Nucleophile- or light-induced synthesis of 3-substituted phthalides from 2-formylarylketones

Article abstract of DOI:10.1021/ol300757m

The surprisingly facile conversion (isomerization) of 2-formyl-arylketones into 3-substituted phthalides, as observed for the marine natural product pestalone and its per-O-methylated derivative, was investigated using a series of simple 2-acylbenzaldehydes as substrates. The transformation generally proceeds smoothly in DMSO, either in a Cannizarro-Tishchenko-type reaction under nucleophile catalysis (NaCN) or under photochemical conditions (DMSO, 350 nm).

Full text of DOI:10.1021/ol300757m

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2338–2341
Nucleophile- or Light-Induced Synthesis
of 3-Substituted Phthalides from
2-Formylarylketones
€
Dario C. Gerbino, Daniel Augner, Nikolay Slavov, and Hans-Gunther Schmalz*
€
Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Koln, Germany
schmalz@uni-koeln.de
Received March 23, 2012
ABSTRACT
The surprisingly facile conversion (isomerization) of 2-formyl-arylketones into 3-substituted phthalides, as observed for the marine natural
product pestalone and its per-O-methylated derivative, was investigated using a series of simple 2-acylbenzaldehydes as substrates. The
transformation generally proceeds smoothly in DMSO, either in a CannizarroꢀTishchenko-type reaction under nucleophile catalysis (NaCN) or
under photochemical conditions (DMSO, 350 nm).
Phthalides, i.e. 1(3H)-isobenzofuran-1-ones, represent a
relevant class of compounds because this structural motif
is found in a large number of natural products,1 synthetic
pharmaceuticals,2 and building blocks for the synthesis of
more complex molecules.3 Of particular importance are C3-
substituted phthalides as exemplified by the natural prod-
ucts cytosporone E (1),4a fuscinarin (2),4b isopestacin (3),4c
and cryphonectric acid (4)4d (Figure 1). Not surprisingly, a
number of methods for the synthesis of 3-substituted phtha-
lides have been developed, most of them exploiting either the
cylization of an 1-hydroxyalkyl-substituted benzoic acid
derivative5 or the alkylation of a preformed phthalide in the
3-position.6 Other established methods are based on the
carbonylative or carboxylative ortho-functionalization of
benzylic alcohols.7 In recent years, several new transi-
tion-metal-catalyzed phthalide syntheses such as the Pd-
or Rh-catalyzed reaction of phthalaldehyde with arylboron
reagents,8 the Ru-catalyzed cross-dehydrogenative CꢀH
bond alkenylation of benzoic acids,9 or the Ru- or Rh-
catalyzed intramolecular hydroacylation of 2-acylyl-
benzaldehydes10 have been developed.
(1) Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds; Academic Press: New York, 1975; Vol. 1, pp 249ꢀ264.
€
(2) (a) Knepper, K.; Ziegert, R. E.; Brase, S. T. Tetrahedron 2004, 60,
8591–8603 and references therein. (b) Hung, T. V.; Mooney, B. A.;
Prager, R. H.; Tippett, J. M. Aust. J. Chem. 1981, 34, 383–395.
(3) (a) Patil, L.; Borate, H. B.; Ponde, D. E.; Deshpande, V. H.
Tetrahedron 2002, 58, 6615–6620. (b) Mal, D.; Pahari, P. Chem. Rev.
2007, 107, 1893–1918.
(4) (a) Brady, S. F.; Wagenaar, M. M.; Singh, M. P.; Janso, J. E.;
Clardy, J. Org. Lett. 2000, 2, 4043–4046. (b) Yoganathan, K.; Rossant,
C.; Ng, S.; Huang, Y.; Butler, M. S.; Buss, A. D. J. Nat. Prod. 2003, 66,
1116–1117. (c) Strobel, G.; Ford, E.; Worapong, J.; Harper, J. K.; Arif,
A. M.; Grant, D. M.; Fung, P. C. W.; Chau, R. M. W. Phytochemistry
2002, 60, 179–183. (d) Arnone, A.; Assante, G.; Nasini, G.; Strada, S.;
Vercesi, A. J. Nat. Prod. 2002, 65, 48–50.
(5) For recent examples, see: (a) Mangas-Sanchez, J.; Busto, E.;
Gotor-Fernandez, V.; Gotor, V. Org. Lett. 2012, 14, 1444–1447. (b)
Yadav, J. S.; Sreenivas, M.; Reddy, A. S.; Reddy, B. V. S. J. Org. Chem.
2010, 75, 8307–8310. (c) Kuriyama, M.; Ishiyama, N.; Shimazawa, R.;
Shirai, R.; Onomura, O. J. Org. Chem. 2009, 74, 9210–9213. (d) Zhang,
B.; Xu, M. H.; Lin, G. Q. Org. Lett. 2009, 11, 4712–4715.
(6) See, for instance: Singh, M.; Argade, N. P. J. Org. Chem. 2010, 75,
3121–3124.
(7) (a) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193–
4198. (b) Larock, R. C.; Fellows, C. J. Am. Chem. Soc. 1982, 104, 1900–
1907. (c) Paleo, M. R.; Lamas, C.; Castedo, L.; Dominguez, D. J. Org.
Chem. 1992, 57, 2029–2033.
(8) (a) Ye, Z.; Lv, G.; Wang, W.; Zhang, M.; Cheng, J. Angew. Chem.,
Int. Ed. 2010, 49, 3671–3674. (b) Luo, F.; Pan, S.; Pan, C.; Qian, P.;
Cheng, J. Adv. Synth. Catal. 2011, 353, 320–32.
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H.; Ryu, I. Chem. Commun. 2009, 6741–6743. See also: (c) Willis, M. C.
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r
10.1021/ol300757m
Published on Web 04/22/2012
2012 American Chemical Society

reveal, we identified NaCN as a convenient and inexpen-
sive nucleophilic catalyst that is more effective than the
originally employed LiSEt. Also, DMSO gave better re-
sults in comparison to DMF. Under the optimized condi-
tions (10 mol % NaCN, DMSO, 4 h, 50 °C) the reaction of
7a proceeded smoothly to afford pure rac-8a in 70%
isolated yield after chromatography.
Table 1. Optimization of the Reaction Conditionsa
Figure 1. Selected phthalide natural products.
In the course of our recent synthesis of the marine anti-
biotic pestalone (5a)11 we observed a surprising tendency
of the permethylated analog 5b to isomerize (dispropor-
tionate) to the 3-arylphthalide rac-6b, for instance on
treatment with LiSEt as a nucleophilic reagent (usually
used for the cleavage of methyl aryl ethers).12 We also
found that 5a is cleanly converted into pestalalactone
(rac-6a) by simple irradiation of a DMSO solution with
UV light at 350 nm (Scheme 1).
entry
nucleophile
solvent
temp
yieldb
1
2
3
4
5
6
7
LiSEt
LiSEt
LiSEt
LiSEt
NaCN
NaCN
NaCN
DMF
25
25
32%
35%
39%
39%
45%
70%
60%
DMSO
DMSO
DMSO
DMF
50
100
50
DMSO
DMSO
50
100
a Conditions: substrate 7a (0.5 mmol) and nucleophile (10 mol %) in
dry solvent (1.5 mL), 4 h, under argon. b Isolated yield.
Scheme 1. Facile Isomerization of Pestalone (5a) and Its Per-
methylated Derivative 5b to Phthalides of Type rac-6 under the
Action of UV Light or LiSEt (As a Nucleophile)
The scope and the general efficiency of the method was
then demonstrated by reacting a set of nine different ortho-
acylbenzaldehydes under the optimized conditions. The
results shown in Table 2 show that the protocol tolerates a
range of functional groups, including nitro-phenyl, pyr-
idyl, bromophenyl, anisyl, and a free phenolic OH func-
tion. The electronic properties of the substituent at the
central arene unit of the substrates (7) had little effect on
the reaction yield.
Mechanistically, we assume that the nucleophile-cata-
lyzed transformation follows a CannizzaroꢀTishchenko-
type pathway11a,15 involving a primary attack of the
nucleophilic catalyst at the aldehyde function of the sub-
strate 7 (Scheme 2). The resulting intermediate 9 then
undergoes an intramolecular hydride transfer (dispropor-
tionation) to form an alkoxide intermediate (10). In the
final step, the lactone ring is established through a 5-exo-
trig attack of the alkoxide at the carbonyl function under
release of the nucleophilic catalyst.16
The surprising tendency of 5a/b to convert to the cor-
responding phthalides under different conditions prompted
us to probe the generality of this type of transformation
using a set of 2-acylbenzaldehydes (7), which were readily
prepared as described before13 following the procedure of
Kotali.14
At first, we studied the nucleophile-induced phthalide
formation starting from 2-formylbenzophenone (7a) as
a model substrate. We found that catalytic amounts
(10 mol %) of a nucleophile are sufficient to achieve the
desired transformation. As the results shown in Table 1
In the second part of the study, we investigated the light-
induced isomerization of ortho-formyl-arylketones using
the same set of substrates (7aꢀi). And indeed, on irradia-
tion of a DMSO solution with UV light (350 nm) for 3
€
(11) (a) Slavov, N.; Cvengros, J.; Neudorfl, J.-M.; Schmalz, H.-G.
Angew. Chem., Int. Ed. 2010, 49, 7588–7591. (b) For the isolation and
structure elucidation of 5a, see: (b) Cueto, M.; Jensen, P. R.; Kauffman,
C.; Fenical, W.; Lobkovsky, E.; Clardy, J. J. Nat. Prod. 2001, 64, 1444–
1446.
(12) Cvengros, J.; Neufeind, S.; Becker, A.; Schmalz, H. G. Synlett
2008, 1993–1998.
(15) (a) Cannizzaro, S. Justus Liebigs Ann. Chem. 1853, 88, 129. (b)
Tishchenko, V. E. J. Russ. Phys. Chem. Soc. 1906, 38, 355–418. For a
review, see: (c) Torrmakangas, O. P.; Koskinen, A. M. P. Recent Res.
Dev. Org. Chem. 2001, 225–255. See also: (d) Cronin, L.; Manoni, F.;
Connor, C. J. O.; Connon, S. J. Angew. Chem., Int. Ed. 2010, 49, 3045–
3048.
€
€
€
(13) Augner, D.; Gerbino, D. C.; Neudorfl, J.-M.; Schmalz, H.-G.
Org. Lett. 2011, 13, 5374–5377.
(16) For the formation of phthalides from phthalaldehyde under
solid-base catalysis, see: (a) Seki, T.; Tachikawa, H.; Yamada, T.;
Hattori, H. J. Catal. 2003, 217, 117–126. For a mechanistically related
reaction mediated by a N-heterocyclic carbene, see: (b) Chan, A.;
Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558–4559.
(14) (a) Kotali, A.; Papapetrou, M.; Dimos, V.; Harris, P. Org. Prep.
Proc. Int. 1998, 30, 177–181. (b) Kotali, A.; Tsoungas, P. G. Tetrahedron
Lett. 1987, 28, 4321–4322. (c) Jacq, J.; Einhorn, C.; Einhorn, J. Org. Lett.
2008, 10, 3757–3760.
Org. Lett., Vol. 14, No. 9, 2012
2339

Table 2. Conversion of Various 2-Acyl-benzaldehydes (7) into
the Isomeric Phthalides (rac-8)a
Scheme 2. Nucleophile-Induced Conversion of 2-Formyl-ar-
ylketones (7) to Phthalides (8) through a Cannizar-
roꢀTishchenko-Type Mechanism
days, all compounds cleanly afforded the corresponding
isobenzofuranones (rac-8aꢀi) in good isolated yields
(71ꢀ85%) after chromatographic purification (Table 2).
By performing the photolysis experiments in NMR tubes
(employing d6-DMSO) the reaction progress could be
monitored by 1H NMR (compare Figure 2) and no inter-
mediate species could be detected this way. A control
experiment in the dark ensured the necessity of light to
induce the phthalide formation. In all cases, the photo-
chemical protocol gave rise to the phthalide products (rac-
8aꢀi) in slightly higher yields as compared to the NaCN-
catalyzed reactions (Table 2).
A plausible mechanism for the light-induced process
(Scheme 3) starts with a Norrish II type reaction and a
concomitant formation of a photoenol, i.e. an enol-ketene
of type 11.17 Assumably, this intermediate then cyclizes
through intramolecular addition of the OH function to the
ketene to give a 1-hydroxy-isobenzofurane (12) which
finally tautomerizes to the more stable phthalide rac-8.
As mentioned above, the work described herein was
triggered by some surprising observations made in the
course of our synthesis of pestalone (5a).11a Therefore,
we were in the position to probe the developed protocols
once more using a sample of synthetic 5a. To our satisfac-
tion, treatment of 5a with 10 mol % of NaCN in DMSO
proceeded smoothly to give pure pestalalactone (rac-6a) in
62% yield after recrystallization (Scheme 4).18
a Conditions: NaCN (10 mol %), DMSO, 50 °C, 4 h; or hν 35 nm,
DMSO, rt, 3 d. b Isolated yield.
The photochemical isomerization of 5a into rac-6a was
carefully monitored by means of 1H NMR spectroscopy.
Figure 1 shows the very clean conversion as indicated, for
instance, bythedisappearance/reappearanceoftheolefinic
signal (H20). An interesting observation is the doubling of
certain signals (e.g., H3 and H5) in the product (rac-6a) as
a consequence of a hindered rotation of the 3-aryl sub-
stituent on the NMR time scale (generation of atrop-
diastereomers).
Scheme 3. Proposed Mechanism of the Light-Induced Conver-
sion of 2-Formyl-arylketones (7) to Phthalides of Type 8
(17) (a) Sato, T.; Tamura, K.; Maruyama, K.; Ogawa, O.; Imamura,
T. J. Chem. Soc., Perkin Trans. 1 1976, 779–783. (b) Netto-Ferreira,
J. C.; Scaiano, J. C. Can. J. Chem. 1993, 71, 1209–1215. (c) Plistil, L.;
Solomek, T.; Wirz, J.; Heger, D.; Klan, P. J. Org. Chem. 2006, 71, 8050–
8058.
(18) The structure of rac-6a was unambiguously proven by X-ray
crystallograpy (CCDC 781113).
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Org. Lett., Vol. 14, No. 9, 2012

mild conditions. The smooth transformations and, in
particular, the ease of conversion of 5a into rac-6a even
raises the question whether the biosynthesis of natural
phthalides4 (compare Figure 1) might proceed (at least in
certain cases) in a related fashion via ortho-formyl aryl-
ketone precursors,19 which (in principle) could be isomer-
ized into the corresponding phthalides under the action
of a thiamine- (vitamine B1-) derived nucleophilic car-
bene.16b,20 An interesting aspect of the photochemical
method developed is the proposed emergence of an enol-
ketene (11) and an isobenzofuran (12) intermediate, which
could possibly be trapped by an appropriate dienophile in
a DielsꢀAlder-type reaction.21
Scheme 4. NaCN-Catalyzed Conversion of Pestalone (5a) into
Pestalalactone (rac-6a)
The methods described here for the synthesis of phtha-
lides can also be be classified as a redox-neutral intercon-
version (fusion) of two functional groups.22 Due to the
mild reaction conditions the methodology may prove of
value in the context of the synthesis of more complex and
highly functionalized molecules. A remaining challenge, of
course, is to render the process enantioselective, for in-
stanceby employing chiral nucleophilic catalysts instead of
NaCN.23
Acknowledgment. This work was supported by the
Alexander von Humboldt Foundation (G. Forster post-
doctoral fellowship to D.C.G.). We also thank Prof. A.
Griesbeck, University of Cologne, for technical support
concerning the photochemical transformations.
Figure 2. Monitoring the photolysis of 5a by 1H NMR (in
d6-DMSO).
Supporting Information Available. Detailed experimen-
1
tal procedures, characterization data, and copies of H
In conclusion, we have developed two complementary
protocols for the nucleophile- or light-induced synthesis of
3-substituted phthalides from 2-formylarylketones under
and 13C NMR spectra of all phthalides prepared. This
material is available free of charge via the Internet at
http://pubs.acs.org. The authors declare no competing
financial interest.
(19) For other natural products with an ortho-formylbenzophenone
substructure, see: (a) Kralj, A.; Kehraus, S.; Krick, A.; Eguereva, E.;
€
Kelter, G.; Maurer, M.; Wortmann, A.; Fiebig, H.-H.; Konig, G. M.
€
(22) (a) Jurberg, I. D.; Peng, B.; Wostefeld, E.; Wasserloos, M.;
J. Nat. Prod. 2006, 69, 955–1000 (Arugosin H). (b) Hashimoto, T.;
Tahara, S.; Takaoka, S.; Tori, M.; Asakawa, Y. Chem. Pharm. Bull.
1994, 42, 1528–1530 (Daldinals AꢀC). (c) Zhang, C.; Ondeyka, J. G.;
Herath, K. B.; Guan, G.; Collado, J.; Platas, G.; Pelaez, F.; Leavitt,
P. S.; Gurnett, A.; Nare, B.; Liberator, P.; Singh, S. B. J. Nat. Prod. 2005,
68, 611–613 (Tenellones AþB). (d) Hida, T.; Ishii, T.; Kanamaru, T.;
Muroi, M. J. Antibiot. 1991, 44, 600–612 (TAN-931).
Maulide, N. Angew. Chem., Int. Ed. 2012, 51, 1950–1953. (b) Mori, K.;
Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133,
6166–6169. (c) Haibach, M. C.; Deb, I.; De, C. K.; Seidel, D. J. Am.
Chem. Soc. 2011, 133, 2100–2103.
(23) So far, only the Rh-catalyzed intramolecular hydroacylation
allows this type of reaction to proceed in an enantioselective fashion (in
the presence of a chiral ligand); see ref 10a.
(20) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
(21) Compare: (a) Quinkert, G.; Stark, H. Angew. Chem., Int. Ed.
Engl. 1983, 22, 637–655. (b) Nicolaou, K. C.; Gray, D.; Tae, J. S. Angew.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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