The synthesis of substituted benzo[c]chromen-6-ones by a Suzuki coupling and lactonization sequence using ionic liquids - From laboratory scale to multi-kilogram synthesis

Article abstract of DOI:10.1002/ejoc.200600188

A series of benzo[c]chromen-6-ones are prepared by a Suzuki coupling and lactonization sequence starting with 2-methoxyphenylboronic acids and methyl 2-bromobenzoate derivatives. The use of ionic liquids in this synthesis has been explored. It was found that the Suzuki coupling proceeds much faster when a catalytic amount of the ionic liquid [BMIM][PF₆] is used. By using the Lewis acidic ionic liquids [BMIM][Al₂Cl₇] or [TMAH][Al₂Cl₇] the methyl 2-(2-methoxyphenyl)benzoate product obtained from the Suzuki coupling can be converted to benzo[c]chromen-6-ones in one step, while the conventional route involves three steps. The use of ionic liquids is demonstrated in the synthesis of a variety of benzo[c]chromen-6-ones. It is also shown that the application of ionic liquids is not limited to laboratory scale experiments, as a process was developed and performed on a multi-kilogram scale. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600188

FULL PAPER
DOI: 10.1002/ejoc.200600188
The Synthesis of Substituted Benzo[c]chromen-6-ones by a Suzuki Coupling
and Lactonization Sequence Using Ionic Liquids – from Laboratory Scale to
Multi-Kilogram Synthesis
Gerardus J. Kemperman,*[a] B. Ter Horst,[a] D. Van de Goor,[a] T. Roeters,[a] J. Bergwerff,[a]
R. Van der Eem,[a] and J. Basten[a]
Keywords: Ionic liquids / Lactonization / Suzuki coupling / Benzo[c]chromen-6-one
A series of benzo[c]chromen-6-ones are prepared by a Su-
zuki coupling and lactonization sequence starting with 2-
methoxyphenylboronic acids and methyl 2-bromobenzoate
derivatives. The use of ionic liquids in this synthesis has been
explored. It was found that the Suzuki coupling proceeds
much faster when a catalytic amount of the ionic liquid
[BMIM][PF6] is used. By using the Lewis acidic ionic liquids
[BMIM][Al2Cl7] or [TMAH][Al2Cl7] the methyl 2-(2-meth-
oxyphenyl)benzoate product obtained from the Suzuki coup-
ling can be converted to benzo[c]chromen-6-ones in one
step, while the conventional route involves three steps. The
use of ionic liquids is demonstrated in the synthesis of a vari-
ety of benzo[c]chromen-6-ones. It is also shown that the ap-
plication of ionic liquids is not limited to laboratory scale ex-
periments, as a process was developed and performed on a
multi-kilogram scale.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
tions[7] and nucleophilic substitutions[8] display deviating
behavior when conducted in these contemporary solvents.
Introduction
The use of ionic liquids in organic synthesis has been This paper deals with the use of ionic liquids in the synthe-
extensively described and reviewed during the past dec- sis of the substituted benzo[c]chromen-6-ones 5. The
ade.[1] There are several examples in which ionic liquids benzo[c]chromen-6-one structure recurs in the synthesis of
have a surprising effect on chemical reactions performed in various pharmaceutically interesting compounds that po-
these solvents. It has been demonstrated that ionic liquids tentially find application as progesterone,[9] glucocort-
profoundly influence the rate of palladium-catalyzed reac- icoid,[10] and androgen receptor ligands.[11] The synthesis of
tions.[2–5] Also Diels–Alder reactions,[6] Friedel–Crafts reac- the benzo[c]chromen-6-one structure generally starts with a
Scheme 1.
[a] Department of Process Chemistry, Organon NV,
P. O. Box 20, 5340 BH Oss, The Netherlands
E-mail: gerjan.kemperman@organon.com
Eur. J. Org. Chem. 2006, 3169–3174
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3169

G. J. Kemperman, et al.
FULL PAPER
Suzuki coupling of a 2-methoxyphenylboronic acid 1 and a not possible for reactions carried out in toluene, as during
methyl 2-bromobenzoate 2 followed by a lactonization se- work up of these reactions the catalyst was not recoverable.
quence. This synthesis, which is shown in Scheme 1, allows The results of the reactions in toluene and [BMIM][PF6],
many functional groups in both aromatic blocks.
respectively, as well as the results with the recycled ionic
For both the Suzuki coupling and the lactonization se- liquid/catalyst solution are shown in Table 1. It should be
quence, alternatives employing ionic liquids can be envis- mentioned that the reaction in toluene (Entry 1) and the
aged. Firstly, the Suzuki coupling reaction has been de- first three cycles in ionic liquid (Entry 2–4) ran to complete
scribed in ionic liquids.[5] This paper details an investigation conversion, while during the fourth and fifth recycle (Entry
of the effect of ionic liquids on the Suzuki coupling of 2- 5–6) the reaction was not completed even after 22 hours.
methoxyphenylboronic acid and methyl 2-bromobenzoate.
Table 1. Suzuki coupling of 1a and 2a in [BMIM][PF6] and toluene.
This study sheds light on the effect of the palladium source
and phosphane ligands in organic solvents and ionic li-
quids. Also the possibility of recycling of catalyst and the
ionic liquid is elucidated.
Secondly, shorter alternatives for the three-step lactoniz-
ation sequence depicted in Scheme 1 have been elaborated.
The advantages of the benzo[c]chromen-6-one synthesis
mediated by ionic liquids are demonstrated for a series of
compounds bearing a variety of functional groups. Further-
more, the present study was aimed at the development of
Entry Solvent
Cycle
Reaction time [h] Isolated yield [%]
1
2
3
4
5
6
toluene
n.a.
1
2
3
4
30
0.5
20
20
22+
22+
99
75
91
68
43
10
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
5
Clearly, the rate of the reaction in ionic liquids decreased
an up scalable process for the preparation benzo[c]chromen- after each recycle of the ionic liquid/catalyst system. The
6-ones. Lastly, the feasibility of ionic-liquid technology on first three cycles (Entry 2–4) the reaction time was shorter
multi-kilogram scale has been demonstrated.
than in toluene, but the average yield was lower in ionic
liquids. Remarkably, the yield of the second cycle (Entry 3)
is higher than that of the first cycle although both reactions
ran to complete conversion. This poor reproducibility is at-
tributed to the difficult extraction of product from the ionic
liquid layer. The deterioration of the catalyst/ionic liquid
system can be explained by catalyst leaking from the ionic
liquid during the extensive toluene washings required to ex-
tract the product from the ionic liquid. The recycling ex-
periment described in Scheme 2 and Table 1, was repeated
using Pd(OAc)2 and Pd/C as palladium sources in combina-
tion with triphenylphosphane. These series showed the
same deteriorating results as those in Table 1. In summary,
the ionic liquid has a beneficial effect on the kinetics of
the Suzuki coupling reaction as concluded from comparing
Entries 1 and 2. However, because of the difficult extraction
of product from the ionic liquid, the isolated yield from
the reaction in toluene is higher than that in [BMIM][PF6].
Furthermore, reuse of the [BMIM][PF6]/catalyst system in
a reproducible manner appeared not feasible.
Results
Suzuki Coupling of 2-Methoxyphenylboronic Acid and
Methyl 2-Bromobenzoate in Toluene and [BMIM][PF6]
The paper of Welton et al.[5] has been used as a starting
point for our investigation. The conditions employed in this
paper for the Suzuki coupling of bromobenzene and phen-
ylboronic acid were also applied for the coupling of 2-meth-
oxyphenylboronic acid and methyl 2-bromobenzoate
(Scheme 2), viz. using Pd(PPh3)4 as the catalyst and aque-
ous Na2CO3 and ionic liquid as a biphasic medium at
100 °C. Instead of the water-miscible [BMIM][BF4], we
used the water-immiscible ionic liquid [BMIM][PF6] to al-
low for easier separation of the ionic liquid from the water
layer. The reaction was also conducted under the same con-
ditions in toluene.
In view of these results it was investigated whether the
beneficial effect of ionic liquids on the reaction rate, and
the easy work up using toluene as a solvent could be com-
bined. To this end, a series of reactions were performed
with 1.2 mol-% of catalyst in toluene either with or without
4.8 mol-% of [BMIM][PF6]. The ratio of Pd/[BMIM][PF6]
of 1:4 was chosen assuming that the ionic liquid may serve
as a ligand to the palladium catalyst in which case four
equivalents would be required if all phosphane ligands were
Scheme 2.
The Suzuki coupling in [BMIM][PF6] was completed af- to be displaced. No efforts have been put in reducing this
ter 30 minutes reaction time. After cooling the reaction mix- amount of [BMIM][PF6]. As catalysts Pd(PPh3)4, as well as
ture the aqueous layer was separated from the ionic liquid. Pd(OAc)2 and Pd/C in combination with PPh3 were sub-
The ionic liquid was extracted five times with toluene, after jected. The results are shown in Table 2.
which virtually no more product was extracted. The ionic
The results in Table 2 reveal that for the three palladium
liquid containing the catalyst was washed twice with water sources used, viz. Pd(PPh3)4, Pd(OAc)2, and Pd/C, the cata-
to remove salts and was reused subsequently. The latter was lyst activity is enhanced by the presence of 4.8 mol-% of
3170
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3169–3174

Benzochromenones via Suzuki coupling and lactonization in ionic liquids
FULL PAPER
Table 2. The effect of a catalytic amount of [BMIM][PF6] on the was treated with aluminum chloride, no trace of 5a could be
Suzuki coupling reaction.
detected, which points at a difference in reactivity between
aluminum chloride and [BMIM][Al2Cl7].
Catalyst[a]
[BMIM][PF6][b] Yield [%] Reaction time [h]
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2, PPh3
Pd(OAc)2, PPh3
Pd/C, PPh3
N
Y
N
Y
N
Y
99
90
88
90
94
90
30
0.5
30
3.5
22
8
[b]
[b]
[b]
[b]
Pd/C, PPh3
[a] 1.2 mol-% of palladium. [b] 4.8 mol-%.
Scheme 3. Lactonization of 4a by [BMIM][Al2Cl7].
[BMIM][PF6]. The reaction rate is up to a factor 10 higher
when a catalytic amount of [BMIM][PF6] is added to the
reaction mixture. Interestingly, only the kinetics is positively
influenced by the presence of [BMIM][PF6], while the yields
are about the same. This is in contrast to the experiments
with [BMIM][PF6] as a solvent, as with those conditions
extraction problems caused a significant decrease of the iso-
lated product yield. The reactions were repeated with
4.8 mol-% of the salt [BMIM]Cl, which is the precursor of
the ionic liquid [BMIM][PF6]. In the presence of [BMIM]
Cl virtually identical results were observed. A plausible ex-
planation for the effect of the [BMIM] cation is that imid-
azolium carbene species are formed through deprotonation
in the basic medium. It has been reported that imidazolium
carbenes are excellent ligands for palladium catalysts.[12]
The enhancement of the catalyst activity resulting in a 10-
fold shorter reaction time presents notable example of pro-
cess intensification by ionic liquids.
In a further attempt to shorten the three-step process for
the conversion of 3a into 5a, the ester 3a was subjected to
the same conditions (Scheme 4). Astonishingly, the ester 3a
was readily converted to the lactone 5a when treated with
3 equiv. of [BMIM][Al2Cl7] in dichloromethane. The lac-
tone was obtained after work up in a yield of 93%. Al-
though the yield is comparable to that of the three-step pro-
cedure described in Scheme 1, viz. 91%, the ionic liquid-
mediated lactonization is much faster and less elaborate,
and features a perfect example of process intensification.
Despite the fact that the ionic liquid needs to be destructed
by aqueous work up of the reaction, resulting in the forma-
tion of aluminate salts as a waste product, the environmen-
tal impact is tremendously reduced by using less organic
solvents and avoiding reagents such as thionyl chloride.
Lactonization of Methyl 2-(2-Methoxyphenyl)benzoate (3a)
to Benzo[c]chromen-6-one (5a) Using Lewis Acidic
Chloroaluminate Ionic Liquids
The lactonization of 3 to 5 by the process described in
Scheme 1 involves three subsequent steps. First the ester is
saponified. The thus obtained acid 4a is converted into its
acid chloride by reaction with thionyl chloride and sub-
sequently treated with aluminum chloride giving the lactone
Scheme 4. Lactonization of ester 3a with [BMIM][Al2Cl7].
It should be noted that upon treatment of the ester 3a
5. Although this sequence proceeds in high yield, it is a with three equiv. of aluminum chloride, we observed a
rather elaborate process that requires a large amount of or- much slower reaction leading to incomplete conversion to
ganic solvents in the consecutive steps and work up pro- 5a after 48 hours, while the reaction with three equiv. of
cedures. In addition, the use of thionyl chloride is not pre- [BMIM][Al2Cl7] was completed within 5 hours.
ferred on industrial scale.
The differences observed between the effectiveness of
The lactonization in Scheme 1 includes an aromatic ether aluminum chloride and [BMIM][Al2Cl7] in the lactoni-
cleavage. As chloroaluminate-based ionic liquids have zation of the ester 3a and acid 4a, led to the following
proven to be particularly useful in aromatic ether cleav- mechanistic considerations. Lactonization via the acid chlo-
age,[13] their application in the lactonization of 3 can be ride most likely proceeds by acylative ether cleavage
envisaged. Our first objective was to avoid the use of thionyl (Scheme 5 route a).[14] In this mechanism, reaction of the
chloride for the activation of carboxylic acid 4a by treating acid chloride with aluminum chloride leads to an acylium
the acid with the Lewis acidic ionic liquid [BMIM][Al2Cl7] ion that coordinates with the oxygen atom of the methoxy
(Scheme 3). To our satisfaction, the lactonization of the car- function. Subsequent attack of a chloride ion to the meth-
boxylic acid by [BMIM][Al2Cl7] was achieved, and the oxide carbon cleaves the methyl ether bond and liberates
product was isolated in a yield of 67%. Because in-process the lactone and chloromethane. As acylium-ion formation
analysis showed complete conversion of 4a to 5a, it is sus- from a carboxylic acid or ester is much more cumbersome
pected that the relatively low yield of 67% can be attributed than from acid chlorides, the lactonization of the ester 3a
to product losses during work up. When carboxylic acid 4a is deemed to proceed through another mechanism as de-
Eur. J. Org. Chem. 2006, 3169–3174
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3171

G. J. Kemperman, et al.
FULL PAPER
Scheme 5. Tentative mechanism of lactonization via the acid chloride (route a) and via the ester (route b).
picted in Scheme 5, route b. In this mechanism, the methyl The Synthesis of a Variety of Substituted Benzo[c]chromen-
ether is cleaved, and the thus formed phenoxide-aluminate 6-ones
complex subsequently undergoes lactonization. It has been
reported that chloroaluminate ionic liquids are highly active
After having developed the two-step synthesis for
ether-cleaving agents that are superior to their conventional benzo[c]chromen-6-one (5a) employing ionic liquids, the
counterpart aluminum chloride.[13] This supports route b in scope of this methodology was explored. To this end several
Scheme 5 as for the conversion of 3a or 4a into the lactone substituted phenylboronates and methyl bromobenzoates
5a, aluminum chloride was not reactive, respectively less re- were used to prepare the corresponding benzo[c]chromen-
active, than [BMIM][Al2Cl7].
6-ones. The results are shown in Table 3.
Table 3. The results of the synthesis of substituted benzo[c]chromen-6-ones 5a–f.
[a] For the synthesis of 3f 3,5-difluoro-2-methoxyphenylboronic acid was used.
3172
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3169–3174

Benzochromenones via Suzuki coupling and lactonization in ionic liquids
FULL PAPER
Scheme 6. Large-scale process for the conversion of 3f into 5f.
As is evident from Table 3, the developed methodology viz. catalyst enhancement, and the advantage of toluene as
can be used for the synthesis of a variety of substituted a solvent, viz. easy work up, were efficiently combined by
benzo[c]chromen-6-ones. All Entries provide the product in using 4.8 mol-% of [BMIM][PF6] or its precursor [BMIM]-
only two steps in good overall yield. The methodology al- Cl in the reaction in toluene. In this way, the ionic liquid
lows both electron-withdrawing and electron-releasing enhanced the rate of the reaction by a factor ten and the
groups to be present at either of the aromatic rings. Entry easy work up furnished the products in excellent yields.
c did not furnish the expected methoxy derivative but the
The methyl 2-(2-methoxyphenyl)benzoates 3 formed
hydroxy derivative 5c instead. We have reported before, that could be converted into benzo[c]chromen-6-ones 5 in one
Lewis acidic ionic liquids are excellent ether cleaving step by treatment with a Lewis acidic chloroaluminate ionic
agents.[13] The conversion of 3c into 5c, involves two reac- liquid. This procedure proved much more efficient than the
tions, viz. lactonization and methyl-ether cleavage, which three-step sequence that was deployed originally. In ad-
proceed in an overall yield of 59%.
dition, by using the one-step ionic liquid-mediated reaction,
To demonstrate the feasibility of industrial application of the amount of organic solvents used decreased significantly,
the developed methodology, the lactonization process was and the use of thionyl chloride could be avoided. By using
also studied using the Lewis acidic ionic liquid derived from a low-cost ionic liquid prepared from trimethylamine hy-
trimethylamine hydrochloride and aluminum chloride in- drochloride and aluminum chloride, the lactonization pro-
stead of [BMIM][Al2Cl7]. Trimethylamine hydrochloride is cess was developed and scaled up to 7-kg scale. This dem-
much cheaper than 3-butyl-1-methyl-imidazolium chloride onstrates the industrial feasibility of this process using ionic
([BMIM]Cl) and is readily available in bulk. By using liquids.
[TMAH][Al2Cl7] an up scalable process for the conversion
The results described in this paper show how the applica-
of 3f into 5f was developed. This process is outlined in tion of water-stable and Lewis acidic ionic liquids can be
Scheme 6. To a suspension of aluminum chloride, trimeth- used for process intensification, reducing both reaction time
ylamine hydrochloride was added in portions. In this way, and waste of reagents and organic solvents.
the exothermicity of the reaction can be controlled excel-
lently. To the thus prepared solution of the ionic liquid 7,
the starting material 3f was added. After completion of the
reaction, water was added to quench the chloroaluminate
ionic liquid and to dissolve the resulting aluminate and
amine salts. The product precipitated and was filtered off
Experimental Section
General Remarks: Reactions were monitored with a HP 6890 Series
GC and TLC (silica gel). The NMR spectra were recorded with a
Bruker DPX-400. Mass spectroscopy was performed with a PE
after the removal of dichloromethane by distillation. The
Sciex API 165.
process shown in Scheme 6 has been performed in our Kilo-
Methyl 2-(2-Methoxyphenyl)benzoate (3a): A mixture of o-meth-
oxyphenylborate (0.78 g, 5.1 mmol), methyl o-bromobenzoate
(0.653 mL, 4.7 mmol), Na2CO3 (1.05 g, 9.9 mmol), Pd(OAc)2
(12.7 mg, 1.2 mol-%), triphenylphosphane (59 mg, 4.8 mol-%), and
lab facility four times on 7-kg scale. This example demon-
strates that the developed methodology not only serves as
an efficient synthesis for benzo[c]chromen-6-ones on labo-
ratory-scale, but is feasible on multi-kilogram scale as well.
[BMIM][Cl] (20 mg, 4.8 mol-%) in water (3 mL) and toluene
(7 mL) was heated to reflux temperature. The progress of the reac-
tion was monitored by TLC (silica gel, ethyl acetate/heptane, 1:3).
The reaction was completed after 3.5 hours. The toluene layer was
separated, and the water layer was extracted twice with toluene
(7 mL). The combined toluene fraction was washed with an aque-
Conclusions
The Suzuki coupling of 2-methoxyphenylboronic acids 1
and methyl 2-bromobenzoates 2 proceeds much faster in
imidazolium-based ionic liquids compared with toluene.
However, the poor extractability of the products from the
ionic liquid resulted in a low yield when reactions were con-
ous NaHCO3 solution and with brine. The toluene was dried with
MgSO4 and the solvents evaporated to dryness. Yield 1.13 g (99%)
of the title compound. 1H NMR (400 MHz, CDCl3): δ = 7.87 (dd,
1 H), 7.54 (t, 1 H), 7.39 (t, 1 H), 7.30–7.36 (m, 2 H), 7.25 (dd, 1
ducted in ionic liquids. The advantage of the ionic liquid, H), 7.04 (t, 1 H), 6.91 (d, 1 H), 3.72 (s, 3 H), 3.65 (s, 3 H) ppm.
Eur. J. Org. Chem. 2006, 3169–3174
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3173

G. J. Kemperman, et al.
FULL PAPER
Methyl 2-(2-Methoxyphenyl)-5-methylbenzoate (3b): The procedure
was the same as for 3a. Yield: 1.18 g (98%). H NMR (400 MHz,
CDCl3): δ = 7.68 (s, 1 H), 7.29–7.37 (m, 2 H), 7.21–7.25 (m, 2 H),
7.02 (t, 1 H), 6.88 (d, 1 H), 3.71 (s, 3 H), 3.64 (s, 3 H), 2.41 (s, 3
H) ppm.
4,6-Difluoro-8-nitrobenzo[c]chromen-6-one (5f). Preparation on
Multi-Kilogram Scale: Aluminum chloride (16.7 kg, 125.4 mol) was
suspended in dichloromethane (48 L). To this suspension, trimeth-
ylammonium chloride (6.0 kg, 62.7 mol) was added in portions at
5 °C. To the resulting solution, a solution of methyl 2-(3,5-difluoro-
2-methoxyphenyl)-5-nitrobenzoate (3f) (6.75 kg, 20.9 mol) in
dichloromethane (10 L) was added within 60 minutes. The reaction
mixture was stirred at ambient temperature. After 20 hours the re-
action was complete according to HPLC analysis and the reaction
mixture was poured into water (145 L). The dichloromethane was
distilled and the remaining suspension was stirred overnight. The
suspension was filtered and the crystals were washed three times
with water (15 L). The crystals were dried on a filter. Yield: 5.63 kg
1
Methyl 2-(2-Methoxyphenyl)-5-methoxybenzoate (3c): The pro-
cedure was the same as for 3a. Yield: 1.10 g (86%). 1H NMR
(400 MHz, CDCl3): δ = 7.40 (d, 1 H), 7.31 (t, 1 H), 7.21–7.27 (m,
2 H), 7.08 (dd, 1 H), 7.02 (t, 1 H), 6.88 (d, 1 H), 3.87 (s, 3 H), 3.72
(s, 3 H), 3.64 (s, 3 H) ppm.
Methyl 5-Chloro-2-(2-methoxyphenyl)benzoate (3d): The procedure
was the same as for 3a. Yield: 0.921 g (71%). 1H NMR (400 MHz,
CDCl3): δ = 7.85 (d, 1 H), 7.51 (dd, 1 H), 7.34 (t, 1 H), 7.27 (d, 1
H), 7.21 (d, 1 H), 7.03 (t, 1 H), 6.90 (d, 1 H), 3.72 (s, 3 H), 3.66 (s,
3 H)
1
of 5f (98%). H NMR (400 MHz, CDCl3): δ = 9.27 (d, 1 H), 8.68
(dd, 1 H), 8.22 (d, 1 H), 7.61 (dt, 1 H), 7.21 (m, 1 H) ppm.
Methyl 2-(2-Methoxyphenyl)-5-nitrobenzoate (3e): The procedure
was the same as for 3a. Yield: 0.885 g (68%). 1H NMR (400 MHz,
CDCl3): δ = 8.71 (d, 1 H), 8.37 (dd, 1 H), 7.53 (d, 1 H), 7.41 (t, 1
H), 7.26 (dd, 1 H), 7.08 (t, 1 H), 6.94 (d, 1 H), 3.74 (s, 6 H) ppm.
[1] T. Welton, Chem. Rev. 1999, 99, 2071–2084; P. Wasserscheid,
W. Keim, Angew. Chem. Int. Ed. 2000, 39, 3772–3789; J. D.
Holbrey, K. R. Seddon, Clean Products and Processes 1999, 1,
223–226; J. S. Wilkes, Green Chem. 2002, 4, 73–80.
[2] A. J. Carmichael, M. J. Earle, J. D. Holbrey, P. B. McCormac,
K. R. Seddon, Org. Lett. 1999, 1, 997–1000; V. Caló, A. Nacci,
L. Lopez, N. Mannarini, Tetrahedron Lett. 2000, 41, 8973–
9076.
Methyl 2-(3,5-Difluoro-2-methoxyphenyl)-5-nitrobenzoate (3f): The
procedure was the same as for 3a. Yield: 382 g (88%). 1H NMR
(400 MHz, CDCl3): δ = 8.81 (d, 1 H), 8.41 (dd, 1 H), 7.52 (d, 1
H), 6.94 (m, 1 H), 6.77 (m, 1 H), 3.81 (s, 3 H), 3.63 (s, 3 H) ppm.
[3] J. E. L. Dullius, P. A. Z. Suarez, S. Einloft, R. F. de Zouza, J.
Dupont, J. Fischer, A. D. Cian, Organometallics 1998, 17, 815–
819.
Benzo[c]chromen-6-one (5a): Methyl 2-(2-methoxyphenyl)benzoate
(3a) (1.00 g, 4.1 mmol) was dissolved in dichloromethane (20 mL).
To this solution, [BMIM][Al2Cl7] (4.6 mL, 12.3 mmol) was added.
Then the reaction mixture was heated to reflux. After 20 hours the
reaction was completed (TLC, silica gel/toluene) and the reaction
mixture was cooled to room temperature. The reaction mixture was
poured into ice water and the dichloromethane was separated and
the water layer was extracted three times with dichloromethane.
The combined dichloromethane layers were washed with saturated
NaHCO3 solution and water. Then the organic layer was dried with
MgSO4 and the solvents evaporated. Yield: 0.801 g of 5a (93%).
1H NMR (400 MHz, CDCl3): δ = 8.42 (dd, 1 H), 8.14 (d, 1 H),
8.08 (dd, 1 H), 7.83 (t, 1 H), 7.60 (t, 1 H), 7.50 (t, 1 H), 7.34–7.39
(m, 2 H) ppm. This compound has been reported in the litera-
ture.[15]
[4] W. Chen, L. Xu, C. Chatterton, J. Xiao, Chem. Commun. 1999,
1247–1248.
[5] C. J. Mathews, P. J. Smith, T. Welton, Chem. Commun. 2000,
1249–1250.
[6] T. Fischer, A. Sethi, T. Welton, J. Woolf, Tetrahedron Lett.
1999, 40, 793–796.
[7] A. Stark, B. L. MacLean, R. D. Singer, J. Chem. Soc. Dalton
Trans. 1999, 63–66.
[8] M. J. Earle, P. B. McCormac, K. R. Seddon, Chem. Commun.
1998, 2245–2246.
[9] J. P. Edwards, S. J. West, K. B. Marschke, D. E. Mais, M. M.
Gottardis, T. K. Jones, J. Med. Chem. 1998, 41, 303–310; L.
Zhi, C. M. Tegly, K. B. Marschke, D. E. Mais, T. K. Jones, J.
Med. Chem. 1999, 42, 1466–1472.
[10] Y.-Y. Ku, T. Grieme, P. Raje, P. Sharma, S. A. King, H. E. Mor-
ton, J. Am. Chem. Soc. 2002, 124, 4282–4286; M. J. Coghlan,
P. R. Kym, S. W. Elmore, A. X. Wang, J. R. Luly, D. Wilcox,
M. Stshko, C.-W. Lin, J. Miner, C. Tyree, M. Nakane, P. Ja-
cobsen, B. C. Lane, J. Med. Chem. 2001, 44, 2879–2885.
[11] L. G. Hamann, R. I. Higuchi, L. Zhi, J. P. Edwards, X.-N.
Wang, K. B. Marchke, J. W. Kong, L. J. Farmer, T. K. Jones, J.
Med. Chem. 1998, 41, 623–639.
8-Methylbenzo[c]chromen-6-one (5b): The procedure was the same
1
as for 5a. Yield: 0.947 g (98%). H NMR (400 MHz, CDCl3): δ =
8.21 (s, 1 H), 8.01–8.06 (m, 2 H), 7.65 (d, 1 H), 7.46 (t, 1 H), 7.31–
7.37 (m, 2 H), 2.50 (s, 3 H) ppm. This compound has been reported
in the literature.[15]
8-Hydroxybenzo[c]chromen-6-one (5c): The procedure was the same
[12] T. Weskamp, V. P. W. Böhm, W. A. Herrmann, J. Organomet.
Chem. 1999, 585, 348–352; W. A. Herrmann, V. P. W. Böhm,
C. W. K. Gstöttmayr, M. Grosche, C.-P. Reisinger, T. Wes-
kamp, J. Organomet. Chem. 2001, 617, 616–628.
[13] G. J. Kemperman, T. A. Roeters, P. W. Hilberink, Eur. J. Org.
Chem. 2003, 1681–1686.
1
as for 5a. Yield: 0.497 g (59%). H NMR (400 MHz, CDCl3): δ =
8.04 (d, 1 H), 8.01 (d, 1 H), 7.72 (d, 1 H), 7.46 (t, 1 H), 7.33–7.45
(m, 4 H) ppm.
8-Chlorobenzo[c]chromen-6-one (5d): The procedure was the same
1
as for 5a. Yield: 0.412 g (70%). H NMR (400 MHz, CDCl3): δ =
[14] L. Green, I. Hemeon, R. D. Singer, Tetrahedron Lett. 2000, 41,
8.38 (d, 1 H), 8.08 (d, 1 H), 8.03 (d, 1 H), 7.78 (d, 1 H), 7.52 (t, 1
H), 7.34–7.40 (m, 2 H) ppm. This compound has been reported in
the literature.[15]
1343–1346.
[15] Q. J. Zhou, K. Worm, R. E. Dolle, J. Org. Chem. 2004, 69,
5147–5149.
[16] L. Zhi, J. D. Ringgenberg, J. P. Edwards, C. M. Tegley, S. J.
West, B. Pio, M. Motamedi, T. K. Jones, K. B. Marschke, D. E.
Mais, W. T. Schrader, Bioorg. Med. Chem. Lett. 2003, 13, 2075–
2078.
8-Nitrobenzo[c]chromen-6-one (5e): The procedure was the same as
for 5a. Yield: 0.692 g (93%). 1H NMR (400 MHz, CDCl3): δ = 9.24
(d, 1 H), 8.64 (dd, 1 H), 8.32 (d, 1 H), 8.13 (dd, 1 H), 7.63 (t, 1
H), 7.42–7.47 (m, 2 H) ppm. This compound has been reported in
the literature.[16]
Received: March 3, 2006
Published Online: May 12, 2006
3174
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3169–3174