A synthetic route to chiral C(3)-functionalized phthalides via a Ag(I)-catalyzed allylation/transesterification sequence

Article abstract of DOI:10.1016/j.tet.2013.02.002

A Ag(I)-catalyzed synthesis of chiral C₍₃₎-substituted phthalides (8a-f) via a Sakurai-Hosomi allylation/transesterification reaction is described (ee ≤86%). A notable feature of this reaction is that it utilizes ortho-substituted aldehydes, which are a class of compounds that generally afford poor levels of stereoinduction when applying most known catalytic asymmetric allylation approaches. It was also found that elongation of the n-alkyl chain length (R¹, up to n=6; R²=H) of the starting alkyl 2-formylbenzoates (7g-i) improved the enantiomeric excess (ee) of the product.

Full text of DOI:10.1016/j.tet.2013.02.002

Tetrahedron 69 (2013) 3287e3292
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A synthetic route to chiral C(3)-functionalized phthalides via
a Ag(I)-catalyzed allylation/transesterification sequence
*
Roya Mirabdolbaghi, Travis Dudding
Department of Chemistry, Brock University, 500 Glenridge Avenue, St. Catharines, ON, Canada L2S 3A1
a r t i c l e i n f o
a b s t r a c t
Article history:
A Ag(I)-catalyzed synthesis of chiral C(3)-substituted phthalides (8aef) via a SakuraieHosomi allylation/
transesterification reaction is described (ee ꢀ86%). A notable feature of this reaction is that it utilizes
ortho-substituted aldehydes, which are a class of compounds that generally afford poor levels of ster-
eoinduction when applying most known catalytic asymmetric allylation approaches. It was also found
that elongation of the n-alkyl chain length (R1, up to n¼6; R2¼H) of the starting alkyl 2-formylbenzoates
(7gei) improved the enantiomeric excess (ee) of the product.
Received 4 December 2012
Received in revised form 29 January 2013
Accepted 1 February 2013
Available online 8 February 2013
Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric methodologies as well as our recent report of a stoi-
chiometric in-mediated approach for preparing C(3)-substituted
Catalytic asymmetric reaction methodologies mediated by
chiral Ag(I)-complexes, have provided chemists with a rich port-
folio of CeC bond-forming strategies over the last two-decades. In
this regard, the Ag(I)-catalyzed asymmetric SakuraieHosomi ally-
lation methodologies of Yamamoto et al. have found considerable
use as key synthetic routes to chiral homoallylic alcohols.1 For
instance, Rodríguez-García et al. employed Yamamoto’s (R)-p-
tol-BINAP$AgIOTf (p-tol-BINAP¼2,20-bis(di-p-tolylphosphino)-1,10-
binaphthyl) catalyzed allylation approach as a pivotal disconnec-
tion in the reported synthesis of the antifungal agents (ꢁ)-trans-
pterocarpin (1) and (ꢁ)-cis-pterocarpin.2 Similarly, Kanai et al. in
route to the natural antibiotic fostriecin (2) and 8-epi-fostriecin (3)
employed a (R)-p-tol-BINAP$AgIF catalyzed allylation as a strategic
stereochemical setting step (Scheme 1).3
In a related context, our group has recently discovered an
overlooked strength of these Ag(I)-catalyzed allylation procedures
in terms of their operational compatibility with ortho-substituted
arylaldehydes, which are a class of compounds that generally afford
poor levels of stereoinduction when applying most known catalytic
asymmetric allylation approaches.4 More specifically, while de-
veloping synthetic methodology for preparing C(1)-chiral 3-meth-
ylene-indan-1-ols, we found that under the Ag(I)-catalyzed
allylation conditions of Yamamoto, ortho-halogenated benzalde-
hydes provided chiral homoallylic alcohol intermediates with re-
spectable levels of enantiomeric excess (ee).5 In following up on
this advancement and our ongoing interest in developing catalytic
phthalides, we report herein a catalytic Ag(I)-catalyzed approach to
chiral C(3)-substituted phthalides 8aef (ee ꢀ86%) from alkyl 2-
formylbenzoates 7aem (Table 1).6 Additionally, the somewhat
counterintuitive discovery, based upon steric factors (inter alia),
was the finding that a marked improvement in product ee occurred,
up to a point, with elongation of the n-alkyl chain (R1, up to n¼6;
R2¼H) of the starting alkyl 2-formylbenzoate (7gei).
As for the existing synthetic methodologies to C(3)-chiral
phthalides, over the past two-decades a number of chiral auxiliary7
and organometallic8 approaches have been reported.6 In contrast,
however, only a few catalytic asymmetric methods have been
published, including enantioselective ketone hydroacylation,9
enantioselective transfer hydrogenation, and transesterification
sequences,10 chiral
b-amino alcohol mediated additions of zinc
reagents to aldehydes,11 and a tandem enantioselective Ni(II)/(S)-
BINAP complex catalyzed process.12 Furthermore, an enantiose-
lective Rh(I)-catalyzed transesterification/[2þ2þ2] cycloaddition
sequence,13 propenol-promoted enantioselective alkylation pro-
cess,14 enantioselective CoI2(S,S)dipamp-catalyzed cyclization,15
and
L-prolinamide organocatalyzed enantioselective aldol-lactoni-
zation reaction have been reported.16 It is also noteworthy that C(3)
-
substituted phthalides are prevalent throughout nature in medic-
inally useful compounds, such as the Sporotrichum laxum metabo-
lite spirolaxine (4) that possesses specific activity against the
microaerophilic Gram-negative bacterium Helicobacter pylori, and
has been the target of many recent total syntheses (Scheme 2).17aec
Moreover, Kittakoop et al. have recently isolated from a culture of
Colletotrichum sp. CRI53502 the phthalide containing natural
product Colletorialide (5), which has oxygen radical absorbance
capacity against peroxy radicals.17d,e Furthermore, the Apium seed
* Corresponding author. Tel.: þ1 905 688 5550x3405; fax: þ1 905 682 9020;
e-mail address: tdudding@brocku.ca (T. Dudding).
0040-4020/$ e see front matter Crown Copyright Ó 2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.002

3288
R. Mirabdolbaghi, T. Dudding / Tetrahedron 69 (2013) 3287e3292
Scheme 1. Structure of (ꢁ)-trans-pterocarpin (1), fostriecin (2), and 8-epi-fostriecin (3).
Table 1
substrates. Regardless, we were delighted to find early on that under
A
Ag(I)-catalyzed asymmetric SakuraieHosomi allylation/transesterification of
the reported SakuraieHosomi allylation conditions of Yamamoto
et al. that allyltrimethoxysilane reacted with methyl 2-formyl ben-
zoate (7a) in the presence of (R)-BINAP$AgIF (6e10 mol %) to afford
the (R)-C(3)-substituted phthalide 8a in 71% ee (Table 1, entry 1).1
Encouraged by this result, we further explored the scope of this re-
action by reacting a range of substituted methyl 2-formyl-benzoates
(7bem).
functionalized aldehydes
More specifically, the reaction of 7b having an inductively
withdrawing/resonance donating para-bromo substituent had
a negative impact on the reaction as the target phthalide 8b was
generated with a low level of enantioinduction (Table 1, entry 2).
Similarly, the incorporation of an electron withdrawing para-nitro
substituent, which introduced the added complication of potential
catalyst binding, afforded the targeted phthalide 8c in low ee (Table
1, entry 3). Likewise, the reaction of the electron deficient para-
carbamate substituted substrate 7d lead to erosion in product ee
(Table 1, entry 4). Having identified the limitations of this reaction
toward the use of electronic deficient substrates, the more electron
rich para-phenyl 7e was reacted, generating phthalide 8e with re-
spectable yield in 61% ee (Table 1, entry 5). More encouraging,
however, was the subsequent finding that the electron rich sub-
strate methyl 2-formyl-5-methoxybenzoate (7f) afforded phthalide
8f with even higher ee (Table 1, entry 6).
Entry Substrate R1
R2
t [h] Product Yieldb eec
(%)
(%)
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
CH3
CH3
CH3
CH3
CH3
CH3
H
Br
NO2
5
5
5
5
5
5
5
4
4
10
10
10
10
8a
8b
8c
8d
8e
8f
8a
8a
8a
8a
d
d
8a
68
57
52
65
67
55
58
73
70
54
0
71
39
33
43
61
86
80
86
86
63
dd
d
isobutyleCO2NH
Ph
OCH3
H
H
H
H
H
H
H
7
8
9
10
11
12
13
7g
7h
7i
7j
7k
7l
C2H5
C6H13
C12H25
CH2Ph
CH(CH3)2
C(CH3)3
Solid
0
68
7m
76
At that stage, our investigation shifted from an analysis of what
effect the aryl substitution had on this reaction by elongating the
n-alkyl chain length of the starting 2-formylbenzoate. In this vein,
the ethyl ester functionalized 7g was reacted, which surprisingly
afforded 8a with respectable ee, despite the slightly more sterically
supporte
aAllyl trimethoxysilane, (R)-BINAP$AgF (6e10 mol %), in MeOH, ꢁ20 ꢂC.
b
Yields of isolated products after flash chromatography.
Enantiomeric excess was determined by HPLC analysis.
Not applicable.
Merrifield resin was used.
c
d
e
Scheme 2. Examples of natural products containing C(3)-chiral substituted phthalides.
extract (S)-3-n-butylphthalide (6) has recognized potential as
demanding nature of this substrate (Table 1, entry 7). Intrigued by
this finding, hexyl-2-formylbenzoate (7h) was then subjected to
the reaction conditions to afford 8a in the highest ee yet (Table 1,
entry 8). Notably, the ee of phthalide 8a derived from 7h was al-
most the same as the homoallylic alcohol 10 obtained from the
reaction of benzaldehyde (ee¼87%, Scheme 3), which according to
the proposed reaction cycle of Scheme 4 (vide infra), implied that
once the stereochemical setting allylation step had occurred there
was no erosion in ee and the bulky ortho-ester group of 7h had no
deleterious effect on the reaction outcome.
a treatment for stroke and pretreatment for Parkinson disease
(PD).17f,18
At the outset of this study and based upon our recent report of
a stoichiometric in-mediated approach to C(3)-chiral phthalides it
was reasoned that the development of a mechanistically similar
catalytic approach for producing these important targets would be of
synthetic value.6 However, we were somewhat concerned as to the
viability of this approach considering the aforementioned challenges
associated with the use of ortho-substituted arylaldehydes as

R. Mirabdolbaghi, T. Dudding / Tetrahedron 69 (2013) 3287e3292
3289
2-formyl-benzoates 7k and 8l were reacted, which only afforded
unreacted starting materials (Table 1, entry 11, 12). In drawing
on the foreseeable use of our reaction methodology within the
context of ‘split-and-pool’, ‘parallel synthesis’ or other combina-
torial based solid-support approaches the reaction of the Merri-
field resin bound 7m was investigated.19 Eventfully, the desired
phthalide was afforded in 76% ee, despite the heterogenous nature
of this reaction (Table 1, entry 13). Furthermore, from an experi-
mental standpoint it is noteworthy that the desired phthalide was
Scheme 3. SakuraieHosomi allylation/transesterification of benzaldehyde.
Scheme 4. Envisioned mechanistic cycle for the synthesis of chiral C(3)-substituted phthalides.
To further explore this interesting trend between the steric size
of n-alkyl ester chain length of the substrate and product ee, the
dodecyl derivative 7i was reacted to afford phthalide 8a with the
same ee as that obtained from 7h (Table 1, entry 9). As to the origin
of this interesting dependence of the n-alkyl chain length on the
enantioinduction of this reaction, it is thought that micelle aggre-
gation effects play a decided role in this respect. Nevertheless, we
are currently looking into this intriguing reaction outcome in
greater detail.
freed from the solid support by transesterification, thus alleviating
the need for post-allylation cleavage of the product from the solid
support.
Taking into consideration the above results, we tentatively
propose the mechanistic cycle depicted in Scheme 4. According to
this posit a short-lived complex GS1 is initially formed from
methyl-2-formylbenzoate (7a), allyltrimethoxysilane, and the cat-
alyst; wherein the allyltrimethoxysilane reagent resides at the pe-
riphery of the inner coordination sphere, containing the directly
bound catalyst and aldehyde assembly. From GS1, a fluoride assis-
ted transmetalation occurs to form a highly reactive Ag-allyl spe-
cies that rapidly undergoes enantioselective allylation via TS1 in
a re-stereofacial CeC bond-forming process that provides the Ag-
alkoxy bound intermediate GS2. Thereafter, an intramolecular
In branching out from an analysis of the n-alkyl chain length of
the starting substrate, benzyl-2-formylbenzoate (7j) was reacted
to provide 8a in a moderate 63% ee (Table 1, entry 10). The in-
fluence of further branching at the
a-carbon of the ester group
was probed next. To this end, the iso-propyl and tert-butyl

3290
R. Mirabdolbaghi, T. Dudding / Tetrahedron 69 (2013) 3287e3292
transesterification (likely Ag-facilitated) follows to afford (R)-3-
allylisobenzofuran-1(3H)-one (8a), tetramethoxysilane and turn-
over of the catalyst for another productive cycle.
and extracted with EtOAc. The combined organic phases were dried
and concentrated under reduced pressure.
As outlined above a unique synthetic entry-point to chiral C(3)
-
2.2.2.1. Methyl 5-bromo-2-formylbenzoate (7b). 6-Bromoph-
thalide was prepared by portion wise addition of phthalide (1 g,
7.45 mmol) to a mixture of trifluoroacetic acid (TFA) (3.7 mL) and
sulfuric acid (1.7 mL) at room temperature for 9 h. The reaction
mixture was stirred at room temperature for 60 h, then poured onto
ice and extracted with ethyl acetate. The combined organic phases
were subsequently washed with a saturated solution of sodium
bicarbonate and brine. After evaporation of the solvents in vacuum,
the crude product was purified by column chromatography on
silica gel (n-hexane/EtOAc: 9/1) to yield the desired product. 1H
phthalides, that relies upon the use of Yamamoto’s variant of the
SakuraieHosomi reaction has been described. A second unique
feature of this reaction is that it utilizes ortho-substituted alde-
hydes, which in general are known to afford poor levels of stereo-
induction when applying most of the catalytic asymmetric
allylation technologies reported to date. As well, the counterintui-
tive finding that a marked improvement in product ee occurred, up
to a point, upon elongation of the n-alkyl chain (R1, up to n¼6;
R2¼H) of the starting alkyl 2-formylbenzoate was discovered.
NMR (300 MHz, CDCl3):
d
¼8.01 (d, J¼1.8 Hz, 1H), 7.80 (dd, J¼8.4,
1.8 Hz, 1H), 7.41 (d, J¼7.8 Hz, 1H), 5.29 (s, 2H). 13C NMR (75 MHz,
2. Experimental
2.1. General
CDCl3):
d¼169.5, 145.2, 137.2, 128.7, 127.9, 123.9, 123.1, 69.6. The
representative procedures B and A outlined above were follo-
wed to prepare 7b, which was isolated as a light yellow solid.
Mp¼114e116 ꢂC. 1H NMR (300 MHz, CDCl3):
¼10.57 (s,1H), 8.11 (d,
d
Materials were obtained from commercial suppliers (Sigmae
Aldrich) and were used without further purification. Dry (DCM)
dichloromethane, THF (tetrahydrofuran), DMF (dimethylforma-
mide), and toluene were obtained by Puresolv MD 5 purification
system. All reactions were performed under an inert atmosphere.
Reactions were monitored by thin layer chromatography (TLC)
using TLC silica gel 60 F254, EMD Merck. Flash column chroma-
tography was performed over Silicycle ultrapure silica gel
(230e400 mesh). NMR spectra were obtained with a Bruker DPX-
300 (1H 300 MHz, 13C 75.5 MHz) in CDCl3. The chemical shifts are
J¼1.8 Hz, 1H), 7.80 (s, 1H), 7.79 (d, J¼1.8 Hz, 1H), 3.99 (s, 3H). 13C
NMR (75 MHz, CDCl3):
d
¼191.0, 165.4, 135.7, 133.5, 133.4, 130.0,
128.1, 53.2. HRMS (EI): m/z calcd for C9H7BrO3 (Mþ): 241.9579;
found: 241.9577.
2.2.2.2. Methyl 2-formyl-5-nitrobenzoate (7c). The starting 6-
nitrophthalide was prepared by the reported procedure of Wang
et al.20 Thereafter, the representative procedures B and A outlined
above were followed, respectively. Mp¼62e64 ꢂC. 1H NMR
(300 MHz, CDCl3):
d
¼10.67 (s, 1H), 8.80 (d, J¼2.1 Hz, 1H), 8.47e8.43
reported as
d values (parts per million) relative to tetramethylsi-
(m, 1H), 8.08 (d, J¼8.4, 1H), 4.03 (s, 3H). 13C NMR (75 MHz, CDCl3):
lane. Enantiomeric excess was measured on an Agilent 1100 series
high pressure liquid chromatography (HPLC) with (OD-H or AS-H)
column, wavelength¼245 nm. Mass spectra were obtained on an
MSI/Kratos concept IS Mass spectrometer. Optical rotations were
recorded on a Perkin Elmer 341 with sodium lamp polarimeter. FT-
IR spectra were obtained on an ATI Mattson Research Series spec-
trometer using KBr discs and solids were mixed with Nujol.
d
¼190.5, 164.7, 150.0, 141.5, 133.0, 130.1, 127.2, 125.8, 53.6. HRMS
(EI): m/z calcd for C9H7NO5 (Mþ): 209.0324; found: 209.0326.
2.2.2.3. Methyl 2-formyl-5-((isobutoxycarbonyl)amino)benzoate
(7d). 6-Aminophthalide was prepared by the reported procedure
of Pokhodylo et al.21 4-Dimethylamino pyridine (DMAP) (0.12 g,
1 mmol) and isobutyl chloroformate (1.5 g, 11 mmol) were added to
a mixture of 6-aminophthalide (1.49 g, 10 mmol) in acetonitrile
(30 mL). The reaction mixture was stirred at room temperature
overnight. After evaporation of the solvents in vacuum, the crude
product was purified by column chromatography on silica gel
(n-hexane/EtOAc: 1/1) to yield corresponding carbamate. 1H NMR
2.2. Synthesis
2.2.1. Representative procedure A: synthesis of alkyl 2-for-
mylbenzoate. Iodomethane (0.6 mL, 9.5 mmol) was added to
a stirred solution of 2-formylbenzoic acid (0.765 g, 5.1 mmol) and
potassium carbonate (0.387 g, 2.8 mmol) in DMF (4 mL). The re-
action mixture was refluxed for 4 h, diluted with water (8 mL), and
extracted with DCM. The combined organic phases were washed
with 1 N HCl (4 mL), saturated aqueous NaHCO3 (4 mL), and dried
over Na2SO4. After filtration and evaporation of the solvents in
vacuum, the crude product was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc: 6/1) to yield 7a as a colorless oil
(0.673 g, 80.4%).
(300 MHz, CDCl3):
7.40 (d, J¼8.4 Hz, 1H), 5.26 (s, 2H), 3.94 (d, J¼6.6 Hz, 2H), 1.98e1.89
(m, 1H), 0.92 (d, 6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3):
d
¼7.93 (s, 1H), 7.85 (d, J¼8.4 Hz, 1H), 7.60 (s, 1H),
d¼171.2,
153.9, 140.9, 139.6, 126.4, 125.1, 122.7, 114.9, 71.6, 69.7, 27.94, 19.02.
HRMS (EI): m/z calcd for C13H15NO4 (Mþ): 249.1001; found:
249.1006. The representative procedure B and A was followed, re-
spectively, to yield 7d as a light yellow solid. Mp¼104e106 ꢂC. 1H
NMR (300 MHz, CDCl3):
d
¼10.50 (s, 1H), 8.04 (d, J¼2.1 Hz, 1H), 7.95
(d, J¼8.4 Hz, 1H), 7.70 (dd, J¼8.4, 1.9 Hz, 1H), 7.45 (s, 1H), 4.00 (d,
J¼6.6 Hz, 2H), 3.95 (s, 3H), 2.04e1.89 (m, 1H), 0.95 (d, J¼6.6 Hz, 6H).
2.2.1.1. Methyl 2-formylbenzoate (7a). 1H NMR (300 MHz,
13C NMR (75 MHz, CDCl3):
d
¼190.9, 166.6, 153.2, 142.9, 133.7, 131.1,
CDCl3):
d
¼10.59 (s, 1H), 7.97e7.90 (m, 2H), 7.65e7.62 (m, 2H), 3.96
130.2, 120.8, 119.2, 71.9, 52.8, 27.9, 19.0. HRMS (EI): m/z calcd for
(s, 3H). 13C NMR (75 MHz, CDCl3):
d
¼192.3, 166.9, 137.1, 134.5, 133.1,
C14H17NO5 (Mþ): 279.1107; found: 279.1110.
132.5, 130.5, 128.5, 52.9. HRMS (EI): m/z calcd for C9H8O3 (Mþ):
164.0473; found: 164.0468.
2.2.2.4. Methyl 4-formyl-[1,10-biphenyl]-3-carboxylate (7e). For
preparation of the intermediate 6-phenylphthalide, toluene
(2.3 mL) was added to a mixture of 6-bromophthalide (280 mg,
1.3 mmol), phenylboronic acid (319.4 mg, 2.6 mmol), tetrakis(tri-
phenylphosphine) palladium (pd(pph3)4) (75.7 mg, 0.065 mmol),
and sodium carbonate solution (1.9 mL, 2 M). The reaction mixture
was refluxed for 5 h followed by adding water (2 mL) and extraction
with ethyl acetate (10 mL, three times). The combined organic
phase was dried and concentrated under the reduced pressure. The
crude product was purified by column chromatography on silica gel
2.2.2. Representative procedure B: synthesis of 5-substituted 2-for-
mylbenzoic acid. 1,2-Dichloroethane (25 mL) was added to a mixture
of 6-methoxyphthalide (670 mg, 4.5 mmol), N-bromosuccinimide
(890 mg, 5 mmol), azobisisobutyronitrile (41 mg, 0.2 mmol), and
refluxed for 1 h. The reaction mixture was kept in an ice bath for 2 h
then filtered. The solvent was removed under reduced pressure.
Water (10 mL) was then added and the resulting mixture refluxed
for 1 h. The reaction mixture was then cooled to room temperature

R. Mirabdolbaghi, T. Dudding / Tetrahedron 69 (2013) 3287e3292
3291
(n-hexane/EtOAc: 1/1) to yield the desired product. 1H NMR
(300 MHz, CDCl3):
¼8.14 (s, 1H), 7.93 (dd, J¼8.1, 1.8 Hz, 1H),
7.65e7.60 (m, 3H), 7.50e7.43 (m, 3H), 5.38 (s, 2H). 13C NMR
washed with brine, and dried. The crude product was purified by
column chromatography on silica gel (n-hexane/EtOAc: 6/1) to
yield 7l as a white solid (1.1 g, 80.0%). Mp¼80e81 ꢂC. 1H NMR
d
(75 MHz, CDCl3):
d
¼171.2, 145.4, 142.8, 139.5, 133.3, 129.2, 128.3,
(300 MHz, CDCl3):
d
¼10.58 (s, 1H), 7.85 (d, J¼7.8 Hz, 1H), 7.70e7.65
127.3, 124.1, 122.6, 69.7. HRMS (EI): m/z calcd for C14H10O2 (Mþ):
210.0681; found: 210.0684. The representative procedures B and A
outlined above were then followed, respectively, to yield 7e as
(m, 1H), 7.57e7.47 (m, 2H), 6.54 (s, 1H), 1.44 (s, 9H). 13C NMR
(75 MHz, CDCl3):
d
¼196.2, 146.5, 134.3, 130.5, 127.2, 125.2, 123.3,
98.0, 77.8, 28.7. HRMS (EI): m/z calcd for C12H14O3 (Mþ): 206.0943;
a white solid. Mp¼77e79 ꢂC. 1H NMR (300 MHz, CDCl3):
d
¼10.62 (s,
found: 206.0937.
1H), 8.15 (s, 1H), 7.97 (d, J¼8.1 Hz, 1H), 7.79 (dd, J¼8.1, 1.5 Hz, 1H),
7.60 (dd, J¼8.4, 1.8 Hz, 2H), 7.48e7.40 (m, 3H), 3.40 (s, 3H). 13C NMR
2.2.2.12. 2-Formylphenylcarboxymethyl polystyrene (7m). Com-
pound 7m was synthesized by following the procedure reported by
Knepper et al.4d Spectroscopic data was in full agreement with
spectral data of an authentic sample.
(75 MHz, CDCl3):
d
¼191.6, 166.7, 145.7, 138.6, 130.5, 129.1, 128.9,
128.8, 127.2, 52.8. HRMS (EI): m/z calcd for C15H12O3 (Mþ):
240.0786; found: 240.0783.
2.2.2.5. Methyl 2-formyl-5-methoxybenzoate (7f). Starting 6-
methoxyphthalide was prepared by the reported procedure of
Napoletano et al.22 The representative procedures B and A outlined
above were then followed, respectively. 1H NMR (300 MHz, CDCl3):
2.2.3. Representative procedure C: synthesis of substituted (R)-3-al-
lylisobenzofuran-1(3H)-one. A round-bottomed flask wrapped in
aluminum foil was charged with AgF (7.75 mg, 0.061 mmol), (R)-
BINAP (22.8 g, 0.035 mmol), anhydrous MeOH (0.2 mL), and stirred
for 10 min at room temperature. The mixture was cooled to ꢁ20 ꢂC
(dry ice/xylene bath) followed by dropwise addition of methyl 2-
formylbenzoate 7a (100 mg, 0.61 mmol) and allyltrimethoxysilane
d
¼10.39 (s, 1H), 7.89 (d, J¼8.7 Hz, 1H), 7.32 (d, J¼2.4 Hz, 1H), 7.04
(dd, J¼8.4, 2.1 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H). 13C NMR (75 MHz,
CDCl3):
d¼190.5, 166.6, 163.2, 134.4, 130.8, 129.4, 117.4, 115.3, 55.7,
52.7. HRMS (EI): m/z calcd for C10H10O4 (Mþ): 194.0579; found:
(154 mL, 0.91 mmol). After 4 h, the reaction mixture was quenched
194.0573.
with a mixture of 1 N HCl (3 mL) and KF (ca. 0.3 g) and stirred for
30 min. The resulting precipitate was filtered and the filtrate was
dried over MgSO4. After evaporation of the solvents in vacuum, the
crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc: 1/1) to yield 8a as a colorless oil (72.1 mg, 68%
yield).
2.2.2.6. Ethyl 2-formylbenzoate (7g). 1H NMR (300 MHz, CDCl3):
d
¼10.90 (s, 1H), 7.96e7.88 (m, 2H), 7.63e7.60 (m, 2H), 4.41 (q,
J¼7.2 Hz, 2H), 1.40 (t, J¼7.2, 3H). 13C NMR (75 MHz, CDCl3):
¼192.1,
d
166.3, 137.0, 132.9, 132.5, 132.3, 130.3, 128.3, 61.9, 14.3. HRMS (EI):
m/z calcd for C10H10O3 (Mþ): 178.0630; found: 178.0627.
2.2.3.1. (R)-3-Allylisobenzofuran-1(3H)-one (8a). Representative
procedure C was followed to prepare 8a from substrates 7a, 7gej,
and 7m and the spectroscopic data was in full agreement with
spectral data of an authentic sample.6 1H NMR (300 MHz, CDCl3):
2.2.2.7. Hexyl-2-formylbenzoate (7h). 1H NMR (300 MHz,
CDCl3):
d
¼10.59 (s, 1H), 7.95e7.87 (m, 2H), 7.63e7.57 (m, 2H), 4.34
(t, J¼3.6 Hz, 2H), 1.80e1.70 (m, 2H), 1.43e1.25 (m, 6H), 0.87 (t,
J¼6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d¼192.0, 166.2, 137.0,
d
¼7.88 (d, J¼7.8 Hz, 1H), 7.67 (t, J¼7.6 Hz, 1H), 7.53e7.47 (m, 2H),
5.77e5.50 (m, 1H), 5.521 (t, J¼6 Hz, 1H), 5.16e5.13 (m, 2H),
2.75e2.62 (m, 2H). 13C NMR (75 MHz, CDCl3):
132.8,132.2,130.3,128.3, 66.0, 31.3, 28.5, 25.6, 22.5,13.9. HRMS (EI):
m/z calcd for C14H18O3 (Mþ): 234.1256; found: 234.1250.
d¼170.5, 149.4, 134.0,
131.3, 129.3, 126.3, 125.8, 122.1, 119.8, 80.3, 38.7. The product 8a was
obtained from substrate 7g (61.5 mg, 58%), 7h (77.4 mg, 73%), 7i
(74.3 mg, 70%), 7j (57.3 mg, 54%), 7m (72.1 mg, 68%). For 8a pre-
2.2.2.8. Dodecyl 2-formylbenzoate (7i). 1H NMR (300 MHz,
CDCl3):
d
¼10.62 (s, 1H), 7.98e7.91 (m, 2H), 7.65e7.62 (m, 2H), 4.37
(t, J¼6.6 Hz, 2H), 1.81e1.76 (m, 2H), 1.43e1.26 (m, 18H), 0.87 (t,
pared from 7a [
a
]
20 þ50.5 (c 1.74, CHCl3). For 8a prepared from 7g
D
20
20
J¼6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d¼192.0, 166.3, 137.1,
[
a
]
þ63.0 (c 2.0, CHCl3). For 8a prepared from 7h [
a
]
þ70.1 (c
D
D
132.9, 132.4, 132.2, 130.3, 128.3, 66.0, 31.9, 29.6, 29.5, 29.5, 29.3,
29.2, 28.6, 26.0, 24.7, 22.7, 14.1. HRMS (EI): m/z calcd for C20H30O3
(Mþ): 318.2195; found: 318.22047.
2.05, CHCl3). For 8a prepared from 7i [
a
]
D
20 þ65.7 (c 1.5, CHCl3). For
8a prepared from 7j [
a
]
20 þ62.3 (c 1.5, CHCl3). For 8a prepared from
D
20
7m [
a]
þ61.4 (c 1.95, CHCl3). The enantioselectivity was de-
D
termined by HPLC analysis on a chiral column (OD-H, hexane/iPrOH
95:5, flow rate 0.5 mL minꢁ1, wavelength¼245 nm). For 8a pre-
pared from 7a enantiomeric excess¼71%, (tminor¼20.41 min (S),
area%¼14.23; tmajor¼19.00 min (R), area%¼85.77). For 8a prepared
from 7g enantiomeric excess¼63%, (tminor¼18.97 min (S), area%¼
18.60; tmajor¼20.47 min (R), area%¼81.40). For 8a prepared from 7h
enantiomeric excess¼86%, (tminor¼18.58 min (S), area%¼7.24;
tmajor¼19.52 min (R), area%¼92.75. For 8a prepared from 7i enan-
tiomeric excess¼86%, (tminor¼18.72 min (S), area%¼6.76;
tmajor¼19.85 min (R), area%¼93.24). For 8a prepared from 7j en-
antiomeric excess¼63%, (tminor¼18.97 min (S), area%¼18.60;
tmajor¼20.47 min (R), area%¼81.40). For 8a prepared from 7m en-
antiomeric excess¼76% (racemic), (tminor¼19.37 min (S), area%¼
12.18; tmajor¼20.68 min (R), area%¼87.82). Absolute configuration
assigned as (R) by comparison of optical rotation with a literature
value.7b
2.2.2.9. Benzyl-2-formylbenzoate (7j). 1H NMR (300 MHz,
CDCl3):
d
¼10.62 (s, 1H), 7.97e7.87 (m, 2H), 7.58e7.55 (m, 2H),
7.46e7.33 (m, 5), 5.39 (s, 2H). 13C NMR (75 MHz, CDCl3):
d¼191.7,
165.8, 136.9, 135.2, 132.7, 132.2, 131.7.3, 130.2, 128.5, 128.3, 128.2,
128.2, 67.3, HRMS (EI): m/z calcd for C15H12O3 (Mþ): 240.0786;
found: 240.0783.
2.2.2.10. Isopropyl 2-formylbenzoate (7k). Mp¼77e79 ꢂC. 1H
NMR (300 MHz, CDCl3):
d
¼10.45 (s, 1H), 7.81e7.67 (m, 2H),
7.51e7.41 (m, 2H), 5.20e5.05 (m, 1H), 1.24 (d, J¼6, 6H). 13C NMR
(75 MHz, CDCl3):
d¼192.0, 165.7, 136.9, 132.8, 132.0, 130.2, 128.2,
69.7, 21.8. HRMS (EI): m/z calcd for C11H12O3 (Mþ): 192.0786;
found: 192.0781.
2.2.2.11. tert-Butyl 2-formylbenzoate (7l). To a vigorously stirred
suspension of anhydrous magnesium sulfate (3.2 g, 27 mmol) in
DCM (27 mL), sulfuric acid (0.4 mL, 6.7 mmol) was added. The re-
action mixture was stirred for 15 min; 2-carboxy benzaldehyde
(1 g, 6.7 mmol) and tert-butanol (3.2 mL) were added and stirred for
18 h at room temperature followed by quenching with saturated
sodium bicarbonate (75 mL). The organic phase was separated,
2.2.3.2. (R)-3-Allyl-6-bromoisobenzofuran-1(3H)-one (8b). Repre-
sentative procedure C was followed. The crude product was purified
by column chromatography on silica gel (n-hexane/EtOAc: 1/1) to
yield 8b (87.9 mg, 57%). The spectroscopic data was in full agreement
with spectral data of an authentic sample.6 1H NMR (300 MHz,

3292
R. Mirabdolbaghi, T. Dudding / Tetrahedron 69 (2013) 3287e3292
CDCl3):
d
¼8.05 (d, J¼1.6 Hz, 1H), 7.79 (dd, J¼8.1, 1.7 Hz, 1H), 7.37 (d,
2.2.4. Preparation of the (R)-1-phenylbut-3-en-1-ol (10). Represen-
tative procedure C was followed. The crude product was purified by
column chromatography on silica gel (n-hexane/EtOAc: 6/1) to
yield 10 (79.5 mg, 88%). The spectroscopic data was in full
agreement with spectral data of an authentic sample.1 1H
J¼6 Hz, 1H), 5.82e5.69 (m, 1H), 5.508 (t, J¼6 Hz, 1H), 5.23e5.17 (m,
2H), 2.75e2.67 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
¼167.8, 147.0,
20
136.1, 131.9, 129.9, 122.7, 119.3, 79.2, 37.6. [
a]
þ0.14 (c 10, CHCl3).
D
The enantioselectivity was determined by HPLC analysis on a chiral
column (AS-H, hexane/iPrOH 90:10, flow rate mL minꢁ1
1
,
NMR (300 MHz, CDCl3):
d
¼7.30e7.39 (m, 5H), 5.77e5.91 (m,
wavelength¼245 nm) to be 39%: tminor¼7.51 min (S), area%¼30.43,
1H), 5.15e5.22 (m, 2H), 4.75 (t, J¼7 Hz, 1H), 2.51e2.57 (m, 2H),
tmajor¼8.02 min (R), area%¼69.56.
2.22 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
d
¼144.0, 134.5,
20
128.5, 127.7, 125.9, 118.5, 73.4, 43.9. [
a
]
þ43.1 (c 0.8, CHCl3).
D
2.2.3.3. (R)-3-Allyl-6-nitroisobenzofuran-1(3H)-one (8c). Repre-
sentative procedure C was followed. The crude product was puri-
fied by column chromatography on silica gel (n-hexane/EtOAc: 1/1)
to yield 8c (69.5 mg, 52%). The spectroscopic data was in full
agreement with spectral data of an authentic sample.6 1H NMR
The enantioselectivity was determined by HPLC analysis on
a chiral column (OD-H, hexane/iPrOH 97:3, flow rate 0.5 mL minꢁ1
,
wavelength¼245 nm) to be 87%: tminor¼12.03 min (S),
tmajor¼10.52 min (R).
(300 MHz, CDCl3):
d
¼8.72 (s, 1H), 8.54 (dd, J¼8.1, 2.1 Hz, 1H), 7.67 (t,
J¼8.4 Hz, 1H), 5.67e5.63 (m, 2H), 5.23e5.17 (m, 2H), 2.78e2.76 (m,
Acknowledgements
2H). 13C NMR (75 MHz, CDCl3):
128.1, 123.5, 121.4, 121.4, 80.2, 38.2. [
d
¼167.8, 154.5, 149.1, 130.0, 128.8,
a]
20 þ10.1 (c 0.62, CHCl3). The
D
We are grateful to the Natural Sciences and Engineering Re-
search Council of Canada (NSERC) and Brock University for funding
of this research. We thank Dr. Costa Metallinos and Joshni John of
Brock University for use of equipment.
enantioselectivity was determined by HPLC analysis on a chiral
column (AS-H, hexane/iPrOH 80:20, flow rate
1 ,
mL minꢁ1
wavelength¼245 nm) to be 33%: tminor¼13.20 min (S), area%¼
33.33, tmajor¼17.65 min (R), area%¼66.67.
2.2.3.4. (R)-Isobutyl (3-allyl-1-oxo-1,3-dihydroisobenzofuran-5-
yl)carbamate (8d). Representative procedure C was followed. The
crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc: 1/1) to yield 8e (114.7 mg, 65%). The spectroscopic
data was in full agreement with spectral data of an authentic sam-
References and notes
1. Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.; Asakawa, K.; Matsumoto, Y.;
Yamamoto, H. Angew. Chem., Int. Ed. 1999, 38, 3701.
ꢀ
ꢀ
ꢀ
~
~
2. Jimenez-Gonzalez, L.; García-Munoz, S.; Alvarez-Corral, M.; Munoz-Dorado, M.;
Rodríguez- García, I. Chem.dEur. J. 2006, 12, 8762.
ple.6 1H NMR (300 MHz, CDCl3):
d¼7.87 (s, 1H), 7.86 (s, 1H), 7.41 (d,
3. Maki, K.; Motodi, R.; Fujii, K.; Kanai, M.; Kobayashi, T.; Tamura, S.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 17111.
J¼8.4, Hz, 1H), 7.22 (s, 1H), 5.82e5.68 (m, 1H), 5.49 (t, J¼6 Hz, 1H),
5.21e5.13 (m, 2H), 3.98 (d, J¼6.6 Hz, 2H), 2.77e2.58 (m, 2H),
2.05e1.94 (m, 1H), 0.98 (d, J¼6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3):
4. (a) Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774; (b)
Haddad, T. D.; Hirayama, L. C.; Singaram, B. J. Org. Chem. 2010, 75, 642; (c)
Hrdina, R.; Valterova, I.; Hodacova, J.; Cisarova, I.; Kotora, M. Adv. Synth. Catal.
2007, 349, 822; (d) Knepper, K.; Ziegert, R. E.; Brase, S. Tetrahedron 2004, 60,
8591.
5. Mirabdolbaghi, R.; Dudding, T. Tetrahedron 2012, 68, 1988.
6. Mirabdolbaghi, R.; Dudding, T. Org. Lett. 2012, 14, 3748.
7. (a) Kosaka, M.; Sekiguchi, S.; Naito, J.; Uemura, M.; Kuwahara, S.; Watanabe, M.;
Harada, N.; Hiroi, K. Chirality 2005, 17, 218; (b) Pedrosa, R.; Sayalero, S.; Vicente,
M. Tetrahedron 2006, 62, 10400; (c) Karnik, A. V.; Kamath, S. S. Synthesis 2008,
1832.
d
¼19.2,152.7,143.0,138.6,130.3,127.3,126.3,123.8,121.8,118.9, 79.3,
70.9, 37.9, 27.1,18.2. [
a]
D
20 þ30.3 (c 0.23, CHCl3). The enantioselectivity
was determined by HPLC analysis on a chiral column (AS-H, hex-
ane/iPrOH 90:10, flow rate 1 mL minꢁ1, wavelength¼245 nm) to be
43%: tmajor¼31.31 min (S), area%¼28.38, tminor¼28.28 min (R), area%¼
71.62.
8. Ramachandran, P. V.; Chen, G.-M.; Brown, H. H. C. Tetrahedron Lett. 1996, 37,
2205.
2.2.3.5. (R)-3-Allyl-6-phenylisobenzofuran-1(3H)-one (8e). Repre-
sentative procedure C was followed. The crude product was purified
by column chromatography on silica gel (n-hexane/EtOAc: 1/1) to
yield 8e (102.3 mg, 67%). The spectroscopic datawas in full agreement
with spectraldata of an authenticsample.6 1HNMR (300 MHz, CDCl3):
9. Phan, D. H. T.; Kim, B.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 15608.
10. (a) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509; (b)
Everaere, K.; Scheffler, J.-L.; Mortreux, A.; Carpentier, J.-F. Tetrahedron Lett. 2001,
42, 1899; (c) Everaere, K.; Mortreux, A.; Carpentier, J.-F. Adv. Synth. Catal. 2003,
345, 67.
11. Watanabe, M.; Hashimoto, N.; Araki, S.; Butsugan, Y. J. Org. Chem. 1992, 57, 742.
12. Lei, J.-G.; Hong, R.; Yuan, S.-G.; Lin, G.-Q. Synlett 2002, 927.
13. (a) Tanaka, K.; Nishida, G.; Wada, A.; Noguchi, K. Angew. Chem., Int. Ed. 2004, 43,
6510; (b) Tanaka, K.; Osaka, T.; Noguchi, K.; Hirano, M. Org. Lett. 2007, 9, 1307;
(c) Yamamoto, Y.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 9625.
14. Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46, 7664.
15. Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem.dEur. J. 2007, 13, 4356.
16. Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J. Org. Chem. 2010,
75, 368.
17. (a) Robinson, J. E.; Brimble, M. A. Chem. Commun. 2005, 1560; (b) Nannei, R.;
Dallavalle, S.; Merlini, L.; Bava, A.; Nasini, G. J. Org. Chem. 2006, 71, 6277; (c)
Keaton, K. A.; Phillips, A. J. Org. Lett. 2007, 9, 2717; (d) Arnone, A.; Assante, G.;
Nasini, G.; Depava, O. V. Phytochemistry 1990, 29, 613; (e) Tianpanich, K.;
Prachya, S.; Wiyakrutta, S.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. J. Nat. Prod.
2011, 74, 79; (f) Xiong, N.; Huang, J.; Chen, C.; Zhao, Y.; Zhang, Z.; Jia, M.; Zhang,
Z.; Hou, L.; Yang, H.; Cao, X.; Liang, Z.; Zhang, Y.; Sun, S.; Lin, Z.; Wang, T.
Neurobiol. Aging 2012, 33, 1777.
d
¼8.13(s,1H), 7.92(dd, J¼6.6,1.6Hz,1H), 7.65e7.63 (m, 2H), 7.67e7.43
(m, 4H), 5.90e5.76 (m, 1H), 5.59 (t, J¼6 Hz, 1H), 5.27e5.19 (m, 2H),
2.83e2.72 (m, 2H). 13C NMR (75 MHz, CDCl3):
¼170.4, 148.2, 142.9,
139.5, 133.2, 131.3, 129.2, 128.3, 127.4, 127.2, 124.1, 122.5, 119.9, 80.3,
d
20
38.9. [
a]
D
þ30.1 (c 0.71, CHCl3). The enantioselectivity was de-
termined by HPLC analysis on a chiral column (AS-H, hexane/iPrOH
90:10, flow rate 1 mL minꢁ1, wavelength¼245 nm) to be 61%:
tminor¼20.14 min (S), area%¼19.38, tmajor¼14.88 min (R), area%¼80.62.
2.2.3.6. (R)-3-Allyl-6-methoxyisobenzofuran-1(3H)-one
(8f).
Representative procedure C was followed. The crude product was
purified by column chromatography on silica gel (n-hexane/EtOAc:
1/1) to yield 8f (68.5 mg, 55%). The spectroscopic data was in full
agreement with spectral data of an authentic sample.6 1H NMR
(300 MHz, CDCl3):
1H), 5.80e5.69 (m,1H), 5.47 (t, J¼5.9 Hz,1H), 5.21e5.14 (m, 2H), 3.87
(s, 3H), 2.71e2.57 (m, 2H). 13C NMR (75 MHz, CDCl3):
¼170.5,160.7,
141.8, 131.3, 127.6, 122.9, 122.9, 119.7, 107.5, 80.1, 55.8, 38.8. [
18. For more examples see: (a) Blaser, M. J. Clin. Infect. Dis. 1992, 15, 386; (b) Bava,
A.; Clericuzio, M.; Giannini, G.; Malpezzi, L.; Meille, S. V.; Nasini, G. Eur. J. Org.
Chem. 2005, 11, 2292; (c) Radcliff, F. J.; Fraser, J. D.; Wilson, Z. E.; Heapy, A. M.;
Robinson, J. E.; Bryant, C. J.; Flowers, C. L.; Brimble, M. A. Bioorg. Med. Chem.
2008, 16, 6179.
d¼7.36 (s,1H), 7.33 (d, J¼2.1 Hz,1H), 7.20e7.24 (m,
d
19. Jung, G. Combinatorial Chemistry, Synthesis, Analysis, Screening; Wiley VCH:
Weinheim, Germany, 1999, pp 1e34.
20
a
]
D
20. Wang, J.; Johnson, D. M. Polym. Int. 2009, 58, 1234.
21. Pokhodylo, N. T.; Matiychuk, V. S.; Obushak, M. D. Chem. Heterocycl. Compd.
þ19.3 (c 0.4, CHCl3). The enantioselectivity was determined by HPLC
analysis on a chiral column (OD-H, hexane/iPrOH 99:1, flow rate
0.5 mL minꢁ1, wavelength¼245 nm) to be 86%: tminor¼36.09 min (S),
area%¼7.12, tmajor¼37.59 min (R), area%¼92.88.
2010, 46, 140.
22. Napoletano, M.; Norcini, G.; Pellacini, F.; Marchini, F.; Morazzoni, G.; Ferlenga,
P.; Pradella, L. Bioorg. Med. Chem. Lett. 2001, 11, 33.