Tandem reversible addition-intramolecular lactonization for the synthesis of 3-functionalized phthalides

Article abstract of DOI:10.1016/j.tetlet.2009.10.079

A new tandem process based on reversible nucleophilic addition and intramolecular lactonization of methyl 2-formylbenzoate leads to the efficient synthesis of 3-functionalized phthalides, which are important precursors for the synthesis of quinone skeletons via Hauser-Kraus annulation. The reactions are successfully carried out under mild conditions in single operations.

Full text of DOI:10.1016/j.tetlet.2009.10.079

Tetrahedron Letters 51 (2010) 75–78
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Tetrahedron Letters
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Tandem reversible addition–intramolecular lactonization for the synthesis
of 3-functionalized phthalides
*
Morakot Sakulsombat , Marcus Angelin , Olof Ramström
KTH-Royal Institute of Technology, Department of Chemistry, Teknikringen 30, S-10044 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A new tandem process based on reversible nucleophilic addition and intramolecular lactonization of
methyl 2-formylbenzoate leads to the efficient synthesis of 3-functionalized phthalides, which are impor-
tant precursors for the synthesis of quinone skeletons via Hauser–Kraus annulation. The reactions are
successfully carried out under mild conditions in single operations.
Received 6 August 2009
Revised 10 October 2009
Accepted 19 October 2009
Available online 22 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Reversible chemical phenomena constitute a class of essential
fundamental reactions in chemistry. A key feature of these reac-
tions is their sensitivity to changes in the reaction conditions such
as temperature, pressure, and pH, resulting in control of the equi-
librium displacement that potentially leads to enhanced formation
of desired products. Numerous applications of reversible reactions,
both covalent and non-covalent bond formation, have been re-
ported in many areas.1–5 Highly intriguing applications are one-
pot multi-step reactions, in which several transformations are
combined in a one-pot process without isolating any intermedi-
ates. This cascade- or tandem strategy is very useful for decreasing
the number of synthetic steps and increasing the product yield as
well as the efficiency of the process.6–8
We recently reported an efficient, stereoselective tandem nitro-
aldol-lactamization concept for kinetic resolution of complex dy-
namic nitroaldol systems.9,10 In this case, the reversible
nitroaldol process was used to generate a library of nitroaldol ad-
ducts, which subsequently was resolved when certain species
underwent cyclization and an irreversible intramolecular rear-
rangement leading to 3-substituted isoindolin-1-one products. In
the present study, a new synthetic methodology for generating
functionalized phthalides has been developed involving base-cata-
lyzed tandem nucleophilic addition–lactonization in a single oper-
ation (Scheme 1). The base-catalyzed reversible reaction between
an aldehyde 1 and a nucleophile generated alcohol intermediate
2, which spontaneously lactonized to produce a 3-substituted
phthalide product 3.
O
H
O
X
O
HX, base
O
O
O
OH
O
X
1
2
3
Scheme 1. Base-catalyzed tandem reversible nucleophilic addition–lactonization.
cially useful methodology resulting in a facile, one-pot process.
This annulation reaction was originally developed in the late
1970s by Hauser and Kraus,18,19 where phthalides 3 (Hauser–Kraus
donors) were reacted with Michael acceptors 4, under strongly ba-
sic conditions, generating substituted naphthalene products 5
(Scheme 2).
A variety of substituted quinone skeletons for highly substi-
tuted natural product synthesis can be prepared using phthalide
derivatives 3, and also those having different substitution patterns
on the aromatic ring. The aromatic substituents on phthalide 3,
however, affect the regioselectivity in annulated product forma-
tion. The 3-position of Hauser–Kraus annulation donors 3 has been
investigated thoroughly for many functional groups, including
phenylsulfanyl, phenylsulfonyl, cyano, methoxyester, phosphonyl
groups, etc.20–22 These functional groups were primarily evaluated
for enhancing the acidity of the benzylic protons, for stabilizing the
The 3-functionalized phthalides 3 are important key precursors
for the synthesis of quinone skeletons which form core structures
of quinoid natural products,11–13 and are the basis of disperse
anthraquinone dyes.14 Although there are a variety of strategies
for the synthesis of quinones,15–17 phthalide annulation is an espe-
* Corresponding author. Tel.: +46 8 7909651; fax: +46 8 7912333.
E-mail address: ramstrom@kth.se (O. Ramström).
Authors contributed equally to this work.
Scheme 2. Hauser–Kraus annulation.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.079

76
M. Sakulsombat et al. / Tetrahedron Letters 51 (2010) 75–78
Table 1
formation of the anion, and also for acting as good leaving groups
in the annulation reaction. Many efforts have been reported where
the functional groups of different functionalized phthalides have
been evaluated with respect to electron-withdrawing ability in
comparison to annulation reactivities under basic conditions.23,24
Although the functionalized phthalides 3a–c are the most com-
monly used precursors in Hauser–Kraus annulations, there are
only a few reports of synthetic modifications of these com-
pounds.18,19,25,26 In the present study, a new synthetic strategy is
proposed for efficient formation of phthalides 3a and 3c. In this
strategy, the advantage of using multi-step reactions of combined
reversible- and irreversible processes in a single operation have
been explored. The key to this strategy is the base-catalyzed gen-
eration of alcohol intermediates 2 from the reversible reactions
of nucleophiles with benzaldehyde 1. Adducts 2 subsequently
underwent spontaneous lactonization to produce stable phthalide
products 3a and 3c, all under very mild reaction conditions.
Organosulfur compounds play an important role in organic syn-
thesis, in part due to the fact that sulfur groups can stabilize carb-
anion formation, and serve as good leaving groups.27 Phthalides 3a
and 3b provide excellent demonstrations of these effects. These
precursors are commonly used in Hauser–Kraus annulation reac-
tions because both phenylsulfanyl and phenylsufonyl groups act
as good stabilizing and leaving groups. However, there have been
only a few attempts made to modify the sulfur moiety in the 3-thi-
ophthalide building blocks.18,26,27 To overcome these limitations, a
new series of 3-thiophthalides were prepared successfully using a
large range of different thiols. Furthermore, 3-cyanophthalide 3c,
one of the most frequently used donors in the Hauser–Kraus annu-
lation, has also been prepared using the same synthetic concept.
The results are summarized in Table 1.
During the synthesis of 3-thiophthalides 8, the reversible reac-
tions between benzaldehyde 1 and the thiols 6 were initially inves-
tigated in the presence of a variety of catalysts, including bases, and
Brønsted and Lewis acids. The reaction worked well with a catalytic
amount of triethylamine and generated the hemithioacetal inter-
mediates 7 which lactonized to afford the 3-thiophthalides 8. How-
ever, dithioacetals were also formed as by-products in low amounts.
The amount of triethylamine was further optimized to avoid dithio-
acetal formation while still enhancing the reaction rate. Subse-
quently, the reactions of a series of aliphatic and aromatic thiols,
including thiols containing other functional groups were investi-
gated using the optimized reaction conditions. Isolation of pure
products was easily accomplished by flash chromatography.
The formation of 3-thiophthalides based on short aliphatic thi-
ols has not been reported because the reaction conditions were not
suitable for thiols with lower boiling points.18,19,26,27 In our strat-
egy, reactions of thiols 6a–f containing linear (entries 1 and 2),
branched (entries 3, 4, and 6), and cyclic (entry 5) aliphatic struc-
tures, however, successfully generated the corresponding products
8a–f. The primary aliphatic thiols 6a–c gave phthalides 8a–c in less
than 5 h. As expected, the steric hindrance of the secondary and
tertiary thiols 6d–f affected unfavorably the formation of products
8d–f, which displayed slow reaction rates of 12, 13, and 48 h,
respectively.
Synthesis of 3-thiophthalides 8 and 3-cyanophthalide 3c
Entry
1
Nucleophile
Product
Timea (h)
O
HS
O
5
S
6a
8a
O
HS
O
2
3
4
5
6
4
S
6b
8b
O
HS
O
4
S
6c
8c
8d
8e
O
HS
O
12
13
48
S
6d
O
HS
O
S
6e
O
HS
O
S
6f
8f
O
HS
O
Modification of the aromatic thiol part in 3-sulfanylphthalides
has been studied,28 and a moderately electron-releasing methyl
substituent in the para-position of the aromatic thiol moiety re-
sulted in smooth Hauser–Kraus annulationto afford the correspond-
ing annulated product in high yield. To further expand the scope of
the donor properties, 3-thiophthalides based on aromatic thiols
6g–j were evaluated (entries 7–10). Thiophenol 6g, thionaphthol
6j, and 3-methoxythiophenol 6h, bearing an electron-releasing
group, thus formed the corresponding products in 4–5 h, whereas
4-trifluoromethylthiophenol 6i formed the corresponding product
8i in a longer reaction time (46 h, entry 9). Furthermore, thiols
7
8
4
4
S
6g
8g
O
O
HS
O
O
S
6h
8h

M. Sakulsombat et al. / Tetrahedron Letters 51 (2010) 75–78
77
Table 1 (continued)
Entry
Nucleophile
Product
Timea (h)
O
HS
O
9
46
CF
S
3
6i
6j
8i
CF
3
Scheme 3. Formation of sulfone products 11b and 11g.
O
HS
O
tions.29 Applying the same reaction conditions as for 3-thiophtha-
lides 8, however, resulted in degradation of the cyanohydrin
intermediate 10 upon precipitation of the triethylammonium cya-
nide salt. Decreasing the amount of triethylamine to 1 equiv solved
this problem, but instead resulted in formation of the dimerized
phthalide as the major product.27 After further optimization, the
preparation of 3-cyanophthalide 3c was successfully accomplished
in the presence of a catalytic amount of triethylamine at 0 °C. Purifi-
cation by flash chromatography afforded 3-cyanophthalide 3c in
55% yield.30
Finally, the possibility to convert 3-thiophthalides 8 into the
corresponding sulfones, which are known to be good Hauser–Kraus
donors, was demonstrated. 3-Phenylthiophthalide 8g and 3-pen-
tylthiophthalide 8b were subjected to oxidation with 5 equiv of
m-chloroperbenzoic acid (m-CPBA) in dichloromethane to afford
the corresponding sulfone products 11b and 11g in good yields
(Scheme 3).
10
5
S
8j
O
HS
HS
O
11
12
3
7
S
6k
6l
8k
8l
O
O
O
O
S
O
In this study, a powerful tandem reaction has been developed
for the synthesis of 3-functionalized phthalides, which are useful
synthons for the preparation of quinone skeletons. The strategy
is based on a combination of reversible alcohol formation under
mildly basic reaction conditions, followed by spontaneous lact-
onization, all in a single operation. A new series of 3-thiophtha-
lides were formed using this strategy. Oxidation of the 3-
thiophthalides gave 3-sulfonylphthalides for Hauser–Kraus
annulations.
HS
HS
O
13
14
15
5
S
6m
8m
O
O
O
O
O
8
S
As expected, the reaction kinetics of thiophthalide formation
was found to be influenced by the structures and reactivities of
6n
O
8n
the corresponding thiols. Reactions between benzaldehyde
1
O
and a series of aliphatic thiols, including linear, branched, and
cyclic structures, all successfully produced 3-thiophthalides,
whereas, steric effects retarded phthalide formation. For aromatic
thiols, substituent effects were investigated, and the reaction of
thiophenols with electron-releasing groups accelerated the reac-
tion rate. Aliphatic thiols carrying aryl and ester groups were also
evaluated.
Furthermore, 3-cyanophthalide 3c was successfully formed in
high yield using the same synthetic methodology. The reversible
cyanohydrin reaction using acetone cyanohydrin in the presence
of a catalytic amount of base at low temperature was utilized to
produce the 3-cyanophthalide product.
HO CN
O
b
—
9
CN
3c
a
Reagents and conditions: benzaldehyde 1 (0.25 mmol), thiol 6 (1.25 mmol),
triethylamine (2.5 mmol) in CDCl3 (0.5 mL). After benzaldehyde 1 was converted
into phthalide product at >95% conversion (1H NMR), all products were purified by
flash chromatography (hexane/CH2Cl2 1:1, v/v) giving 80–93% isolated yield.
b
For 3-cyanophthalide 3c formation, the mixture of benzaldehyde
1
(0.25 mmol), acetone cyanohydrin 9 (0.37 mmol), and triethylamine (0.02 mmol) in
chloroform (2 mL) was stirred at room temperature overnight and then at 0 °C until
benzaldehyde 1 has been completely consumed.
Acknowledgments
6k–n containing aromatic moieties (entries 11–13) and ester groups
yielded products 8k and 8m in only three and 5 h, respectively. In
thiols 6l and 6n, the nucleophilicity at sulfur was reduced by the fur-
an and ester moieties, leading to slow formation of phthalide prod-
ucts 8l and 8n in 7 and 8 h, respectively.
This work was supported by the Swedish Research Council, the
Royal Institute of Technology, and the European Commission (con-
tract no. MRTN-CT-2006-035614).
In addition to the thiol nucleophiles, formation of 3-cyanoph-
thalide 3c was also investigated using the same concept. Reversible
cyanohydrin reaction under basic conditions was thus used, cou-
pled with a secondary lactonization reaction. Acetone cyanohydrin
9 was chosen as the cyanide source because it releases cyanide
ions, and acetone as a by-product, under mild reaction condi-
Supplementary data
Supplementary data (characterization data of phthalides 3a–c)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.10.079.

78
M. Sakulsombat et al. / Tetrahedron Letters 51 (2010) 75–78
15. Liebeskind, L. S. Tetrahedron 1989, 45, 3053–3060.
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