Catalytic asymmetric synthesis of 3-aryl phthalides enabled by arylation-lactonization of 2-formylbenzoates

Article abstract of DOI:10.1039/c8ob02872a

The catalytic asymmetric synthesis of 3-aryl phthalides is reported through a sequential asymmetric arylation-lactonization reaction. The reaction is enabled by a boron-zinc exchange to generate reactive arylating agents, which react with 2-formylbenzoates in the presence of a chiral amino naphthol ligand. The enantiodetermining step is the arylation of the aldehyde, which then undergoes a lactonization event to yield the corresponding phthalides in good yields and enantioselectivities.

Full text of DOI:10.1039/c8ob02872a

Organic &
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PAPER
Catalytic asymmetric synthesis of 3-aryl phthalides
enabled by arylation–lactonization of
2-formylbenzoates†
Cite this: Org. Biomol. Chem., 2019,
17, 283
Andressa M. M. Carlos, Rafael Stieler and Diogo S. Lüdtke
*
The catalytic asymmetric synthesis of 3-aryl phthalides is reported through a sequential asymmetric aryla-
tion–lactonization reaction. The reaction is enabled by a boron–zinc exchange to generate reactive
arylating agents, which react with 2-formylbenzoates in the presence of a chiral amino naphthol ligand.
The enantiodetermining step is the arylation of the aldehyde, which then undergoes a lactonization event
to yield the corresponding phthalides in good yields and enantioselectivities.
Received 16th November 2018,
Accepted 5th December 2018
DOI: 10.1039/c8ob02872a
rsc.li/obc
chiral sugar14 and amino-aldehydes,15 and ketenimium ions.16
Based on our experience in this subject, we hypothesized that
Introduction
Optically active 3-substituted isobenzofuranones, commonly a catalytic asymmetric arylation reaction, enabled by the
termed phthalides, are important structures in medicinal
chemistry as well as in organic synthesis, and are frequently
encountered in natural products. They are characterized by a
bicyclic framework, with a benzene ring fused to a γ-lactone.1
Several biologically relevant phthalides have been reported in
the literature (Scheme 1A). For example, n-butylphthalide is
marketed as an anti-convulsant drug for the treatment of
ischemia-cerebralapoplexy,2 while natural products basidiffer-
quinone A,3 isopestacin,4 and concentricolide5 have been
reported to display fruiting bodies, and anti-fungal/anti-
oxidant and anti-HIV activities, respectively. Despite their
importance, the catalytic asymmetric synthesis of 3-substituted
isobenzofuranones has been scarcely studied, most notably
those bearing an aryl moiety at this position. Available
methods are centered on the metal-catalyzed intramolecular
cyclization of diketones,6 organocatalyzed aldol-cyclization
reactions,7 and halogen-metal exchange-cyclization catalyzed
by cobalt8 or mediated by bimetallic Mg–Li reagents.9
Rhodium10 and ruthenium-catalyzed11 additions of organo-
boronic acids to formylbenzoates have also been described.
Our research group has been involved in the development
of stereoselective reactions using organozinc reagents,12 with
the development of catalytic asymmetric addition of arylzinc
reagents to aldehydes13 and diastereoselective arylations of
Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av. Bento
Gonçalves 9500, 91501-970 Porto Alegre, RS, Brazil. E-mail: dsludtke@iq.ufrgs.br;
Tel: +55 51 3308 9637
†Electronic supplementary information (ESI) available: Copies of NMR spectra
and HPLC chromatograms for all compounds. CCDC 1869439. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c8ob02872a
Scheme 1 Key precedents and this work.
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boron/zinc exchange of arylboronic acids with Et2Zn,17 which the aziridino methanol ligand L2, despite the still moderate
has been well described for aryl and alkyl aldehydes yield of 45% (entry 2). Trost’s ProPhenol ligand resulted in a
(Scheme 1B), would serve as a tool for the development of a very low conversion and racemic product. More promising
sequential asymmetric arylation–lactonization reaction, ulti- results have been achieved with ligands from the amino
mately leading to a catalytic asymmetric synthesis of 3-aryl naphthol family L4–L7. The simplest ligand L4 was able to
phthalides (Scheme 1C).18
deliver the desired phthalide 2a in 57% yield and a good
enantioselectivity of 55% (entry 4). Gratifyingly, when the
bulkier ligand L5, bearing an ortho-tolyl substituent (instead
of a phenyl in L4), resulted in an improved ee of 80%, while
maintaining the yield (entry 5). Additional changes of the
Results and discussion
Our initial investigation began with a ligand screening in the ligand at the aryl or N-R moieties didn’t result in additional
enantioselective arylation of methyl 2-formylbenzoate (1a), improvements (entries 6 and 7). With these results in hand,
with the transferable phenyl group generated by the B/Zn we proceeded to further optimization studies using L5 as the
exchange reaction between phenylboronic acid and diethylzinc ligand of choice. Changes have been made in time and temp-
(Table 1). Chiral amino alcohols bearing pyrrolidine,19 aziri- erature at which the reaction was performed. Gratifyingly,
dine,20 Trost’s ProPhenol,21 and amino naphthol22 backbones when the reaction was performed at lower temperatures, sig-
have been evaluated (Fig. 1).
nificant improvement of the enantioselectivity was observed
The initial experiments revealed that L1 resulted in a very (entries 8–11). Carrying out the reaction at 0 °C in the pres-
low yield and ee for the desired product 2a (entry 1), while a ence of 20 mol% of L5 resulted in product 2a in 83% and
much better enantioselectivity of 73% was observed using 80% ee (entry 8). An additional decrease in the temperature
to −5 °C resulted in an additional increase in the enantio-
selectivity of the arylation reaction and 3-phenyl phthalide
Table 1 Optimization of the chiral ligand
2a was isolated with 91% ee, with the best yield of 80%
obtained after 5 h (entry 11). An attempt at lowering the
ligand loading to 10 mol% resulted in a decrease in both
yield and enantiomeric excess (entry 12). Decreasing the
temperature even further didn’t result in product formation
after 5 h (entry 13).
After establishing the optimal conditions for the phthalide
synthesis, we proceeded to examine the reaction scope in
respect of the arylboronic acid (Scheme 2).
Entry
Ligand
T (°C)
t (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L5
L5
L5
L5
L5
L5
25
25
25
25
25
25
25
0
−5
0
−5
−5
−20
24
24
24
24
24
24
24
24
24
2
16
45
28
57
69
25
28
83
73
56
80
75
NR
31 (S)
73 (S)
0
The reaction proceeded efficiently for a number of different
arylating groups bearing both electron-donating and electron-
withdrawing groups, typically at a synthetically useful level of
enantioselectivity. For example, the arylation of 1a using arylat-
ing agents with different substitution patterns such as p-Me
(2c), p-Ph (2d), p-Cl (2e), p-Br (2f), p-OMe (2g), and 2,4-difluoro
(2l) was well tolerated and the corresponding aryl phthalides
were obtained in good yields and enantioselectivities ranging
from 80% to 91% ee. Notably, a single recrystallization of the
3-aryl phthalide 2 in chloroform/petroleum ether resulted in a
significant enantioenrichment of the compounds, with pro-
ducts 2a and 2c–g, and 2l being obtained in >95% ee. Worth
pointing out is that the mass recovery after recrystallization is
always of >80%, in both 0.3 mmol and 1 mmol scales, which
renders this process useful for preparative purposes. Steric
effects have also been examined and the reaction is slightly
less enantioselective when ortho substituents are present at the
arylation agent. Hence, product 2b, obtained by the transfer of
a o-tolyl group, was obtained in 83% ee, while product 2i, with
an o-OMe was isolated in a diminished ee of 34%. The pres-
ence of two ortho methyl groups causes more severe steric hin-
drance and hampers the formation of the desired product 2m.
Finally, aryl phthalides with the opposite absolute configur-
ation can also be prepared by the use of the enantiomer of the
chiral ligand L5, and the corresponding products ent-2a, ent-
55 (R)
80 (R)
53 (R)
50 (R)
80 (R)
91 (R)
83 (R)
91 (R)
85 (R)
ND
9
10
11
12c
13
5
5
5
a Isolated yields. b Determined by HPLC using the chiral stationary
phase. c Reaction using 10 mol% of L5. NR = no reaction. ND = not
determined.
Fig. 1 Structure of the chiral ligands used in this work.
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Scheme 3 Arylation using substituted formyl benzoates.
ing that the mechanism is the same for the transfer of the aryl
groups, or by comparison of retention times in chiral station-
ary phase HPLC for known compounds (see the ESI† for
details).
Further studies with variations in the substitution pattern
of the electrophile have also been carried out. Substituted
2-formyl benzoates bearing a chlorine substituent were evalu-
ated under the optimized reaction conditions, using p-tolyl-
boronic acid as the aryl source (Scheme 3). The corresponding
3-aryl phthalides 3a–c were obtained in good yields and high
enantioselectivities ranging from 87% to 90% ee, indicating
that the position of the substituent at the aryl ring has little
influence on the efficiency of the arylation reaction.
Conclusions
In summary, we have developed an efficient, catalytic enantio-
selective synthesis of 3-aryl phthalides by a combination of an
asymmetric arylation of an aldehyde with a lactonization reac-
tion. The enantiodetermining event is the asymmetric addition
of an arylzinc reagent to a 2-formylbenzoate. The products
were obtained in good to excellent enantioselectivities, and we
have shown that the ee of the products could be enriched to
very high enantiopurity by a simple recrystallization in an
ordinary chloroform/petroleum ether solvent mixture. The
method developed is preparatively useful and shall find utility
in the synthesis of novel chiral aryl phthalides.
Scheme 2 Scope of the reaction.
Experimental section
General information
2c, ent-2e, and ent-2g were obtained in comparable yields and
enantioselectivities.
The absolute configuration of the 3-aryl phthalides was
assigned as being (R), based on the single crystal X-ray diffrac-
tion studies of compound 2f (Scheme 2, see the ESI† for crys-
tallographic details). The absolute configurations of the
remaining compounds have been assigned by analogy, assum-
Air- and moisture-sensitive reactions were conducted in flame-
or oven-dried glassware equipped with tightly fitted rubber
septa and under a positive pressure of dry argon. Reagents and
solvents were handled by using standard syringe techniques.
Temperatures above room temperature were maintained by the
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use of a mineral oil bath heated on a hotplate. Column chrom-
(R)-3-o-Tolylisobenzofuran-1(3H)-one C15H12O2 (2b). White
atography was performed using silica gel (230–400 mesh) fol- solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]2D0 = +27.4 (c 0.94,
lowing the methods described by Still.23 Thin layer chromato- EtOAc). Melting point = 118–120 °C. Purified by column
graphy (TLC) was performed using supported silica gel GF254, chromatography (hexane/EtOAc 85 : 15) to give the product in
0.25 mm thickness. For visualization, TLC plates were either 86% yield (96 mg) and 83% ee. HPLC: (Chiralcel OD, hexane/
placed under ultraviolet light, or treated with acid vanillin fol- i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) =
lowed by heating. NMR spectra were recorded either with a 300 9.61 min, (R) = 12.82 min. 1H NMR (400 MHz, CDCl3): δ = 2.50
or 400 MHz instrument in CDCl3 solutions. Chemical shifts (s, 3H), 6.69 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 7.11–7.15 (m, 1H),
are reported in ppm, referenced to the solvent peak of residual 7.26–7.28 (m, 2H), 7.34 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.57 (t,
CHCl3 or tetramethylsilane (TMS) as a reference. The data are J = 7.5 Hz, 1H), 7.67 (td, J = 7.5 Hz, J = 1,1 Hz, 1H), 7.98 (d, J =
reported as follows: chemical shift (δ), multiplicity, coupling 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 19.2, 80.4, 122.9,
constant (J) in Hz, and integrated intensity. 13C NMR spectra 125.6, 126.32, 126.35, 127.1, 129.25, 129.29, 131.0, 134.0,
were recorded at 75 and 100 MHz in CDCl3 solutions. 134.1, 137.0, 149.2, 170.5. HRMS (ESI+): Calcd for C15H12O2
Chemical shifts are reported in ppm, referenced to the solvent [M + H]+ requires 225.0916; found 225.0918.
peak CDCl3. Abbreviations to denote the multiplicity of a par-
(R)-3-p-Tolylisobenzofuran-1(3H)-one C15H12O2 (2c). White
ticular signal are: s (singlet), d (doublet), t (triplet), dd (double solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]2D0 = −7.72 (c 0.22,
doublet), m (multiplet), q (quartet), and br (broad singlet). DCM). Melting point = 127–130 °C. Purified by column chrom-
ESI-QTOF-MS measurements were performed in the positive atography (hexane/EtOAc 85 : 15) to give the product in 90%
ion mode (m/z 50–2000 range). Optical rotations were yield (101 mg) and 91% ee. HPLC: (Chiralcel OD, hexane/
measured using a digital polarimeter using 10 cm cells and i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) =
1
are reported as [α]2D0, concentration (g per 100 mL), and 7.82 min, (R) = 9.61 min. H NMR (400 MHz, CDCl3): δ = 2.35
solvent. Formyl benzoates 1 and amino naphthol L5 were pre- (s, 3H), 6.37 (s, 1H), 7.14–7.19 (m, 4H), 7.32 (d, J = 7.6 Hz, 1H),
pared according to literature procedures.24,22d
7.54 (t, J = 7.5 Hz, 1H), 7.64 (td, J = 7.5 Hz, 1.1 Hz, 1H), 7.95 (d,
J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 21.3, 82.6,
122.8, 125.5, 125.6, 126.9, 129.2, 129.5, 133.3, 134.2, 139.3,
General procedure for the aryl transfer reaction
Under an atmosphere of argon, 1.5 M solution of Et2Zn 149.7, 170.5. HRMS (ESI+): Calcd for C15H12O2 [M + H]+
(7.2 equiv., 3.6 mmol, 2.4 mL) was slowly added to a solution requires 225.0916; found 225.0917.
of arylboronic acid (2.4 equiv., 1.2 mmol) in dry toluene
Ent-2f: Purified by column chromatography (hexane/EtOAc
(2 mL). The mixture was stirred at 60 °C for 1 h and after this 85 : 15) to give the product in 78% yield (88 mg) and 84% ee.
time, it was cooled at room temperature and a solution of [α]2D0 = +50.12 (c 0.78, DCM). HPLC: (Chiralcel OD, hexane/
20 mol% of ligand L5 in 1 mL of dry toluene was added. The i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) =
reaction mixture was stirred for 15 min followed by the 9.30 min, (R) = 12.12 min.
addition of the aldehyde (0.5 mmol). After stirring at −5 °C
(R)-3-(p-Biphenyl)isobenzofuran-1(3H)-one C20H14O2 (2d).
for 5 h the reaction mixture was carefully quenched by the White solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]2D0 = +23.6°
addition of 1 M HCl. The aqueous layer was extracted with di- (c 0.22, DCM). Melting point = 209–212 °C. Purified by column
chloromethane (3 × 30 mL). The combined organic layers were chromatography (hexane/EtOAc 85 : 15) to give the product in
dried with anhydrous MgSO4, filtered, and the solvent was 71% yield (102 mg) and 81% ee. HPLC: (Chiralcel OD-H,
evaporated in a vacuum. The crude product was purified by hexane/i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm):
flash chromatography using hexane : ethyl acetate.
1
(S) = 12.02 min, (R) = 14.43 min. H NMR (400 MHz, CDCl3):
(R)-3-Phenylisobenzofuran-1(3H)-one C14H10O2 (2a). White δ = 6.45 (s, 1H), 7.34–7.39 (m, 4H), 7.44 (t, J = 7.5 Hz, 2H),
solid. Rf = 0.4 (hexane/EtOAc 90 : 10). [α]2D0 = −45.4 (c 0.34, 7.55–7.61 (m, 5H), 7.67 (td, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.98 (d,
DCM). Melting point = 152–154 °C. Purified by column chrom- J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 82.4, 122.8,
atography (hexane/EtOAc 90 : 10) to give the product in 80% 125.66, 125.70, 127.1, 127.4, 127.67, 127.69, 128.8, 129.4,
yield (89 mg) and 91% ee. HPLC: (Chiralcel OD, hexane/ 134.4, 135.2, 140.2, 149.9, 170.4. HRMS (ESI+): Calcd for
i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) = C20H14O2 [M + H]+: requires 287.1072; found 287.1072.
8.63 min, (R) = 11.14 min. 1H NMR (400 MHz, CDCl3): δ = 6.40
(R)-3-(p-Chlorophenyl)isobenzofuran-1(3H)-one C14H9ClO2
(s, 1H), 7.26–7.41 (m, 6H), 7.55 (t, J = 7.5 Hz, 1H), 7.64 (td, J = (2e). White solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]2D0 = −34.7
7.5 Hz, J = 1.2 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H). 13C NMR (c 0.22, DCM). Melting point = 156–159 °C. Purified by column
(100 MHz, CDCl3): δ = 82.6, 122.8, 125.50, 125.55, 126.9, 128.9, chromatography (hexane/EtOAc 85 : 15) to give the product in
129.23, 129.29, 134.2, 136.3, 149.6, 170.4. HRMS (ESI+): Calcd 58% yield (71 mg) and 85% ee. HPLC: (Chiralcel OD-H,
for C14H10O2 [M + H]+ requires 211.0759; found 211.0758.
hexane/i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm):
Ent-2a: Purified by column chromatography (hexane/EtOAc (S) = 9.13 min, (R) = 10.36 min. 1H NMR (400 MHz, CDCl3): δ =
90 : 10) to give the product in 87% yield and 97% ee. [α]D20
6.38 (s, 1H), 7.20–7.24 (m, 2H), 7.32 (d, J = 7.6 Hz, 1H),
=
+43.98 (c 0.98, DCM). HPLC: (Chiralcel OD, hexane/i-PrOH = 7.34–7.38 (m, 2H), 7.58 (t, J = 7.5 Hz 1H), 7.67 (t, J = 7.5 Hz,
85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) = 9.34 min, 1H), 7.96 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ =
(R) = 12.19 min.
81.7, 122.7, 125.4, 125.7, 128.3, 129.1, 129.5, 134.4, 134.8,
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135.2, 149.1, 170.2. HRMS (ESI+): Calcd for C14H9ClO2 (c 0.50, DCM). Melting point = 100–103 °C. Purified by column
[M + H]+: requires 245.0369; found 245.0370.
chromatography (hexane/EtOAc 85 : 15) to give the product in
Ent-2b: Purified by column chromatography (hexane/EtOAc 72% yield (86 mg) and 34% ee. HPLC: (Chiralcel AS-H, hexane/
85 : 15) to give the product in 74% yield (91 mg) and 77% ee. i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) =
[α]2D0 = +40.88 (c 0.56, DCM). HPLC: (Chiralcel OD-H, hexane/ 20.80 min, (R) = 18.37 min. 1H NMR (400 MHz, CDCl3): δ =
i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) = 3.91 (s, 3H), 6.85 (s, 1H), 6.91 (td, J = 7.5 Hz, J = 0.9 Hz, 1H),
8.64 min, (R) = 9.86 min.
6.97 (d, J = 7.6 Hz, 1H), 7.08 (dd, J = 7.6 Hz, J = 1.7 Hz, 1H),
(R)-3-(p-Bromophenyl)isobenzofuran-1(3H)-one C14H9BrO2 7.30–7.34 (m, 1H), 7.44 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.51 (t,
(2f). White solid. Rf = 0.3 (hexane/EtOAc 90 : 10). [α]2D0 = −20.7 J = 7.5 Hz, 1H), 7.61 (td, J = 7.5 Hz, J = 1.1 Hz, 1H), 7.92 (d, J =
(c 0.72, DCM). Melting point = 169–172 °C. Purified by column 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 55.5, 78.0, 110.9,
chromatography (hexane/EtOAc 90 : 10) to give the product in 120.7, 122.8, 124.9, 125.3, 125.5, 126.8, 128.9, 130.0, 134.0,
95% yield (137 mg) and 83% ee. HPLC: (Chiralcel OD-H, 150.3, 156.9, 170.9 pp. HRMS (ESI+): Calcd for C15H12O3
hexane/i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): [M + H]+: requires 241.0865; found 241.0865.
(S) = 9.44 min, (R) = 10.62 min. 1H NMR (400 MHz, CDCl3): δ =
(R)-3-(Naphthalen-1-yl)isobenzofuran-1(3H)-one
C18H12O2
6.37 (s, 1H), 7.17–7.19 (m, 2H), 7.33 (dq, J = 7.7 Hz, J = 0.8 Hz, (2j). White solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]2D0 = +4.46
1H), 7.52–7.54 (m, 2H), 7.57–7.61 (m, 1H), 7.68 (td, J = 7.5 Hz, (c 0.51, DCM). Melting point = 154–157 °C. Purified by column
J = 1.2 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, chromatography (hexane/EtOAc 85 : 15) to give the product in
CDCl3): δ = 81.7, 122.6, 123.3, 125.33, 125.65, 128.5, 129.5, 88% yield (115 mg) and 79% ee. HPLC: (Chiralcel OD-H,
132.0, 134.4, 135.4, 149.0, 170.1. HRMS (ESI+): Calcd for hexane/i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm):
1
C14H979BrO2 [M + H]+: requires 288.9864; found 288.9864; (S) = 15.46 min, (R) = 25.56 min. H NMR (400 MHz, CDCl3):
calcd for C14H981BrO2 [M + H]+: requires 290.9845; found δ = 7.23–7.27 (m, 2H); 7.38 (d, J = 8.1 Hz, 1H); 7.39–7.45 (m,
290.9822.
1H); 7.54–7.68 (m, 4H); 7.87 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0
(R)-3-(p-Methoxyphenyl)isobenzofuran-1(3H)-one C15H12O3 Hz, 1H), 8.1 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H). 13C
(2g). White solid. Rf = 0.4 (hexane/EtOAc 85 : 15). [α]2D0 = +28.5° NMR (100 MHz, CDCl3): δ = 79.6, 122.8, 123.1, 124.4, 125.2,
(c 0.53, DCM). Melting point = 144–147 °C. Purified by column 125.9, 126.0, 126.1, 126.9, 129.0, 131.2, 131.8, 133.9, 134.1,
chromatography (hexane/EtOAc 85 : 15) to give the product in 149.2, 170.5. HRMS (ESI+): Calcd for C18H12O2 [M + H]+
71% yield (85 mg) and 91% ee. HPLC: (Chiralcel OD, hexane/ requires 261.0916; found 261.0918.
i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) =
13.63 min, (R) = 16.58 min. 1H NMR (400 MHz, CDCl3): δ =
(R)-3-(m-(Trifluoromethyl)phenyl)isobenzofuran-1(3H)-one
15H9F3O2 (2k). White solid. Rf = 0.3 (hexane/EtOAc 85 : 15).
C
3.81 (s, 3H); 6.37 (s, 1H); 6.89 (d, J = 8.4 Hz, 2H); 7.17 (d, J = [α]2D0 = −47.4 (c 1.04, EtOAc). Melting point = 98–100 °C.
8.4 Hz, 2H); 7.31 (d, J = 7.6 Hz, 1H); 7.56 (t, J = 7.5 Hz, 1H); Purified by column chromatography (hexane/EtOAc 85 : 15) to
7.64 (t, J = 7.5 Hz, 1H); 7.96 (d, J = 7.6 Hz, 1H) ppm. 13C NMR give the product in 72% yield (100 mg) and 73% ee. HPLC:
(100 MHz, CDCl3): δ = 55.2, 82.6, 114.2, 122.8, 125.3, 125.7, (Chiralcel OD-H, hexane/i-PrOH = 85/15, flow rate = 1.0
128.1, 128.6, 129.1, 134.1, 149.6, 160.3, 170.4. HRMS (ESI+): mL min−1, λ = 254 nm): (S) = 6.73 min, (R) = 8.51 min.
Calcd for C15H12O3 [M + H]+: requires 241.0865; found 1H NMR (400 MHz, CDCl3): δ = 6.45 (s, 1H), 7.35 (dd, J =
241.0862.
7.7 Hz, J = 0.8 Hz, 1H), 7.47–7.55 (m, 2H), 7.58–7.71 (m, 4H), 8.00
Ent-2g: Purified by column chromatography (hexane/EtOAc (d, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 81.5, 122.6,
85 : 15) to give the product in 87% yield (105 mg) and 87% ee. 123.62 (q, 4JC–F = 3.8 Hz), 123.64 (q, JC–F = 271.1 Hz), 125.3, 125.8,
[α]2D0 = −6.76 (c 0.69, DCM). HPLC: (Chiralcel OD, hexane/ 126.0 (q, JC–F = 3.7 Hz), 129.5, 129.7, 130.1, 131.3 (q, JC–F
=
i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm): (S) = 32.6 Hz), 134.5, 137.5, 148.8, 170.0. HRMS (ESI+): Calcd for
12.44 min, (R) = 15.72 min.
C15H9F3O2 [M + H]+: requires 279.0633; found 279.0639.
(R)-3-(m-Methoxyphenyl)isobenzofuran-1(3H)-one C15H12O3
3-(2,4-Difluorophenyl)isobenzofuran-1(3H)-one C14H8F2O2
(2h). Yellow oil. Rf = 0.2 (hexane/EtOAc 85 : 15). [α]D20 = −26.95 (2l). White solid. Rf = 0.3(hexane/EtOAc 85 : 15). [α]2D0 = −15.84
(c 1.52, DCM). Purified by column chromatography (hexane/ (c 0.50, DCM). Melting point = 113–116 °C. Purified by column
EtOAc 85 : 15) to give the product in 80% yield (96 mg) and chromatography (hexane/EtOAc 85 : 15) to give the product in
48% ee. HPLC: (Chiralcel OD-H, hexane/i-PrOH = 85/15, flow 77% yield (95 mg) and 80% ee. HPLC: (Chiralcel OD-H,
rate = 1.0 mL min−1, λ = 254 nm): (S) = 8.13 min, (R) = hexane/i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm):
1
1
8.44 min. H NMR (400 MHz, CDCl3): δ = 3.77 (s, 3H), 6.37 (s, (S) = 7.67 min, (R) = 8.19 min. H NMR (400 MHz, CDCl3): δ =
1H), 6.78–6.80 (m, 1H), 6.87–6.91 (m, 2H), 7.28–7.36 (m, 2H), 6.70 (s, 1H), 6.81–6.96 (m, 2H), 7.11 (td, J = 8.4 Hz, J = 6.3 Hz,
7.53–7.57 (m, 1H), 7.64 (td, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.95 (d, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.69 (td,
J = 7.96 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 55.2, 82.4, J = 7.6 Hz, J = 1.0 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H). 13C NMR
4
112.3, 114.5, 118.9, 122.7, 125.3, 125.4, 129.2, 129.9, 134.2, (100 MHz, CDCl3): δ = 76.1 (d, JC–F = 3.5 Hz), 104.4 (t, J =
2
1
137.8, 149.4, 159.8, 170.4. HRMS (ESI+): Calcd for C15H12O2 25.3 Hz), 111.9 (dd, JC–F = 21.6 Hz, JC–F = 3.7 Hz), 120.0 (d,
[M + H]+: requires 241.0865; found 241.0866.
3JC–F = 13.2 Hz), 122.6 (d, JC–F = 2.0 Hz), 125.4, 125.8, 129.0
3
4
(R)-3-(o-Methoxyphenyl)isobenzofuran-1(3H)-one C15H12O3 (dd, JC–F = 10.0 Hz, JC–F = 4.9 Hz), 129.6, 134.5, 148.8, 160.81
1
3
1
3
(2i). White solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]2D0 = −95.9 (dd, J = 251.1 Hz, J = 12.2 Hz, 163.3 (dd, JC–F = 252.8, JC–F
=
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12.2 Hz), 170.1. HRMS (ESI+): Calcd for C14H8F2O2 [M + H]+
requires 247.0571; found 247.0569.
References
(R)-5-Chloro-3-(p-tolyl)isobenzofuran-1(3H)-one C15H11O2Cl
(3a). White solid. Rf = 0.4 (hexane/EtOAc 85 : 15). [α]2D0 = +71.50
(c 0.40, DCM). Melting point = 139–141 °C. Purified by column
chromatography (hexane/EtOAc 85 : 15) to give the product in
66% yield (85 mg) and 90% ee. HPLC: (Chiralcel OD-H,
hexane/i-PrOH = 85/15, flow rate = 1.0 mL min−1, λ = 254 nm):
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(S) = 10.21 min, (R) = 12.67 min. H NMR (400 MHz, CDCl3):
δ = 2.36 (s, 3H), 6.33 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.20 (d, J =
8.0 Hz, 2H), 7.29–7.31 (m, 1H) 7.52 (dd, J = 8.2 Hz, J = 1.7 Hz,
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(3b). White solid. Rf = 0.4 (hexane/EtOAc 85 : 15). [α]2D0 = −4.07
(c 0.59, DCM). Melting point = 121–124 °C. Purified by column
chromatography (hexane/EtOAc 85 : 15) to give the product in
63% yield (82 mg) and 92% ee. HPLC: (Chiralcel OD-H,
hexane/i-PrOH = 85/15, flow rate = 0.8 mL min−1, λ = 254 nm):
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(S) = 11.36 min, (R) = 14.89 min. H NMR (400 MHz, CDCl3):
δ = 2.35 (s, 3H), 6.35 (s, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.19 (d, J =
8.1 Hz, 2H), 7.26 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 8.2 Hz, J =
1.8 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ = 21.2, 82.6, 124.1, 125.4, 127.0, 127.5, 129.7, 132.7,
134.5, 135.6, 139.6, 147.9, 169.0. HRMS (ESI+): Calcd for
C15H11ClO2: [M + H]+ requires 259.0526; found 259.0527.
[M + H − CH3]+ requires 245.0369; found 245.0371.
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(R)-7-Chloro-3-(p-tolyl)isobenzofuran-1(3H)-one C15H11O2Cl
(3c). White solid. Rf = 0.3 (hexane/EtOAc 85 : 15). [α]D20
=
−109.70 (c 0.85, DCM). Melting point = 97–100 °C. Purified by
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OD-H, hexane/i-PrOH = 85/15, flow rate = 0.8 mL min−1, λ = 12 For selected reviews, see: (a) R. Noyori and M. Kitamura,
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254 nm): (S) = 12.94 min, (R) = 17.22 min. H NMR (400 MHz,
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7.18–7.21 (m, 3H), 7.48 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.7 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ = 21.1, 81.3, 121.3, 122.2,
126.9, 129.6, 130.5, 132.8, 133.0, 135.1, 152.1, 139.5, 167.3.
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+
H]+ requires
259.0526; found 259.0520. [M + H − CH3]+ requires 245.0369;
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
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We are grateful for the financial support provided by agencies
CNPq, CAPES and INCT-Catálise.
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