Regioselective Synthesis of 4,5-Dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-diones through Palladium-Catalyzed Intramolecular Alkoxycarbonylation of 3-Allyl-4-hydroxycoumarins

Article abstract of DOI:10.1002/ejoc.201900649

Seven-membered ring lactones fused to coumarin scaffolds were obtained via a palladium-catalyzed regioselective intramolecular alkoxycarbonylation under a CO atmosphere. Cyclocarbonylation of 3-allyl-4-hydroxycoumarin derivatives was accessed in the absen

Full text of DOI:10.1002/ejoc.201900649

A Journal of
Accepted Article
Title: Regioselective synthesis of 4,5-dihydro-6H-oxepino[3,2-
c]chromene-2,6(3H)-diones via palladium-catalyzed
intramolecular alkoxycarbonylation of 3-allyl-4-hydroxycoumarins
Authors: Diego Oliver Sosa, Karla Almaraz, and Manuel Jose
Amezquita Valencia
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10.1002/ejoc.201900649
European Journal of Organic Chemistry
FULL PAPER
Regioselective synthesis of 4,5-dihydro-6H-oxepino[3,2-
c]chromene-2,6(3H)-diones via palladium-catalyzed
intramolecular alkoxycarbonylation of 3-allyl-4-hydroxycoumarins
D. Oliver Sosa,[a] Karla Almaraz[a] and Manuel Amézquita-Valencia*[a]
Abstract: Seven-membered ring lactones fused to coumarin
derivatives.[9] Various medium to large-sized ring lactams and
lactones can be synthesized by choosing the appropriate
substrate. For example, 2-(2-iodophenoxy)anilines[10] and 2-(2-
ethynylphenoxy)anilines[11] were suitable substrates to form
seven-, eight-, nine- and ten-membered ring lactams via
palladium-catalyzed intramolecular cyclocarbonylation under a
CO atmosphere. Baylis-Hillman acetates were appropriate
precursors to submit to cyclocarbonylation reactions.[12] 2-
Iodobenzyl alcohol and 2-iodophenetyl alcohol in the presence of
internal alkynes and CO as a building block produced seven- and
eight-membered ring lactones.[13] In particular, this class of
heterocycles also can be formed utilizing 2-allylphenol. In 1996,
Alper and co-workers demonstrated that this substrate under
certain conditions affords a mixture of five-, six-, and seven-
membered ring lactones (Scheme 1). To control the
regioselectivity of the process, the palladium source, phosphine
ligand, solvent, temperature, the relative pressure and ratio of the
gases (CO/H2) must be taken into consideration.[14] For example,
five-membered ring lactones are predominately formed by using
of [Pd(PCy3)2(H)(H2O)]+BF4− and dppb under 600 psi of pressure
(1:5, CO/H2). An appropriate monodetate ligand and syngas
conditions change the selectivity, resulting in the formation of six-
membered ring lactones.[15] Using Pd(OAc)2 as catalyst and
bidentate ligand under 300 psi of CO and 300 psi of H2 affords
seven-membered ring lactones.[14] Therefore, we reasoned that
this approach could be an excellent option for fusing lactones and
coumarins.
scaffolds were obtained via a palladium-catalyzed regioselective
intramolecular alkoxycarbonylation under
a
CO atmosphere.
Cyclocarbonylation of 3-allyl-4-hydroxycoumarin derivatives was
accessed in the absence of hydrogen gas, acidic conditions, or any
other additives. The results of the control experiments revealed the
importance of pKa of the substrate for initiating the reaction.
Introduction
The combination of heteroatoms and heterocyclic compounds
occupies
a significant position in heterocyclic chemistry,
extending the exploration of new compounds with a variety of
properties. In particular, coumarins are among the most privileged
frameworks found in numerous bioactive organic materials,
pharmaceuticals, and natural products.[1] The synthesis of
coumarin derivatives has emerged as a potent platform for the
discovery of new compounds.[2-3] In general, this heterocycle has
been functionalized with five and six ring sizes, which have
presented a wide range of applications.[4] Accordingly, several
approaches have been developed for the synthesis of these
compounds.[5]. However, many of these methods are limited to
the synthesis of six-membered ring lactones. Despite the
importance of medium-size lactones, protocols for the synthesis
of 4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-diones are
limited.
Seven-membered ring lactones are important structural
motifs that occur in numerous bioactive natural and synthetic
compounds.[6] This core has presented interesting biological
activities such as antimalarial,[7] antimicrobial, antitumor,
antifungal, and as potential therapeutic agents for the treatment
of inflammatory diseases.[8] Therefore, the construction of seven-
membered ring lactones fused to other skeletons holds great
promise for the preparation of significant molecules that will be
important in chemistry and biology.
Scheme 1. Cyclocarbonylation of 2-allylphenols
Usually, the methodologies previously described to achieve
the carbonylation product and catalytic turnover demanded one
series of additives such as hydrogen gas (H2) or acidic conditions
to help generate the palladium hydride species, which are
responsible for initiating the cyclization reaction. Here, we
reported the results for the synthesis of seven-membered ring
lactones fused to the coumarin scaffold from 3-allyl-4-
hydroxycoumarin derivatives through palladium-catalyzed
intramolecular alkoxycarbonylation using only CO in an additive-
free manner.
Palladium-catalyzed carbonylation reactions represent one
of the most useful tools in the synthesis of medium size carbonyl
[a]
D. Oliver Sosa, Karla Almaraz, Dr. Manuel Amézquita-Valencia.
Universidad Nacional Autónoma de México, Instituto de Química,
Ciudad Universitaria, Ciudad de México, 04510, México.
FAX: +52 5 6162217/6162207.
E-mail: manuel.amezquita@iquimica.unam.mx
https://www.iquimica.unam.mx/dr-manuel-jose-amezquita
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201900649
European Journal of Organic Chemistry
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Results and Discussion
Table 1 Optimizations of reaction conditions[a]
We began our investigation by examining the intramolecular
cyclocarbonylation with 3-allyl-4-hydroxycoumarin (1a) as the
model substrate. The reaction was carried out in presence of H2
and CO in a 1:1 ratio (600 psi) at 120 °C, with Pd(OAc)2 as a
palladium precursor and 1,4-bis-(diphenylphosphino)butane
(dppb) as a ligand (Table 1, entry 1). This led to 2,3-dihydro-2-
methyl-4H-furo[3,2-c][1]benzopyran-4-one (5a) in 86% yield,
because of a C-O coupling promoted by the palladium catalyst.[16]
This result was quite opposite to the desired product. A similar
outcome was obtained using dichloromethane (DCM) as a solvent,
but in this case, small amounts of the cyclocarbonylation products
were observed (Table 1, entry 2). Encouraged by this result,
different solvents, temperatures, and palladium sources were
tested. We observed that both temperature and the solvent played
important roles in obtaining the carbonylation product. When the
reaction was carried out at 105 °C in DCM, six- and seven-
membered ring lactones were obtained in a low conversion and
moderate selectivity of 30% and 70% for (3a/4a), respectively
(Table 1, entry 3). If the reaction was dissolved in toluene, the
seven-membered ring lactone (4a) was obtained in good
selectivity 90% (Table 1, entry 4). Lowering the temperature to
90 °C resulted in low conversion (Table 1, entry 5). Further
screening of solvents such as dichloroethane (DCE),
tetrahydrofuran (THF) and acetonitrile (MeCN) decreased the
catalytic activity (Table 1, entries 6-8). The use of other palladium
sources as catalytic precursors was ineffective for the reaction
(Table 1, entries 9-11).
Then, we studied the impact of the ligand on the selectivity.
The obtained result indicated that dppp showed excellent
conversion, but low selectivity (Table 1, entry 12). In the cases of
Xantphos and dppf, no product formation was observed, which
indicated that dppb is the best option (Table 1, entries 13-14). An
extra reaction was carried out using 300 psi of H2/CO to check the
influence of the pressure. Even though the conversion was
affected, the selectivity for the seven-membered ring lactone (4a)
was increased remarkably (Table 1, entry 15). To our delight, by
using of only CO at 300 psi in DCM as a solvent, seven-
membered ring lactone (4a) was obtained in excellent yield of
90% with a fine selectivity of 100% (Entries 16-18). Here, the
increase of the yield under CO atmosphere can be explained by
the decreased yield of the double bond hydrogenation.
Selectivityb
2-3-4-5
Entry
[Pd]
Solvent
Conv.b (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(cod)Cl2
PdI2
PhMe
DCM
DCM
PhMe
PhMe
DCE
100
100
53
0-0-0-92(86)c
3-8-19-70
3d
0-30-70-0
4d
64
0-10-90(71)c-0
5e
10
traces
6d
58
0-42-58-0
7d
THF
8
traces
8d
MeCN
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
DCM
4
traces
9d
20
traces
10d
11d
12d,f
13d,g
14d,i
15d,j
16d,k
17d,k
18d,l
NRh
NRh
100
NRh
NRh
70
-
-
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0-41-59-0
-
-
0-0-100-0
-
NRh
99
0-0-100(90)c-0
0-0-100(60)c-0
99
[a]Reaction conditions: Substrate 1a (0.25 mmol), 2.0 mol % of [Pd], 2.0 mol %
of dppb as a ligand, 5.0 mL of solvent, H2 (300 psi) and CO (300 psi), 120 °C,
20 h. [b]The conversion and ratio of 2a,3a,4a, 5a were determined by 1H-NMR
spectroscopy of the crude reaction mixture. [c]Isolated yield is shown in
brackets. [d]Reaction at 105°C. [e]Reaction at 90°C. [f]dppp (2.0 mol%) was
used. [g]Xantphos (2.0 mol%) was used. [h]No reaction. [i]dppf (2.0 mol%) was
used. [j]300 psi of H2/CO (1:1 ratio) was used. [k]300 psi of CO was used. [l]200
psi of CO was used.
With the optimal reaction conditions established [Pd(OAc)2,
dppb, 300 psi of CO, 105 °C and 20 h], we next investigated the
generality of the scope of cyclocarbonylation reaction of 3-allyl-4-
hydroxycoumarin derivatives. As depicted in Scheme 2, the
transformation of various substrates (1) proceeded smoothly and
delivered the corresponding oxepino[3,2,c]chromene derivatives
(4) in moderate to good yields. Both electron-donating and
electron-withdrawing groups were well tolerated. NO2 or F
substituents could be used to give the corresponding lactone in
good yield (4b and 4c). Methyl, t-butyl and methoxy substituents
in the 6´ and 7´ positions were well tolerated (4d-4h). The
structure of oxepino[3,2,c]chromene (4d) was further confirmed
by X-ray crystallography (Figure 1).[17]
Figure 1. ORTEP representation of 4d with the thermal ellipsoids set at 50%
probability level, all hydrogen atoms are omitted for clarity.
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10.1002/ejoc.201900649
European Journal of Organic Chemistry
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A similar result was obtained with a substituent in the 8´
position (4i and 4j). Fused aromatics such as the naphthalene
derivative also afforded the corresponding lactone in good yield
(4k). The replacement of the coumarin scaffold by
methylquinolinone (1l) failed to produce the desire product.
However, quinolinone fused to a seven-membered ring lactone
(4l) could be obtained when the reaction was carried out using a
mixture of H2/CO (Ratio 1:1, 600 psi) in the presence of Pd(PPh3)4,
dppb as a ligand in THF at 110 °C for 48 h. Here, hydrogen is
necessary to promote the generation of the hydride palladium [Pd-
H] and to achieve the catalysis.
Figure 2. Reaction conditions for 3a: PdI2 (2.0 mol%), PPh3 (4.0 mol%), toluene
(10 mL), H2/CO (1:5, 600 psi), 110 °C, 20h. For 3l: Pd(PPh3)4 (2.0 mol%), dppb
(2.0 mol%), DCE (10 mL), H2/CO (1:1, 600 psi), 110°C, 24h. [a]The conversion
and ratio were determined by 1H-NMR spectroscopy. [b]Isolated yield of the
mixture of isomers. [c]Isolated yield is shown in brackets.
In contrast, seven-membered ring lactones (4a-4k) from 3-
allyl-4-hydroxycoumarins could be formed in high selectivity using
only CO and without the need to use hydrogen (H2) or acidic
conditions, as a shown in the Scheme 2. We believed that this
behavior would be influenced by the acidic character of the
hydroxy group on the substrate (pKa ≈ 4.16).[18] To confirm our
hypothesis, 2-allylphenol (pKa = 10.88)[19] was treated under
standard reaction conditions, and the lactone (6a) was obtained
in 24% yield along with starting material (Scheme 3, eq. 1). This
outcome is unlike the reaction enriched with hydrogen (300/300
psi of H2/CO) which afforded lactone (6a) in good yield,
demonstrating the need for the hydrogen for initiating the catalytic
turnover. Likewise, utilizing a more nucleophilic substrate such as
3-allyl-4-(phenylamino)-2H-chromen-2-one
(1m),
no
cyclocarbonylation product was found (Scheme 2).
Scheme 2. Scope of coumarins 1. Reaction conditions: 1a-k (0.5 mmol),
Pd(OAc)2 (2.0 mmol %), dppb (2.0 mmol %), 10 mL of dichloromethane, 300 psi
of CO, 105 °C, 20 h. Yields refer to pure products after purification.
A mixture of CO/H2 is well known to generate a high concentration
of palladium hydride species [Pd-H], which can promote double
bond isomerization. Under syngas conditions, six-membered ring
lactones from coumarin (1a) and methylquinolinone (1l) were
obtained in poor yields and low selectivities of 44% and 55%,
respectively (Figure. 2). Several reactions were carried out to
improve the selectivity towards six- or five-membered ring
lactones, but all attempts were fruitless. Alper and co-workers
demonstrated that the selectivity in the cyclocarbonylation
reaction was very sensitive to both the ratio and the pressure of
Scheme 3. Control experiments.
On the other hand, when 3-allyl-4-hydroxycoumarin was
used as a substrate containing a protected hydroxy group (1n),
the cyclocarbonylation was not possible. These results may
indicate that the first step in the reaction is the generation of the
hydride species [Pd-H] through O-H activation. Huang´s group
reported a palladium-catalyzed hydroaminocarbonylation of 2-
vinylbenzylamines in the absence of acidic or any other additives
and demonstrated that the palladium hydride species comes from
N-H bond activation from the substrate.[20] Rationalizing this
possibility, a reaction was carried out between 1.0 equivalent of
palladium precursor and substrate (1a). In the first instance, 1H
NMR analysis indicated that the signal of the hydrogen at the
hydroxyl group disappeared rapidly (1 min approximately). Then,
signals corresponding to the allyl arm became broad and shifted
gases (H2/CO), with regioselectivity continuing to be
challenge.[14]
a
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10.1002/ejoc.201900649
European Journal of Organic Chemistry
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Scheme 5. Proposed catalytic cycle.
down field. This behavior is associated with the formation of a π-
allylpalladium intermediate.[21] Subsequent FAB+ mass
spectroscopy analysis of a similar solution showed a peak at m/z
307 [M+], which agreed with the palladium-hydride intermediate.
To check the participation of the acetate ion, isotopic
labeling experiments using deuterated acetic acid (d-4, 99.9%)
were performed. The 1H NMR analysis of the pure product
showed the incorporation of the deuterium atom was only 7.5% at
the 12-position of 4,5-dihydro-6H-oxepino[3,2-c]chromene-
2,6(3H)-diones (4ad) (Scheme 4). Even when acetic acid was
used in excess (6.0 equivalents), the incorporation of deuterium
was minimal. The above experimental results suggested the poor
participation of the acetate ion for the protonation or deprotonation
process that could help in obtaining the desired product.
Conclusions
In summary, palladium-catalyzed cyclocarbonylation for the
regioselective synthesis of coumarin fused to seven-membered
ring lactones from 3-allyl-4-hydroxycoumarin has been elaborated.
The protocol does not involve hydrogen (H2) or acidic conditions.
The control experiments suggest that the pKa of the substrate is
a key feature in the process. The catalytic system provides a
straightforward route to the synthesis of interesting coumarin
derivatives in good yield.
Experimental Section
General
procedure
for
the
Pd-catalyzed
intramolecular
cyclocarbonylation of 3-allyl-4-hydroxycoumarin derivatives
A mixture of substituted 3-ally-4-hydroxylcoumarin (0.15 mmol), Pd(OAc)2
(2.0 mmol%), dppb (2.0 mmol%), and dichloromethane (10 mL) was
placed in a 45 mL autoclave with a magnetic stirring bar. The autoclave
was flushed three times with CO and pressurized with CO to 300 psi at
room temperature. The autoclave was then immersed in an oil bath
preheated at 105 °C for 20 h. Excess CO was discharged at room
temperature. The reaction mixture was purified by washes with hexane
cool, and ethyl acetate cool to give the corresponding
oxepino[3,2,c]chromene derivatives in good yield.
Scheme 4. Carbonylation reaction in presence of CD3CO2D.
Based on the previous literature reports and the
experimental results,[22] a tentative catalytic cycle is proposed in
Scheme 5. The reaction begins with the generation of palladium
hydride species A from the reaction of [Pd(OAc)2]/dppb and
substrate.[20] Next, π coordination of the olefin to Pd B, followed
by the intramolecular hydropalladation with concomitant
coordination of CO could form C. Subsequent insertion of CO into
the alkyl-palladium bond affords the acyl palladacyclic complex D.
Finally, the intramolecular cyclization leads to the desired product
and regenerates the species A for the next catalytic cycle.
4,5-Dihydro-2H-oxepino[3,2-c]chromene-2,6(3H)-dione (4a): Colorless
solid, 27.1 mg, m.p. 181-182 °C, 90% yield. 1H-NMR (400 MHz, CDCl3, δ
ppm): 7.76 (dd, J = 7.9, 1.5 Hz, 1H), 7.58 (ddd, J = 8.8, 7.4, 1.6 Hz, 1H),
7.40–7.29 (m, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.34
(p, J = 7.3 Hz, 2H). 13C{1H}-NMR (100 MHz, CDCl3, δ ppm): 168.4, 162.1,
157.7, 152.4, 132.6, 124.6, 122.9, 116.7, 114.9, 112.1, 32.5, 26.5, 21.5.
IR (ATR)/cm-1: 1762, 1700, 1640. MS (EI) m/z 230 [M+]. HRMS (EI)
calculated for C13H10O4 230.0579 found 230.0507.
10-Nitro-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione (4b):
Colorless solid 27.3 mg, m.p. 120-122 °C, 91% yield. 1H NMR (500 MHz,
CDCl3,  ppm): 8.63 (d, J = 2.6 Hz, 1H), 8.38 (dd, J = 9.1, 2.7 Hz, 1H), 7.45
(d, J = 9.1 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.34
(q, J = 7.4, 7.2 Hz, 2H). 13C{1H}-NMR (126 MHz, CDCl3,  ppm): 167.2,
160.6, 156.4, 155.6, 144.3, 127.3, 119.4, 118.0, 115.4, 113.9, 32.6, 26.4,
21.2. IR (ATR)/cm-1:1771, 1720, 1634. MS (DART) m/z 276 [M+1]. HRMS
(DART) calculated for C13H9O6 276.0429 found 276.0431.
10-Fluoro-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione
(4c): Colorless solid, 26.7 g, m.p. 190-191 °C 89% yield. 1H-NMR (400
MHz, CDCl3,  ppm): 7.44 (dd, J = 8.1, 2.7 Hz, 1H), 7.37–7.25 (m, 2H),
2.91 (t, J = 7.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 2.42–2.29 (m, 2H). 13C{1H}-
1
NMR (100 MHz, CDCl3,  ppm): 167.9, 161.7, 160.1 (d, JCF = 243 Hz),
4
4
2
156.8 (d, JCF = 3.0 Hz), 148.5 (d, JCF = 2.0 Hz), 120.3-120.0 (d, JCF
=
25.0 Hz), 118.5-118.4 (d, 3JCF = 9.0 Hz), 117.3, 113.0, 108.9-108.6 (d, 2JCF
= 26.0 Hz), 32.5, 26.4, 21.7. IR (ATR)/cm-1: 1782, 1691, 1610. MS (EI) m/z
248 [M+]. HRMS (EI) calculated for C13H9O4F 248.0485 found 248.0478.
10-Methyl-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione
(4d): Colorless solid 27.6 mg, m.p. 187-189 °C, 92% yield. 1H-NMR (400
MHz, CDCl3,  ppm): 7.52 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.5
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10.1002/ejoc.201900649
European Journal of Organic Chemistry
FULL PAPER
Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.38 (s, 3H),
2.35–2.28 (m, 2H). 13C{1H}-NMR (100 MHz, CDCl3,  ppm): 168.6, 162.3,
157.6, 150.6, 134.5, 133.6, 122.5, 116.4, 114.5, 112.0, 32.4, 26.5, 21.5,
20.8. IR (ATR)/cm-1: 1775, 1705, 1632. MS (EI) m/z 244 [M+]. HRMS (EI)
calculated for C14H12O4 244.0736 found 244.0733.
8,9-Dihydro-6H-benzo[h]oxepino[3,2-c]chromene-6,10(7H)-dione
(4k): Colorless solid 27.3 mg, m.p. 198-200 °C, 91% yield. 1H NMR (500
MHz, CDCl3,  ppm): 8.60 (m, 1H), 7.93 (m, 1H), 7.78 (m, 2H), 7.71 (m,
2H), 3.02 (t, J = 7.4 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.42 (p, J = 7.3 Hz,
2H).13C{1H}-NMR (126 MHz, CDCl3,  ppm): 168.5, 162.2, 158.7, 150.0,
135.2, 129.1, 128.0, 127.5, 124.7, 122.7, 122.4, 118.2, 111.4, 110.3, 32.6,
30.9, 26.6, 21.6. IR (ATR)/cm-1: 1780, 1699, 1609. MS (DART) m/z 281
[M+1]. HRMS (DART) calculated for C17H12O4 281.0813 found 281.0813.
10-(tert-Butyl)-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione
(4e): Colorless solid 27.1 mg, m.p. 177-179 °C, 90 % yield. 1H NMR (500
MHz, CDCl3,  ppm): 7.69 (dd, J = 7.9, 1.6 Hz, 1H), 7.61 (dd, J = 7.8, 1.6
Hz, 1H), 7.29 (m, 1H), 2.96 (t, J = 7.4 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H),
2.39 (p, J = 7.4 Hz, 2H), 1.55 (s, 9H). 13C{1H}-NMR (126 MHz, CDCl3, 
ppm): 168.7, 161.6, 158.2, 151.1, 138.0, 130.2, 124.1, 121.0, 115.3, 111.4,
35.0, 32.5, 29.8, 26.6, 21.3. IR (ATR)/cm-1: 1770, 1710, 1636. MS (DART)
m/z 287 [M+]. HRMS (DART) calculated for C17H18O4 287.1283 found
287.1280.
7-Methyl-3,4,5,7-tetrahydrooxepino[3,2-c]quinolone-2,6-dione
(4l):
1
Colorless solid, 24 mg, m.p. 181-182 °C, 80% yield. H-NMR (500 MHz,
CDCl3,  ppm): 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.65 (ddd, J = 8.7, 7.2, 1.6
Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.33 (ddd, J = 8.2, 7.2, 1.0 Hz, 1H), 3.80
(s, 3H), 3.06 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 2.35 (p, J = 7.3
Hz, 2H). 13C{1H}-NMR (126 MHz, CDCl3,  ppm): 169.9, 162.3, 154.3,
138.8, 131.4, 123.2, 122.5, 117.3, 115.3, 114.1, 32.2, 30.1, 26.7, 21.3. IR
(ATR)/cm-1: 1688, 1631, 1605, 1564. MS (DART) m/z 244 [M+1]. HRMS
(DART) calculated for C14H13NO3 244.0974 found 244.0973.
9-Methyl-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione (4f):
Colorless solid 26.4 g, m.p. 187-189 °C, 88% yield. 1H-NMR (400 MHz,
CDCl3,  ppm): 7.67 (d, J = 8.0 Hz, 1H), 7.24–7.11 (m, 2H), 2.93 (t, J = 7.4
Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.50 (s, 3H), 2.37 (p, J = 7.3 Hz, 2H).
13C{1H}-NMR (100 MHz, CDCl3,  ppm): 168.6, 162.4, 157.9, 152.6, 144.1,
125.8, 122.6, 116.8, 112.4, 110.9, 32.5, 26.6, 21.8, 21.4. IR (ATR)/cm-1:
1765, 1708, 1619. MS (DART) m/z 245 [M+1]. HRMS (DART) calculated
for C14H12O4 245.0736 found 245.0735.
4,5-Dihydro-2H-oxepino[3,2-c]chromene-2,6(3H)-dione (4a) and 3-
Methyl-3,4-dihydro-2H,5H-pyrano[3,2-c]chromene-2,5-dione
(3a):
Colorless solid, 9.2 mg, 30% yield. 1H-NMR (500 MHz, CDCl3,  ppm):
7.87 (dd, J = 7.9, 1.6 Hz, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (ddt, J =
8.9, 7.3, 1.5 Hz, 2H), 7.43–7.34 (m, 4H), 3.19 (dd, J = 17.1, 7.2 Hz, 1H),
3.01–2.90 (m, 3H), 2.74 (t, J = 7.2 Hz, 2H), 2.65 (dd, J = 17.1, 12.2 Hz,
1H), 2.39 (p, J = 7.3 Hz, 2H), 1.48 (d, J = 6.8 Hz, 3H). 13C{1H}-NMR (126
MHz, CDCl3,  ppm): 168.49, 168.42, 162.1, 161.2, 157.7, 157.3, 153.0,
152.4, 132.66, 132.63, 124.65, 124.61, 122.9, 122.4, 116.9, 116.7, 114.9,
113.6, 112.1, 103.2, 33.5, 32.5, 26.6, 26.1, 21.5, 15.4. IR (ATR)/cm-1: 1774,
1699, 1651, 1610. MS (DART) m/z 231 [M+1].
9-Methoxy-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione
(4g): Colorless solid 25.8 mg, m.p. 138-139 °C, 86% yield. 1H NMR (500
MHz, CDCl3,  ppm) 7.69 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.4 Hz, 1H),
6.88 (d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 2.92 (t, J = 7.3 Hz, 2H), 2.72 (t, J =
7.3 Hz, 2H), 2.36 (p, J = 7.3, Hz, 2H). 13C{1H}-NMR (126 MHz, CDCl3, 
ppm) 168.7, 163.5, 158.1, 154.3, 124.0, 112.8, 108.8, 108.1, 100.7, 55.8,
32.5, 26.6, 21.3. IR (ATR)/cm-1: 1762, 1704, 1614. MS (DART) m/z 261
[M+1]. HRMS (DART) calculated for C14H13O5 261.07630 found
261.07672.
3,6-Dimethyl-4,6-dihydro-2H-pyrano[3,2-c]quinolin-2,5(3H)-diona (3l):
Colorless solid, 11,4 mg, m.p. 139-141 ºC, 38% yield. 1H NMR (500 MHz,
DMSO,  ppm) 7.99 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (ddd, J = 8.6, 7.1, 1.5
Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.28–7.24 (m, 1H), 3.59 (s, 3H), 3.03–
2.85 (m, 1H), 2.84–2.65 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H). 13C{1H}-NMR
(126 MHz, DMSO,  ppm): 178.3, 163.2, 157.2, 138.9, 130.9, 123.5, 121.7,
116.5, 114.7, 109.3, 38.0, 29.5, 28.1, 16.9. MS (DART): m/z 244 [M+1].
HRMS (DART) calculated for C14H13NO3 244.0973 found 244.0973.
9,10-Dimethyl-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione
(4h): Colorless solid, 24.3 mg, m.p. 197-198 °C, 81% yield. 1H-NMR (400
MHz, CDCl3,  ppm): 7.48 (s, 1H), 7.13 (s, 1H), 2.88 (t, J = 7.4 Hz, 2H),
2.66 (t, J = 7.2 Hz, 2H), 2.39–2.24 (m, 8H). 13C{1H}-NMR (100 MHz, CDCl3,
 ppm): 168.8, 162.5, 157.9, 150.9, 142.9, 133.6, 122.7, 117.2, 112.4,
110.9, 32.5, 26.6, 21.4, 20.3, 19.2. IR (ATR)/cm-1: 1769, 1708, 1608. MS
(EI) m/z 258 [M+1]. HRMS (EI) calculated for C15H14O4 258.0892 found
258.0877.
4,5-Dihydro-2H-oxepino[3,2-c]chromene-2,6(3H)-dione-12-d
(4ad):
1
Colorless solid, 27.6 mg, 90% yield. H-NMR (500 MHz, CDCl3,  ppm):
7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.57–7.50 (m, 1H), 7.36–7.24 (m, 3H), 2.87
(t, J = 7.3 Hz, 2H), 2.69–2.59 (t, 2H), 2.30 (p, J = 7.4 Hz, 1.6H). 13C{1H}-
NMR (126 MHz, CDCl3,  ppm): 168.5, 162.3, 157.7, 152.5, 132.6, 124.6,
122.9, 116.7, 115.0, 112.0, 32.4, 29.7, 21.4. MS (EI) m/z 232 [M+1].
HRMS (DART) calculated for C13H9DO4 232.0720 found 232.0722.
8-Methyl-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione (4i):
Colorless solid 26.7 mg, m.p. 187-189 °C, 89% yield. 1H-NMR (400 MHz,
CDCl3,  ppm): 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.40–7.31 (m, 1H), 7.16 (t,
J = 7.7 Hz, 1H), 2.86 (t, J = 7.3 Hz, 2H), 2.63 (t, J = 7.2 Hz, 2H), 2.41 (s,
3H), 2.33-2.23 (m, 2H). 13C{1H}-NMR (100 MHz, CDCl3,  ppm): 168.6,
162.1, 158.0, 150.8, 133.9, 126.2, 124.1, 120.5, 114.6, 111.8, 32.5, 26.6,
21.5, 15.5. IR (ATR)/cm-1: 1750, 1691, 1625. MS (DART) m/z 245 [M+1].
HRMS (DART) calculated for C14H12O4 245.0736 found 245.0735.
4,5-Dihydro-3H-benzo[b]oxepin-2-one (6a):[15] Yellow oil, 21,4 mg, yield
24%. 1H NMR (500 MHz, CDCl3,  ppm) 2.17 (q, J =7.2 Hz, 2H), 2.46 (t, J
=7.2 Hz, 2H), 2.81 (t, J =7.3 Hz, 2H), 7.07 (d, J =7.9 Hz, 1H), 7.20-7.11 (m,
2H), 7.28-7.23 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3,  ppm) 26.5, 28.2,
31.1, 119.3, 125.9, 128.3, 129.6, 130.1, 151.8, 171.6.
8-(tert-Butyl)-4,5-dihydro-6H-oxepino[3,2-c]chromene-2,6(3H)-dione
(4j): Colorless solid 25.5 mg, m.p. 127-129 °C, 85% yield. 1H NMR (500
MHz, CDCl3/DMSO-d6,  ppm) 7.59 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.7,
2.4 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 2.80 (t, J = 7.4 Hz, 2H), 2.62 (t, J =
7.2 Hz, 2H), 2.24 (p, J = 7.3 Hz, 2H), 1.24 (s, 9H). 13C{1H}-NMR (126 MHz,
CDCl3/DMSO-d6,  ppm) 168.6, 162.1, 157.8, 150.3, 147.8, 130.2, 118.7,
116.1, 114.0, 111.6, 34.6, 32.4, 31.2, 26.5, 21.4. IR (ATR)/cm-1: 1783,
1698, 1635. MS (DART) m/z 287 [M+1]. HRMS (DART) calculated for
C17H18O4 287.1283 found 287.1281.
2-Methyl-2,3-dihydro-4H-furo[3,2-c]chromen-4-one (5a): Colorless
solid, 25.5 mg, 86% yield. 1H NMR (500 MHz, CDCl3, δ ppm): 7.58 (dd, J
= 7.8, 1.7Hz, 1H), 7.48 (td, 8.8, 7.3, 1.6 Hz, 1H), 7.31 (m, J = 8.6, 1.0 Hz,
1H) 7.22 (td, J = 7.8, 1.7 Hz, 1H), 5.21 (dd, 9.7, 7.3, 6.4, 1H), 3.26 (dd, J
= 15.0, 9.7 Hz, 1H), 2.72 (dd, J = 15.0, 7.3 Hz, 1H), 1.51 (d, J = 6.3 Hz,
3H). 13C{1H}-NMR (126 MHz, CDCl3, δ ppm): 166.4, 160.9, 154.9, 132.2,
123.8, 122.7, 116.9, 112.7, 101.8, 84.1, 33.9, 22.0. MS (EI) m/z 202 [M+].
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10.1002/ejoc.201900649
European Journal of Organic Chemistry
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Biomol. Chem., 2017, 15, 8084-8090. (f) G. Cheng, Y. Hu, J. Org. Chem.,
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We gratefully acknowledge the financial support from DGAPA-
UNAM (PAPIIT IA201818) and CONACyT (626716 Fellowship).
We also thank A. Toscano, M. Paz Orta, R. Patiño, S. Hernández-
Ortega, J. Pérez, M. C. García, L. Velasco, C. Márquez, L. Rios,
E. García, G. Cortés (UCTIC), H. Rios, E. Huerta, M. A. Peña, M.
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Keywords: Coumarin, cyclocarbonylation, medium-size
lactones, alcoxycarbonylation, 3-Allyl-4-hydroxycoumarin
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Cyclocarbonylation Reaction*
D. Oliver Sosa, Karla Almaraz and
Manuel Amézquita-Valencia*
Universidad Nacional Autónoma de
México, Instituto de Química, Ciudad
Universitaria, Ciudad de México, 04510,
México.
This work presents a regioselective route to synthesize of seven-membered
ring lactones fused to coumarin scaffold. The protocol presents good yields and
high regioselectivity. Additionality, the carbonylation reaction is in the absence
of acidic or any other additive as hydrogen (H2).
*Corresponding author. FAX: +52 5
6162217/6162207.
E-mail address:
manuel.amezquita@iquimica.unam.mx
*Cyclocarbonylation, coumarin
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