Lewis and Br?nsted acid catalyzed Friedel-Crafts hydroxyalkylation of mucohalic acids: a facile synthesis of functionalized γ-aryl γ-butenolides

Article abstract of DOI:10.1016/j.tetlet.2007.02.009

A catalytic, green and practical method for Friedel-Crafts hydroxyalkylation of mucohalic acid has been accomplished. Reaction of mucohalic acids with various electron-rich aromatic compounds in the presence of catalytic (1 mol % to 10 mol %) In(OTf)

Full text of DOI:10.1016/j.tetlet.2007.02.009

Tetrahedron Letters 48 (2007) 2611–2615
¨
Lewis and Bronsted acid catalyzed Friedel–Crafts
hydroxyalkylation of mucohalic acids: a facile synthesis
of functionalized c-aryl c-butenolides
Ji Zhang,* Peter G. Blazecka and Timothy T. Curran
Research API, Pfizer Global Research and Development, Ann Arbor Laboratories, Pfizer, Inc.,
2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 9 January 2007; revised 30 January 2007; accepted 1 February 2007
Available online 7 February 2007
Abstract—A catalytic, green and practical method for Friedel–Crafts hydroxyalkylation of mucohalic acid has been accomplished.
Reaction of mucohalic acids with various electron-rich aromatic compounds in the presence of catalytic (1 mol % to 10 mol %)
In(OTf)3 or Bro¨nsted acid, such as H2SO4 in acetic acid provides c-aryl c-butenolides in moderate to excellent yield.
Ó 2007 Elsevier Ltd. All rights reserved.
The Friedel–Crafts acylation is one of the most impor-
tant reactions for C–C bond formation in organic chem-
istry and widely utilized in the pharmaceutical industry.1
The classical method generally requires using Lewis
acids, such as AlCl3, ZnCl2, TiCl4, or BF3, to promote
this reaction.2 There are several disadvantages usually
associated with this reaction: (1) The use of excess Lewis
acid results in ‘exciting’ quenches, and significant heat
generated in the decomposition of the complex, thus
also making it impossible to recycle the Lewis acid. (2)
These reactions are commonly carried out under anhy-
drous conditions, requiring the solvent and starting
material to be pre-dried, which adds to time and money
because most of Lewis acids are moisture sensitive. (3)
The Lewis acids cited above often require halogenated
or environmentally harmful and potentially hazardous
solvents, such as CH2Cl2, CHCl3, or CS2, which create
significant waste and it is oftentimes not cost effective.
While a few significant catalytic Friedel–Crafts acylation
reaction systems have been recently developed,3 there
remains room to improve yield, extend scope, reduce
catalyst loading,4 or use of green solvents.5 Although
catalytic Lewis acid processes have been developed,
the use of co-catalysts, such as AgClO4 and/or LiClO4,
was required. In the continued study of mucohalic acid
chemistry, we decided to develop a green version of the
Friedel–Crafts hydroxyalkylation to access substituted
c-aryl c-butenolides.
Some naturally occurring furofuran lignans (Fig. 1) are
substituted c-aryl c-butyrolactones with one or several
phenolic structures. Recently the structural similarity
of lignans with L-ascorbic acid (Vitamin C) prompted
the suggestion that lignans be considered as natural
phenolic antioxidants, like green tea with EGCG,6 and
viewed as health-promoting substances. It is the general
opinion that the dietary intake of these antioxidants is
associated with a lower risk of age-related health
problems including cancer and coronary heart diseases.7
Recently, Eklund et al.8 reported their study results of
antioxidant mechanisms and free radical scavenging
properties of lignans. The SAR (structure–activity rela-
tionship) study indicated lignans showed a good radical
scavenging capacity, and seem to be promising anti-
oxidants, mainly due to their good stability. When
compared to the known standard, such as Vitamin C,
Vitamin E and BHT, some of these lignans showed an
equally good or even better radical-scavenging capacity.
Their most important finding is that those lignans
showed a relatively slow kinetic profile, which may be
useful as pharmaceutical products since the long-lasting
antioxidant efficiency is crucial.
Keywords: Friedel–Crafts hydroxyalkylation; Mucochloric acid;
Mucobromic acid; Indium(III) salt; Green chemistry.
Several bislactones such as styraxin 19 and eupomatilone
210 have been synthesized and studied because of their
broad range of biological activities such as antitumor11
*
Corresponding author. Tel.: +1 734 6223940; fax: +1 734 6223294;
e-mail: ji.zhang@pfizer.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.009

2612
J. Zhang et al. / Tetrahedron Letters 48 (2007) 2611–2615
OMe
OMe
OMe
OMe
O
O
O
O
O
O
O
O
O
H
H
H
H
MeO
MeO
O
MeO
OMe
O
OMe
O
OMe
HO
1
2
3
O
Cl
H3CO
OCH3
O
O
Br
O
Br
HO
O
OCH3
OH
OH
O
HO
OH
Br
OCH3
O
4
5
6
Figure 1. Some naturally occurring lignans, butenolides, substituted THF and L-ascorbic acid (5, vitamin C, antioxidant).
and anti-HIV properties.12 Furthermore, aryl c-buteno-
lides can be used to synthesize substituted tetrahydro-
furans, such as diaryl THF 3 and 4 via reduction.13
We reasoned that mucohalic acids would be ideal to
access aryl c-butenolides since they are functional-
ized pseudo butenolides which are stable under acidic
conditions.
The initial experiment was encouraging. After heating a
mixture of mucochloric acid and 1,2,3-trimethoxybenz-
ene with 2.5 mol % In(OTf)3, the color of the reaction
mixture changed to purple. This color switch turned
out to be a good indicator for a successful reaction.
After 16–18 h at reflux, product 9 was isolated in
47% yield as the sole product. With this result in hand,
we decided to screen a number of Lewis acids (Scheme
1).
There were also limited reports that used unsaturated
aldehydes as the electrophile in Friedel–Crafts hydroxy-
alkylation (acylation).14 Mucohalic acid can be viewed
as an electron deficient unsaturated aldehyde;15 thus
choosing an electron-rich aromatic would build a better
donator–acceptor relationship between these two re-
agents, which we suspected would be ideal for the reac-
tion. Since we planned to use electron-rich aromatics,
such as di- or trimethoxybenzene as reactants which
would provide phenolic or anisolic substructures, classi-
cal strong, oxophilic Lewis acids, such as AlCl3, TiCl4,
were removed from the screening list because these Le-
wis acids make a catalytic process impossible.16 Since
water will be formed in the reaction, a water stable,
green, Lewis acid, such as In(OTf)3 and InCl3, became
our first choice.17
Among several Lewis acids that were studied, their
catalytic activities were found in the order: In(OTf)3 >
Sn(OTf)3 > Sc(OTf)3 ꢀ Mg(OTf)2 > InCl3 > Zn(OTf)2.
But Yb(OTf)3, BiCl3, SnCl22H2O, and ZnCl2 did not
show their efficiency as catalysts for this reaction. Hav-
ing identified In(OTf)3 as an ideal catalyst, we then
determined the appropriate loading (Table 1) and found
that the optimal catalyst level seemed to be 5–10 mol %
(entries 1 and 2) and water removal was not required
(entry 2).
It was also observed that although 1.0 equiv of 1,2,3-tri-
methoxybenzene and 1.0 equiv mucohalic acid was
used, a small amount of mucohalic acid remained, while
We initially surmised that removing water from the
reaction mixture would shift the equilibrium toward
the product. We initially believed that the azeotropic
removal of water using a Dean–Stark trap and toluene
as the solvent maybe necessary, and would be simple.
It was found that no reaction between mucohalic acid
and toluene occurred under In(III) salt and thus toluene
was used as solvent when 1,2,3-trimethoxybenzene
reacted with mucohalic acid.18
Table 1. In(OTf)3 loading study
Cl
Cl
Cl
Cl
HO
Lewis acid
Toluene
+ H2O
+
MeO
MeO
MeO
O
OMe
O
O
O
OMe
OMe
7
8
9
Entry
In(OTf)3 (mol %)
Conversion (%)
1
2
3
4
5
10
5
2.5
1
88a
76
47a
37
Cl
Cl
Cl
Cl
HO
Lewis acid
Toluene
+ H2O
+
MeO
MeO
MeO
0.5
23
O
OMe
O
O
O
OMe
Reaction condition: 20 mL toluene, 24 h, 100–110 °C, water of the
reaction not removed. % Conversion is the molar ratio of the product
to mucochloric acid as determined by HPLC analysis of the reaction
mixture.
OMe
7
8
9
Scheme 1. Lewis acid catalyzed hydroxyalkylation of 1,2,3-trimeth-
oxybenzene with mucochloric acid.
a Isolated yield and water was removed by the Dean trap.

J. Zhang et al. / Tetrahedron Letters 48 (2007) 2611–2615
2613
Table 3. Bro¨nsted acid catalyzed Friedel–Crafts hydroxyalkylation
1,2,3-trimethoxybenzene disappeared indicating it must
undergo some side reaction or decomposition due to
the stability and reactivity of 1,2,3-trimethoxybenzene
8. The purple color is possibly from the oxidation of
1,2,3-trimethoxybenzene or a Friedel–Crafts intermedi-
ate which gave a benzoquinone-like structure. Thus,
we decided to use 1.5 equiv of the electron-rich aromatic
compound, 1,3,5-trimethoxybenzene 10 as starting
material for further study, which provided sole product
11.
Cl
MeO
OMe
Cl
Cl
HO
Cl
O
Catalyst
+
MeO
H2O
+
O
Solvent
100 °C
O
O
MeO
OMe
OMe
10
7
11
Entry Solvent
Catalyst
Time Conversionb Yield
(h)
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
15d
16e
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
H2O
TfOH
MSA
H2SO4
p-TSA
CSA
Amberlyst 15 10
HOAc
HCl
H3PO4
TFA
SDS
—
H2SO4
1
4
1
5
37
99
98
99
98
92
93
22
36
74
93
92
92
86
86
88
84
—
—
—
—
—
—
85
84
98
95
91
95
Although toluene was used initially, CH3NO2 and
CH2Cl2 emerged as the superior solvents (Table 2) for
this reaction, giving excellent conversion (entries 1, 7–
9) and can be operated under mild reaction conditions.
Unfortunately, developing methodology that employed
a green solvent was of considerable importance. This
prompted further investigation of reaction solvents,
and unexpectedly to our delight, when reactions were
repeated using standard glassware and in the absence
25
25
25
41
19
41
HOAc
HOAc
˚
0.5 99
of 4 A molecular sieves, both EtOAc (entry 12) and
HOAc/H2O H2SO4
6
3
2
98
98
98
CH3CN (entry 13) gave superb conversion (with no
water removal). Since water did not hinder the reaction,
we wondered if water could be used as a sole solvent.
Indeed when the reaction was run in water for 48 h at
100 °C, it gave excellent conversion! The more notable
reaction was that performed in HOAc (entry 15), pro-
viding an extremely high reaction rate and the reaction
HOAc
HOAc
H2SO4
H2SO4
a Reaction conditions: identical to Table 2, footnote a.
b Conversion is the molar ratio of the product to mucochloric acid as
determined by HPLC analysis of the reaction mixture.
c A 92% yield was obtained when mucobromic acid was used.
d Used 0.01 equiv catalyst.
e Used 1.10 equiv TMB.
Table 2. Solvent screen in In(OTf)3 catalyzed Friedel–Crafts hydroxy-
alkylation
Cl
MeO
OMe
Cl
Cl
HO
Cl
O
was completed in 1 h! This condition also provided the
simplest work-up procedure, as when the reaction mix-
ture was diluted with water, the product was precipi-
tated making separation and isolation simple (Table 2).
In(OTf)3
Solvent
+
MeO
H2O
+
O
O
O
MeO
OMe
OMe
7
10
11
Entry Solvent Temperature (°C) Time (h) Conversionb (%)
The development of metal-free process is important for
the pharmaceutical industry because a green or environ-
ment friendly process would reduce waste. This coupled
with the above success pressed us to consider the use of
Bro¨nsted acids to catalyze this reaction. It was found in
MeNO2, several Bro¨nsted acids promoted this reaction
and provided product in excellent conversion and
isolated yield (Table 3). The order of their catalytic
activity is H2SO4 = TfOH > MSA > p-TSA > Amber-
lyst > CSA > TFA > H3PO4 > HCl > HOAc. Thus we
decided to use HOAc as the reaction solvent and
H2SO4, the cheap and highly efficient acid as catalyst.
It was found that under these modified conditions
(10 mol % H2SO4 in AcOH) the reaction was completed
in only 0.5 h and the product was isolated in 98% yield.
This condition was also suitable for mucobromic acid,
where the desired product was isolated in an 82% yield
(Fig. 2).
1c
1e
2c
3c
4c
5c
6c
7
MeNO2
MeNO2 100
CH2Cl2
EtOAc
MeCN
THF
70
15
65
22
15
15
15
15
2
3
6
3
6
92
98
70
28
18
6
40
70
70
60
60
DMF
MeNO2 100
0
>99
95
>99
87
99
97
98
51
98
>99
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
EtOAc
MeCN
THF
40
40
40
61
77
81
67
100
100
10d
11
12
13
14
15
16
6
15
23
48
1
H2O
HOAc
a Reaction conditions: 1 equiv (10.0 mmol) of mucochloric acid,
1.5 equiv of 1,3,5-trimethoxybenzene, 0.10 equiv of In(OTf)3 and
20 mL of desired solvent. Water was not removed. Used standard
50 mL rbf and condenser.
b Conversion is the molar ratio of the product to mucochloric acid as
determined by HPLC analysis of the reaction mixture.
Before Bro¨nsted acid catalyzed Friedel–Crafts hydroxy-
alkylation was studied, we also examined the generality
of the In(OTf)3 catalyzed Friedel–Crafts reaction and
the results are listed in Figure 2. The general rule is that
the more methoxy (MeO–) groups attached to the aro-
matic ring, the higher the isolated yield of the corre-
sponding c-butenolide.
c
˚
Used carousel reactor tubes and powdered 4 A molecular sieves were
added to the reaction mixtures.
d Used 0.10 equiv of InCl3 instead of In(OTf)3.
e 10% In(OAc)3 was used.

2614
J. Zhang et al. / Tetrahedron Letters 48 (2007) 2611–2615
Cl
OMe
OMe
Acknowledgments
Cl
Cl
Cl
Cl
Cl
MeO
MeO
MeO
MeO
MeO
O
O
O
O
O
O
We thank Pfizer, Inc for supporting green chemistry
practices. We also acknowledge the assistance of the
High Pressure Lab of Ann Arbor Laboratories, Pfizer,
Inc.
OMe
84%
58%
92%
Br
Br
Cl
Cl
Cl
Cl
MeO
MeO
MeO
MeO
O
O
O
O
O
O
59%
OMe
48%
Cl
OMe
OMe
Supplementary data
71%
Cl
O
Br
Cl
Cl
Br
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.009.
MeO
MeO
MeO
O
O
O
O
O
O
OMe
48%
OMe
85%
82%
Cl
Br
Cl
References and notes
Br
Br
MeO
MeO
MeO
O
O
O
1. (a) Olah, G. A.; Krishnamurit, R.; Prakash, G. K. S.
Friedel–Crafts Alkylation. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 3, pp 293–339; (b) Smyth, T. P.; Corby,
B. W. Org. Proc. Res. Dev. 1997, 1, 264–267, and
references cited therein; use in Sertraline (Zoloft) process,
see: (c) Quallich, G. J.; Williams, M. T.; Friedmann, R. C.
J. Org. Chem. 1990, 55, 4971–4973.
O
OMe
38%
OMe
45%
Figure 2. Products from catalytic Friedel–Crafts hydroalkylation of
mucohalic acid by using 10 mol % In(OTf)3 in toluene.19
The above methodologies have several advantages: (1)
both starting materials are inexpensive and commer-
cially available, (2) reactions proceed smoothly, giving
moderate to excellent yields, (3) products are functional-
ized, leading them to further transformations, and (4) a
catalytic amount of Lewis acid or Bro¨nsted acid was
used (1.5 mol % to 10 mol %). This last point opens a
window for using chiral Lewis acids in the asymmetric
Friedel–Crafts hydroxyalkylation reactions to prepare
optically active c-butenolides.
2. Olah, G. A. Friedel–Crafts and Related Reactions, Part 1;
Wiley-Interscience: New York, 1964; p 2.
3. (a) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron
Lett. 1995, 36, 409; (b) Kobayashi, S.; Iwamoto, S.
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Chadwick, D.; Henderson, D. A. Synlett 2002, 10, 1653.
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20%, see: (a) Chapman, C. J.; Frost, C. G.; Hartley, J. P.;
Whittle, A. J. Tetrahedron Lett. 2001, 42, 773; (b) Ali, T.;
Chauhan, K. K.; Forst, C. G. Tetrahedron Lett. 1999, 40,
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N. T. Org. Lett. 2001, 3, 843–846.
With these building blocks in hand, we decided to
explore further transformations. The importance of
c-butyrolactones has driven us to access these molecules
from these butenolides. A simple, easily operated, clean,
and catalytic hydrogenation procedure gave c-butyro-
lactones in good to excellent yield (Scheme 2).
7. (a) Morton, L. W.; Caccetta, R. A.; Puddey, I. B.; Croft,
K. D. Clin. Exp. Pharmacol. Psysiol. 2000, 27, 152; (b)
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Willfoer, S. M.; Sjoeholm, R. E. Org. Biomol. Chem. 2005,
3, 3336–3347.
In summary, we have developed a simple, efficient, and
selective method to prepare a variety of highly function-
alized, c-aryl c-butenolides using catalytic indium triflate
or Bro¨nsted acid in the Friedel–Crafts hydroxyalkyl-
ation–lactonization process. Further investigations,
including synthesis of novel butenolide-based antioxi-
dants using these synthons via Suzuki coupling will be
reported in due course.
9. (a) Min, B.-S.; Na, M.-K.; Oh, S.-R.; Ahn, K.-S.; Jeong,
G.-S.; Li, G.; Lee, S.-K.; Joung, H.; Lee, H.-K. J. Nat.
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Cl
Cl
Cl
Cl
Cl
Cl
MeO
MeO
MeO
O
MeO
MeO
O
O
O
O
O
OMe
OMe
10% Pd/C
Et N, H
THF, 50 psi
1 h
10% Pd/C
Et N, H
10% Pd/C
Et N, H
THF, 50 psi
1 h
87%
90%
95%
THF, 50 psi
1 h
MeO
MeO
MeO
MeO
O
MeO
O
O
O
O
O
OMe
OMe
Scheme 2. Preparation of c-butyrolactones via hydrogenation.

J. Zhang et al. / Tetrahedron Letters 48 (2007) 2611–2615
2615
11. Antioxidant activity and phenolic compounds of 112
traditional Chinese medicinal plants associated with anti-
cancer, see: Cai, Y.; Luo, Q.; Sun, M.; Corke, H. Life Sci.
2004, 74, 2157–2184.
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see: Planta Medica 2005, 71, 452–457.
16. AlCl3 has been used for demethylation of phenolic methyl
ethers, see: (a) Prager, R. H.; Tan, Y. T. Tetrahedron Lett.
1967, 38, 3661; (b) Li, T.-t.; Wu, Y. L. J. Am.
Chem. Soc. 1981, 103, 7007; (c) Nagaoka, H.; Schmid,
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I.; Waite, D. Synlett 1999, 1743–1744.
18. AlCl3 catalyzed Friedel–Crafts reaction of mucochloric
acid, see: Heterocycles 1990, 31, 1967–74 and Lattmann
and co-workers reported under AlCl3, mucochloric acid
reacts with toluene giving Friedel–Crafts acylation prod-
uct in 62% yield. See: J. Pharm. Pharmacol. 2003, 55,
1259–1265.
19. All compounds were made by using the initial condition
(10 mol % In(OTf)3 in toulene) without optimization or
using 10 mol % H2SO4 as catalyst.
13. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. 1987, 109, 7925.
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Jorgensen recently, see: (a) Gathergood, N.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 12517; (b)
Bigi, F.; Bocelli, G.; Maggi, R.; Sartori, G. J. Org. Chem.
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Org. Chem. 2000, 65, 1597.
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G. Org. Lett. 2002, 4, 4459; (b) Zhang, J.; Das Sarma, K.;
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Chem. 2005, 70, 5890.