Hz, 6H); C{ H} NMR (100 MHz, CDCl3): δ 158.0, 154.2, 133.2, 128.3, 123.3,
1
+
118.3, 111.1, 107.4, 26.5, 21.7 21.3 (x 2C), 7.9. HRMS (ESI-QTOF) m/z: [M+H] Calcd for C13H16O
189.1279; Found 189.1277.
14
ACS Paragon Plus Environment

Page 15 of 24
1
The Journal of Organic Chemistry
2
3
Reaction of elemenone (12) with the system I2/DMSO: Synthesis of curzerene (2) and curzerenone
4
5
(14)
6
7
8
9
The standard procedure was followed using 1 mmol (218 mg) of 12, 0.2 mmol (51 mg) of iodine,
DMSO as solvent (60 ºC) and with a reaction time of 5 h. The crude product was purified by column
chromatography over silica gel using (H/MTBE 99:1) to obtain curzurene (2) (179 mg, 83%).
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Curzerene (2). H NMR (600 MHz, CDCl3) δ 7.08 (bs, 1H), 5.91 (dd, J = 17.5, 10.8 Hz, 1H), 5.02 (dd,
J = 17.5, 0.9 Hz, 1H), 5.00 (dd, J = 10.8, 0.9 Hz, 1H), 4.90 (bs, 1H), 4.78 (bs, 1H), 2.70 (bd, J = 16.3
Hz, 1H), 2.47-2.43 (m, 2H), 2.39 (d, J = 16.3 Hz, 1H), 2.32 (t, J = 7.2 Hz, 1H), 1.95 (d, J = 1.3 Hz,
13
3H), 1.77 (s, 3H), 1.10 (s, 3H); C{ H} NMR(150 MHz, CDCl3): δ 149.6, 147.2, 147.1, 137.2, 119.3,
1
116.5, 112.7, 111.0, 50.0, 40.1, 36.1, 24.5, 24.2, 19.5, 8.1. The spectroscopic data found for this
10b
compound were identical to those reported in the literature.
The standard procedure was followed using 1 mmol (218 mg) of 12, 1 mmol (254 mg) of iodine,
toluene as solvent and with a reaction time of 30 min. The crude product was purified by column
chromatography over silica gel using gel using H and MTBE of increasing polarity as eluent to obtain
16 mg (7%) of compound 13 (H/MTBE 99:1), 43 mg (20 %) of curzurene (2) (H/MTBE 99:1), and 48
mg (21%) of curzerenone (14) (H/MTBE 9:1).
1
9-Ketocurzerene (13). H NMR (500 MHz, CDCl3) δ 7.39 (q, J = 1.1 Hz, 1H), 5.93 (dd, J = 17.5, 10.7
Hz, 1H), 5.16 (dd, J = 10.7, 0.7 Hz, 1H), 5.10 (dd, J = 17.5, 0.6 Hz, 1H), 4.85 (q, J = 1.6 Hz, 1H), 4.77
(sa, 1H), 2.95 (dd, J = 17.1, 5.6 Hz, 1H), 2.88 (t, J = 5.1 Hz, 1H), 2.64 (dd, J = 17.1, 4.7 Hz, 1H), 2.00
13
(d, J = 1.2 Hz, 3H), 1.57 (dd, J = 1.5, 0.7 Hz, 3H), 1.26 (s, 3H); C{ H} NMR (150 MHz, CDCl3): δ
1
188.4, 146.9, 145.5, 144.8, 141.1, 137.3, 120.6, 115,1, 114.6, 53.7, 52.3, 24.4, 23.2, 18.3, 7.7. The
21
spectroscopic data found for this compound were consistent with to those reported in the literature.
1
Curzurenone (14). H NMR (500 MHz, CDCl3) δ 5.85 (dd, J = 17.3, 10.5 Hz, 1H), 5.48 (s, 1H), 5.16
(dd, J = 10.7, 0.7 Hz, 1H), 5.08 (d, J = 10.5 Hz, 1H), 5.02 (d, J = 17.4 Hz, 1H), 4.93 (q, J = 1.6 Hz,
1H), 4.79 (sa, 1H), 2.75 (ddd, J = 17.3, 5.2, 1.3 Hz, 1H), 2.64 (ddd, J = 17.3, 8.5, 1.1 Hz, 1H), 2.48 (dd,
13
J = 8.5, 5.1 Hz, 1H), 1.90 (bs, 3H), 1.71 (bs, 3H), 1.16 (s, 3H); C{ H} NMR (125 MHz, CDCl3): δ
1
171.3, 148.8, 147.8, 145.8, 145.1, 120.4, 114,7, 114.4, 113.5, 50.7, 41.8, 25.4, 23.8, 22.0, 8.45. The
22
spectroscopic data found for this compound matched those reported in the literature.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
Reaction of germacrone (11) with the system I2/DMSO: Synthesis of atractylone (3) and its isomer
4.
1
2
3
4
5
6
7
8
9
The standard procedure was followed using 1 mmol (218 mg) of 11, 1 mmol (254 mg) of iodine, and
hexane as solvent (room temperature) with a reaction time of 48 h. The crude product was purified by
column chromatography over silica gel using (H/MTBE 95:5) to obtain 252 mg (74%) of a 5:1 mixture
of the iododerivatives 20 and 21. This mixture was subjected to HPLC (normal phase, H), to give pure
20 (Rt = 18.5 min) and pure 21 (Rt = 23.2 min).
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4aS,8R,8aR)-8-Iodo-3,8a-dimethyl-5-methylene-4,4a,5,6,7,8,8a,9-octahydronaphtho[2,3-b]furan 20.
1
Brown oil; H NMR (500 MHz, CDCl3) δ 7.08 (bs, 1H), 4.92 (q, J = 1.7 Hz, 1zH), 4.82 (bs, 1H), 4.46
(dd, J = 12.5, 4.1 Hz, 1H), 2.76 (d, J = 15.4 Hz, 1H), 2.50-2.15 (m, 7H), 1.96 (d, J = 1.2 Hz, 3H), 0.92
13
(s, 3H); C{ H} NMR (125 MHz, CDCl3): δ 149.0, 146.6, 137.4, 119.2, 115.9, 109.5, 50.3, 45.4, 41.8,
1
+
41.4, 39.4, 37.6, 22.4, 15.1, 8.2. HRMS (ESI-QTOF) m/z: [M+H] Calcd for C15H20OI 343.0559; Found
343.0543.
1
(4aS,8R,8aR)-8-Iodo-3,5,8a-trimethyl-4,4a,7,8,8a,9-hexahydronaphtho[2,3-b]furan 21. Brown oil; H
NMR (500 MHz, CDCl3) δ 7.08 (bs, 1H), 5.21 (s, 1H), 4.50 (dd, J = 11.6, 5.7 Hz, 1H), 2.91–2.80 (m,
1H), 2.77–2.65 (m, 3H), 2.40 (d, J = 12.4 Hz, 1H), 2.32 (d, J = 16.1 Hz, 1H), 2.07 (dddd, J = 15.4,
13
12.0, 3.1, 1.5 Hz, 3H), 1.96 (d, J = 1.1 Hz, 3H), 1.96 (bs, 3H), 0.94 (s, 3H); C{ H} NMR (125 MHz,
1
CDCl3): δ 150.2, 137.9, 134.9, 122.3, 119.2, 116.7, 47.0, 44.3, 41.6, 38.6, 38.0, 22.8, 21.0, 13.3, 8.2.
+
HRMS (ESI-QTOF) m/z: [M+H] Calcd for C15H20OI 343.0559; Found 343.0538.
Reduction of 20 and 21 with nBu3SnH/AIBN. To a solution of nBu3SnH (0.30 mL, 1.16 mmol) and
AIBN (10 mg, 0.06 mmol) in dry and deoxygenated bencene (4.5 mL), was added dropwise at 90ºC and
under an argon atmosphere, a solution of compound 20 (100 mg, 0.29 mmol) in 1.5 mL of benzene for
15 min. When the addition was completed, the reaction mixture was let to react for additional 50
minutes, and then, the solvent was evaporated in vacuo. The mixture was diluted with MTBE (10 mL)
and then washed with brine (3 x 30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo.
Purification by flash chromatography (H:MTBE, 97:3) provided 34 mg (54%) of atractylon (3).
1
Atractylon (3). H NMR (500 MHz, CDCl3) δ 7.08 (bs, 1H), 4.89 (s, 1H), 4.73 (s, 1H), 2.48–2.28 (m,
5H), 2.17–2.11 (m, 1H), 2.08 (bt, J = 13.3 Hz, 1H), 1.98 (s, 3H), 1.76–1.48 (m, 4H), 0.79 (s, 3H);
13
1
C{ H} NMR (125 MHz, CDCl3): δ 149.9, 149.4, 136.9, 119.6, 116.2, 107.3, 45.8, 41.9, 39.3, 37.3,
16
ACS Paragon Plus Environment

Page 17 of 24
The Journal of Organic Chemistry
36.7, 23.6, 20.9, 17.6, 8.2 The spectroscopic data for this compound matched with those reported in the
1
2
3
10a
literature.
4
5
When the same process was performed with compound 21, a 56% of compound 4 was obtained.
1
Isoatractylon (4). H NMR (500 MHz, CD3COCD3) δ 7.13 (bs, 1H), 5.44 (bs, 1H), 2.65 (dd, J = 15.5,
6
7
8
9
4.2 Hz, 1H), 2.65 (dd, J = 15.5, 4.2 Hz, 1H), 2.37 (bd, J = 17.4 Hz, 1H), 2.32 (dd, J = 15.7, 1.0 Hz,
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H),2,21-2,11(m,2H), 2.03-1.95 (m, 2H), 1.94 (bs, 3H), 1.73 (s, 3H), 1.62-1.50 (m, 2H), 0.83 (s, 3H);
13
1
C{ H} NMR (125 MHz, CD3COCD3): δ 149.8, 137.1, 134.3, 121.6, 119.3, 117.0, 43.7, 38.4, 36.8, 32.9,
22.5, 21.0, 20.6, 15.9, 7.2. The spectroscopic data found for this compound were consistent with to
7
those reported in the literature.
Reaction of eudesmanes 16 and 17 with the system I2/DMSO: Synthesis of atractylone (3) and
isoatractylone (4).
The standard procedure was followed in both cases using 0.5 mmol (107 mg) of 16 or 17, 0.1 mmol
(25 mg) of iodine, MTBE as solvent and with a reaction time of 6 h. The crude product was purified by
column chromatography over silica gel using (H/MTBE 97:3) to obtain atractylone (3) (86 mg, 80%)
from 16, and of isoatractylone (4) (89 mg, 82%) from 17.
Reaction of 4,5-epoxygermacrone (22) with the system I2/DMSO: Synthesis of 23-26 and
linderazulene (5)
The standard procedure was followed using 1 mmol (234 mg) of 22, 0.4 mmol (102 mg) of iodine
using MTBE as solvent and with a reaction time of 1 h 30 min. The crude product was purified by
column chromatography over silica gel using mixtures of H and MTBE of increasing polarity as eluent
to obtain 4 mg (2%) of linderazulene (H), 49 mg (21%) of compound 23 (H/MTBE 2:1), 75 mg (32%)
of a 1:1 mixture of compounds 24 and 25 (H/MTBE 2:1), and 7 mg (3%) of compound 26 (H/MTBE
1:1).
1
Linderazulene (5). H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.46 (d, J = 3.4 Hz, 1H), 7.44 (d, J =
1.5 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 3.8 Hz, 1H), 2.85 (s, 3H), 2.75 (s, 3H), 2.40 (d, J = 1.3 Hz, 3H).;
13
1
C{ H} NMR (125 MHz, CDCl3): δ 158.55, 139.38, 139.02, 135.62, 133.11, 131.41, 126.95, 125.15,
121.12, 119.54, 115.91, 111.23, 24.51, 13.09, 8.09. The spectroscopic data found for this compound
8a
were consistent with those reported in the literature.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 24
(1R,8aR)-1-Hydroxy-1,4-dimethyl-7-(propan-2-ylidene)-2,7,8,8a-tetrahydroazulen-6(1H)-one (26).
1
2
3
1
Colorless oil; H NMR (400 MHz, CDCl3) δ 6.09 (q, J = 2.7 Hz, 1H), 5.95 (s, 1H), 2.77-2.69 (m, 2H),
4
5
6
7
2.55 (bd, J = 17.5 Hz, 1H), 2.48 (dd, J = 17.5, 3.4 Hz, 1H), 2.03 (d, J = 1.2 Hz, 3H), 1.98 (bt, J = 13.3
13
Hz, 1H), 1.88 (s, 3H), 1.81 (s, 3H), 1.24 (s, 3H); C{ H} NMR (100 MHz, CDCl3): δ 196.1, 144.0,
1
8
9
142.0, 139.9, 134.8, 132.7, 130.3, 82.5, 57.8, 47.1, 26.7, 22.9, 22.7 (x 2C), 21.3. HRMS (ESI-QTOF)
+
m/z: [M+H] Calcd for C15H21O2 233.1542 [M+H] ; Found 233.1535.
+
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction of 23-26 with the system I2/DMSO: Synthesis of linderazulene (5)
The standard procedure was followed using 120 mg of 23-26, 0.25 mmol (64 mg) of iodine using
toluene as solvent and with a reaction time of 5 min. The crude product was purified by flash column
chromatography (H) to obtain linderazulene (5) (49 mg, 46%).
Reaction of 4,5-epoxygermacrone (22) with the system I2/DMSO: Synthesis of linderazulene (5)
The standard procedure was followed using 1 mmol (234 mg) of 22, 0.5 mmol (127 mg) of iodine and
30 mmol (2.13 mL) of DMSO using toluene as solvent and with a reaction time of 5 min. The crude
product was purified by flash column chromatography (H) to obtain a linderazulene (5) (44 mg, 21%).
Insect bioassays
Spodoptera littoralis, Myzus persicae and Rhopalosiphum padi colonies were reared on artificial diet,
bell pepper (Capsicum annuum) and barley (Hordeum vulgare) plants respectively, and maintained at
22 ± 1 ºC, >70% relative humidity with a photoperiod of 16:8 h (L:D) in a growth chamber.
The bioassays were conducted with ten-twenty newly emerged S. littoralis L6 larvae and two hundred
17
M. persicae or R. padi adults. Feeding or settling inhibition (% FI or % SI) were calculated as reported
and the antifeedant effects (FI/SI) were analyzed for significance by the non-parametric Wilcoxon
signed-rank test.
Ixodicidal bioassay.
18
ACS Paragon Plus Environment

Page 19 of 24
The Journal of Organic Chemistry
Engorged females of the tick Hyalomma lusitanicum Koch 1844 (Ixodoidea: Ixodida) were collected
1
2
from their host (deer) in central Spain (Finca La Garganta. Ciudad Real), and maintained at 22-24ºC.
70% RH until oviposition and larval hatching. Larvae (4-6 weeks old) were used for the bioassay as
described by Ruiz-Vásquez et al.28 The larvicidal activity data are presented as percentage of mortality
corrected according to Schneider-Orelli’s formula.29 Lethal doses (LC50 and LC90) were calculated by
Probit Analysis (five 1:2 serial dilutions. STATGRAPHICS Centurion XVI. version 16.1.02).
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
Supporting Information.
This material is available free of charge via on the ACS Publications website at DOI:
1
13
Copies of H and C NMR spectra, and mechanistic proposal for the formation of compounds 7, 8 and
10 (PDF).
AUTHOR INFORMATION
Corresponding Author
* Email: jfquilez@ugr.es
* Email:afbarre@ugr.es
ORCID
José F. Quílez del Moral:0000-0003-4806-6693
Alejandro. F. Barrero: 0000-0002-3058-8760
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was provided by the Junta de Andalucia (P08-FQM-3596) and
Ministerio de Economía y Competitividad (CTQ-2015-64049-C3-3-R).
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 24
REFERENCES
1
2
3
(1) Hayashi, N.; Komae, H. Chemistry and Distribution of Sesquiterpene Furans in Lauraceae.
4
5
Biochem. System. Ecol. 1980, 8, 381–383.
6
7
(2) Kumar, B.; Shukla, A. K.; Samad, A. Development and Characterization of the Menthofuran-rich
8
9
Inter-specific Hybrid Peppermint Variety CIMAP-Patra. Mol. Breeding 2014, 34, 717–724.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) Picard, M.; de Revel, G.; Marchand, S. First Identification of Three p-menthane Lactones and
Their Potential Precursor, Menthofuran, in Red Wines. Food Chem. 2017, 217, 294–302.
(4) (a) Boni, G.C.; de Feira, S. M.B.; de Laet Santana, P.; Anibal, P. C.; Gomes Boriolo, M. F.; Buso-
Ramos, M. M.; Barbosa, J. P.; Rossini de Oliveira, T.; Höfilng, J. F. Antifungal and Cytotoxic Activity
of Purified Biocomponents as Carvone, Menthone, Menthofuran and Pulegone from Mentha Spp. Afr. J.
Plant Sci. 2016, 10, 203–210. (b) Khojasteh, S. C.; Oishi, S. Nelson, S.D. Metabolism and Toxicity of
Menthofuran in Rat Liver Slices and in Rats. Chem. Res. Toxicol. 2010, 23, 1824–1832.
(5) (a) Chen, C.; Chen, Y.; Hsi, Y.-T., Chang, C.-S.; Huang, L.-F.; Ho, C.-T.; Way, T.-D.; Kao, J.-Y.
Chemical Constituents and Anticancer Activity of Curcuma zedoaria Roscoe Essential Oil against Non-
Small Cell Lung Carcinoma Cells in Vitro and in Vivo. J. Agr. Food Chem. 2013, 61, 11418–11427. (b)
Quassinti, L.; Maggi, F.; Barboni, L.; Ricciutelli, M.; Cortese, M.; Papa, F.; Garulli, C.; Kalogris, C.;
Vittori, S.; Bramuci, M. Wild Celery (Smyrnium olusatrum L.) Oil and Isofuranodiene Induce
Apoptosis in Human Colon Carcinoma Cells. Fitoterapia 2014, 97, 133–141. (c) Quassinti, L.;
Bramuci, M.; Lupidi, G.; Barboni, L.; Ricciutelli, M.;Sagratini, G.; Papa, F.; Caprioli, G.; Petrelli, D.;
Vitali, L. A.; Vittori, S.; Maggi, F. In vitro Biological Activity of Essential Oils and Isolated
Furanosesquiterpenes from the Neglected Vegetable Smyrnium olusatrum L. (Apiaceae). Food Chem.
2013, 138, 808–813. (d) Wang, Y.; Li, J.; Guo, J.; Wang, Q.; Zhu, S.; Gao, S.; Wei, M.; Pan, X.; Zhu,
W.; Ding, D.; Gao, R.; Zhang, W.; Wang, J.; Zang, L. Cytotoxic and Antitumor Effects of Curzerene
from Curcuma longa. Planta Med. 2017, 83, 23–29.
(6) (a) Chen, L.-G.; Jan, Y.-S., Tsai, P.-W.; Norimoto, H.; Michihara, S.; Murayama, C.; Wang, C.-C.
Anti-inflammatory and Antinociceptive Constituents of Atractylodes japonica Koidzumi. J. Agric. Food
Chem. 2016, 64, 2254−2262. (b) Han, N.-R.; Moo, P.-D.; Nam, S.-Y.; Ryu, K.-J.; Yoou, M.-S.; Coi, J.;
20
ACS Paragon Plus Environment

Page 21 of 24
The Journal of Organic Chemistry
Hwan, S.-Y.; Kim. H.-M.; Jeong, H.-J. Inhibitory Effects of Atractylone on Mast Cell-mediated
Allergic Reactions. Chem. Biol. Interact. 2016, 258, 59–68. (c) Wang, C.-C.; Chen, L.-G.; Yang, L.-L.
Cytotoxic Activity of Sesquiterpenoids from Atractylodes ovata on Leukemia Cell Lines. Planta Med.
2002, 68, 204–208. (d) Cheng, Y.; Mai, J.-Y.; Hou, T.-L.; Ping, J.; Chen, J.-J. Antiviral Activities of
Atractylon from Atractylodis Rhizoma. Mol. Med. Rep. 2016, 14, 3704–3710. (e) Chu, S. S.; Jiang, G.
H.; Liu, Z. L. Insecticidal Compounds from the Essential Oil of Chinese Medicinal Herb Atractylodes
chinensis. Pest. Manag. Sci. 2011. 67, 1253–1257.
1
2
3
4
5
6
7
8
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Gavagnin, M.; Mollo, E.; Castelluccio, F.; Crispino, A.; Cimino, G. Sesquiterpene Metabolites of
the Antarctic Gorgonian Dasystenella acanthina. J. Nat. Prod. 2003, 66, 1517–1519.
(8) (a) Imre, S.; Thomson, R. H.; Yalhi, B. Linderazulene, a New Naturally Occurring Pigment from
the Gorgonian Paramuricea chamaeleon. Experientia 1980, 37, 442–443. (b) Sakemi, S.; Higa, T. 2,3-
Dihydrolinderazulene, a New Bioactive Azulene Pigment from the Gorgonian Acalycigorgia sp.
Experientia 1987, 43, 624–625. (c) Reddy, N. Srinivasa; Reed, J. K.; Longley, R. E.; Wright, Amy E.
Two New Cytotoxic Linderazulenes from a Deep-Sea Gorgonian of the Genus Paramuricea. J. Nat.
Prod. 2005, 68, 248–250. (d) Patino Cano, L. P.; Quintana Manfredi, R.; Perez, M.; Garcia, M.;
Blustein, G.; Cordeiro, R.; Perez, C. D.; Schejter, L.; Palermo, J. A. Isolation and Antifouling Activity
of Azulene Derivatives from the Antarctic Gorgonian Acanthogorgia laxa. Chem. Biodiversity 2018,
15, e1700425. (e) Higa, T.; Sakemi, S. PCT Int. Appl. 1988, WO 8800191 A2 19880114.
(9) (a) Shishido, K. Furanoterpene Synthesis Via Intramolecular Nitrile Oxide Cycloaddition
Reaction: A Total Synthesis of (+)-Menthofuran. Heterocycles 1993, 36, 345–358, and referenced cited
therein. (b) Rai. A. Synthesis, characterization and Commercial Application of Menthofuran (4,5,6,7-
Tetrahydro-3,6-dimethyl-benzofuran). Univ. J. Phytochem. Ayurvedic Heights 2011, 10, 4–7.
(10) (a) Bagal, S. K.; Adlington, R.M.; Baldwin, J. E.; Marquez, R. Dimerization of Butenolide
Structures. A Biomimetic Approach to the Dimeric Sesquiterpene Lactones (±)-Biatractylolide and (±)-
Biepiasterolide. J. Org. Chem. 2004, 69, 9100–9108. (b) Friedrich, D.; Bohlmann, F. Total Synthesis of
various Elemanolides. Tetrahedron 1988, 44, 1369–1392. (c) Honan, M. C. Total Synthesis of (±)-
Atractylon and (±)-Lindestrene. Tetrahedron Lett. 1985, 26, 6393–6396.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
(11) For recent reviews on the use of iodine, see: (a) Breugst, M.; von der Heiden, D. Mechanisms in
Iodine Catalysis. Chem. Eur. J. 2018, 24, 9187–9199. (b) Iodine Chemistry and Applications; T. Kaiho,
T., Ed.; Wiley: Hoboken, 2015. (c) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. T. Recent
1
2
3
4
5
6
7
Developments in the Synthesis of Five- and Six-Membered Heterocycles Using Molecular Iodine.
8
9
Chem. Eur. J. 2012, 18, 5460–5489. (d) Kepper, F. C.; Feiters, M. C.; Olofsson, B.; Kaiho, T.;
Yanagida, S.; Zimmermann, M. B.; Carpenter, L. J.; Luther, G. W. ; Lu, Z.; Jonsson, M.; Kloo, L.
Commemorating Two Centuries of Iodine Research: An Interdisciplinary Overview of Current
Research. Angew. Chem. Int. Ed. 2011, 50, 11598–11620.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) For previous uses of the I2/DMSO system, see: (a) Liang, Y.-F.; Li, X.; Wang, X.; Zou, M.;
Tang, C.; Liang, Y.; Song, S.; Jiao, N. Conversion of Simple Cyclohexanones into Catechols. J. Am.
Chem. Soc. 2016, 138, 12271−12277. (b) Domingo, V.; Prieto, C.; Silva, L.; Castillo, A.; Quílez del
Moral, J. F.; Barrero, A. F. Iodine-Promoted Metal-Free Aromatization: Synthesis of Biaryls, Oligo p-
Phenylenes and A-Ring Modified Steroids. Adv. Synth. Catal. 2015, 357, 3359–3364. (c) Gao, Q.; Wu,
X.; Liu, S.; Wu, A. I2-Promoted Selective Oxidative Cross-Coupling/Annulation of 2-Naphthols with
Methyl Ketones: A Strategy To Build Naphtho[2,1-b]furan-1(2H)-ones with a Quaternary Center. Org.
Lett. 2014, 16, 1732–1735. (d) Ge, W.; Zhu, X.; Wei, Y. Iodine-Catalyzed Selective Synthesis of
2-Sulfanylphenols via Oxidative Aromatization of Cyclohexanones and Disulfides. Adv. Synth. Catal.
+
2013, 355, 3014−3021. For the discussion of the stabilization of the cation of I caused by DMSO, see:
(e) Ashikari, Y.; Shimizu, A.; Nokami, T.; Yoshida, J. Halogen and Chalcogen Cation Pools Stabilized
by DMSO. Versatile Reagents for Alkene Difunctionalization. J. Org. Chem. 2013, 135, 16070−16073.
(13) Gaikwad, N. W.; Madyastha, K. M. Biosynthesis of b-Substituted Furan Skeleton in the Lower
Furanoterpenoids: A Model Study. Biochem. Biophys. Res. Commun. 2002, 290, 589–594.
(14) One of the reviewers brought to our attention that structurally-related a-hydroxy-b,g-unsaturated
ketones can be converted into furans by heating with 20% mol of pTsOH: McInturff, E. L.; Nguyen, K.
D.; Krische, M. J. Redox-Triggered C−C Coupling of Diols and Alkynes: Synthesis of b,g-Unsaturated
a-Hydroxyketones and Furans by Ruthenium-Catalyzed Hydrohydroxyalkylation. Angew. Chem. Int.
Ed. 2014, 53, 3232–3235.
22
ACS Paragon Plus Environment

Page 23 of 24
1
The Journal of Organic Chemistry
(15) Snyder, S. A.; Treitler, D. S.; Brucks, A. Simple Reagents for Direct Halonium-Induced Polyene
2
3
Cyclizations. J. Am. Chem. Soc. 2010, 132, 14303−14313.
4
5
(16) The mechanism proposal for the formation of 7-10 is shown in the Supporting Information.
6
7
8
9
(17) Frérot, E.; Bagnoud, A.; Vuilleumier, C. Menthofurolactone: a New p-Menthane Lactone in
Mentha piperita L.: Analysis, Synthesis and Olfactory Properties. Flavour Frag. J. 2002, 17, 218–226.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) Näf, R.; Velluz, A. Phenols and Lactones in Italo-Mitcham Peppermint Oil Mentha piperita L.
Flavour Frag. J. 1998, 13, 203–208.
(19) Navarro-Rocha, J.; Barrero, A. F.; Burillo, J.; Sonia Olmeda, A.; González-Coloma, A.
Valorization of Essential Oils from two Populations (Wild and Commercial) of Geranium
macrorrhizum L. Ind. Crop. Prod. 2018, 116, 41–45.
(20) Barrero, A. F.; Herrador, M.M.; Quilez del Moral, J. F.; Arteaga, P.; Meine, N.; Pérez-Morales,
M. C.; Catalán, J. V. Efficient Synthesis of the Anticancer β-Elemene and other Bioactive Elemanes
from Sustainable Germacrone. Org. Biomol. Chem. 2011, 9, 1118–1121.
(21) Endo, J. Studies on the Essential Oil of Asarum caulescens. III. Yakugaku Zasshi 1975, 95,
1321–1326.
(22) Xia, G.; Zhou, L.; Ma, J.; Wang, Y.; Ding, L.; Zhao, F.; Chen, L.; Qiu, F. Sesquiterpenes from
the Essential Oil of Curcuma wenyujin and Their Inhibitory Effects on Nitric Oxide Production.
Fitoterapia 2015, 103, 143–148.
(23) Perez Morales, M. C.; Catalán, J. V.; Domingo, V.; Jaraíz, M.; Herrador, M. M.; Quílez del
Moral, J. F.; López-Pérez, J. L.; Barrero, A. F. Structural Diversity from the Transannular Cyclizations
of Natural Germacrone and Epoxy Derivatives: A Theoretical–Experimental Study. Chem. Eur. J. 2013,
19, 6598–6612.
(24) (a) Radulovic, N.; Zlatovic, D.; Dekic, M.; Stojanovic-Radic, Z. Further Antibacterial Geranium
macrorrhizum L. Metabolites and Synthesis of Epoxygermacrones. Chem. Biodiversity 2014, 11, 542–
550. (b) Piet, D. P.; Schrijvers, R.; Franssen, M. C. R.; de Groot, A. Biotransformation of Germacrane
Epoxides by Cichorium intybus. Tetrahedron 1995, 51, 6303–6314.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
(25) Kuroyanagi, M.; Ueno, A.; Koyama, K.; Natori, S. Structures of Sesquiterpenes of Curcuma
aromatica SALISB. II. : Studies on Minor Sesquiterpenes. Chem. Pharm. Bull. 1990, 38, 55–58.
1
2
3
4
5
6
7
8
(26) De Lucia, M.; Mainieri, F.; Verotta, L.; Maffei, M.; Panzella, L.; Crescenzi, O.; Napolitano, A.;
Barone, V.; Appendino, G.; d’Ischia, M. Nitration versus Nitrosation Chemistry of Menthofuran:ꢀ
Remarkable Fragmentation and Dimerization Pathways and Expeditious Entry into
Dehydromenthofurolactone. J. Org. Chem. 2007, 72, 10123–10129.
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
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(27) Moorthy, B.; Madyastha, P.; Madyastha, K. M. Metabolism of a monoterpene ketone, R-(+)-
pulegone--a hepatotoxin in rat. Xenobiotica 1989, 19, 217–224.
(28) Ruiz-Vásquez, L., Olmeda, A.S., Zúñiga, G., Villarroel, L., Echeverri, L. F., González-Coloma,
A., Reina, M. Insect Antifeedant and Ixodicidal Compounds from Senecio adenotrichius. Chem.
Biodivers. 2017, 14, e1600155.
(29) Puntener, W. Manual for Field Trials in Plant Protection, 2nd ed.; Ciba Geigy: Basel, Switzerland,
1981.
24
ACS Paragon Plus Environment