Synthesis of axially chiral N-hydroxyimides, potential new catalysts for asymmetric oxidations

Full text of DOI:10.1021/jo982527o

4542
J . Org. Chem. 1999, 64, 4542-4546
tions. Several structural requirements of NHPI chiral
Syn th esis of Axia lly Ch ir a l
N-Hyd r oxyim id es, P oten tia l New Ca ta lysts
for Asym m etr ic Oxid a tion s
Cathy Einhorn, J acques Einhorn,*
Ce´line Marcadal-Abbadi, and J ean-Louis Pierre
Laboratoire de Chimie Biomime´tique, LEDSS/ UMR 5616,
Universite´ J . Fourier, 38041 Grenoble, France
analogues may be anticipated for their optimal catalytic
properties: Two previous reports1g,2a briefly indicated that
lower efficiencies were observed when NHPI was replaced
by other N-hydroxyimides such as N-hydroxysuccinimide,
indicating that an N-hydroxyphthalimide subunit should
be desirable. Also, owing to the strong oxidizing proper-
ties of NHPI-type catalysts, no oxidizable substituents,
including aliphatic chains, should be present to avoid self-
oxidation of the catalyst. N-Nydroxyimides 1a and 1b
fulfill both requirements. We have first prepared their
racemic form, by similar reaction sequences, as depicted
in Scheme 1.
Bromo acetal 2 gave acetal alcohols 3a and 3b by
standard procedures. Compounds 3a and 3b were next
transformed into the corresponding isobenzofurans which,
after in situ trapping by dimethylfumarate, furnished the
Diels-Alder adducts 4a and 4b.5 Both 4a and 4b were
isolated as mixtures of diastereomers which were aro-
matized in the presence of methanesulfonic acid, furnish-
ing diesters 5a and 5b. The formation of diacids 6a and
6b , followed by their transformation into N-hydroxy-
imides 1a and 1b, was straightforward. When NHPI was
replaced by racemic 1a or 1b in some representative
oxidation experiments,3 very similar results were ob-
tained as with NHPI itself, indicating that both 1a and
1b have the expected catalytic properties. To obtain 1a
and 1b in their optically active form, resolution of the
corresponding diacids 1a and 1b has been undertaken.
In both cases, one of the diastereomeric salts formed with
brucine crystallized preferentially from acetone. Optically
pure 6a and 6b could thus be obtained readily.6 Optically
pure 6a has been transformed into N-hydroxyimide 1a
by standard procedure without any loss of optical purity.7
When the same transformation was effected with opti-
cally pure 6b, the corresponding N-hydroxyimide 1b has
been obtained with an optical purity of only 80%,8
indicating a lower rotational barrier around the biaryl
axis when compared with the former case. Fortunately,
ee of 1b could be raised to nearly 100% after one
Received December 29, 1998
N-Hydroxyphthalimide (NHPI) has recently been rec-
ognized as a valuable catalyst for the oxidation of various
organic compounds. It was first used by Masui et al. as
an electrochemical oxidation mediator,1 i.e., for the
oxidation of secondary alcohols into ketones,1a of com-
pounds having benzylic or allylic carbons into aryl or R,â-
unsaturated ketones,1b,c of amides or lactams to imides,1d
and of ethers to esters1b or for the oxidative deprotection
of 4-phenyl-1,3-dioxolane protecting groups.1e More re-
cently, various oxidations have been conducted in the
presence of molecular oxygen and NHPI under nonelec-
trochemical conditions. Ishii et al. have used NHPI,
generally in association with transition-metal complexes,
for the aerobic oxidation of various organic substrates at
atmospheric pressure and temperatures in the range 25-
100 °C.2
We have reported the oxidation of organic substrates
by molecular oxygen mediated by NHPI and acetaldehyde
under normal pressure and temperature in the absence
of any transition-metal catalyst.3 Although the mecha-
nisms involved in these reactions are not fully under-
stood, a key intermediate in all NHPI-mediated oxida-
tions appears to be phthalimide N-oxyl, a fairly stable
but highly reactive free radical.1c,f,2c,g,4
Taking into account the unique properties of NHPI as
an oxidation catalyst, it is likely that suitably designed
chiral analogues should be of value for asymmetric
catalysis. We report herein the synthesis of two new
chiral N-hydroxyimides, 1a and 1b, and their first use
as catalysts for a few representative asymmetric oxida-
(1) (a) Masui, M.; Ueshima, T.; Ozaki, S. J Chem. Soc., Chem.
Commun. 1983, 479-480. (b) Masui, M.; Hara, S.; Ueshima, T.;
Kawaguchi, T.; Ozaki, S. Chem. Pharm. Bull. 1983, 31, 4209-4211.
(c) Masui, M.; Hosomi, K.; Tsuchida, K.; Ozaki, S. Chem. Pharm. Bull.
1985, 33, 4798-4802. (d) Masui, M.; Hara, S.; Ozaki, S. Chem. Pharm.
Bull. 1986, 34, 975-979. (e) Masui, M.; Kawaguchi, T.; Ozaki, S. J .
Chem. Soc., Chem. Commun. 1985, 1484-1485. (f) Ueda, C.; Noyama,
M.; Ohmori, H.; Masui, M. Chem. Pharm. Bull. 1987, 35, 1372-1377.
(g) For a general review, see: Masui, M. Stud. Org. Chem. 1987, 30,
137-144.
(2) (a) Ishii, Y.; Nakayama, K.; Takeno, M.; Sakaguchi, S.; Iwahama,
T.; Nishiyama, Y. J . Org. Chem. 1995, 60, 3934-3935. (b) Iwahama,
T.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. Tetrahedron Lett. 1995, 36,
6923-6926. (c) Ishii, Y.; Iwahama, T.; Sakaguchi, S.; Nakayama, K.;
Nishiyama, Y. J . Org. Chem. 1996, 61, 4520-4526. (d) Ishii, Y.; Kato,
S.; Iwahama, T.; Sakaguchi, S. Tetrahedron Lett. 1996, 37, 4993-4996.
(e) Ishii, Y. J . Mol. Catal. A: Chem. 1997, 117, 123-137. (f) Sakaguchi,
S.; Eikawa, M.; Ishii, Y. Tetrahedron Lett. 1997, 37, 7075-7078. (g)
Yoshino, Y.; Hayashi, Y.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J . Org.
Chem. 1997, 62, 6810-6813. (h) Kato, S.; Iwahama, T.; Sakaguchi,
S.; Ishii, Y. J . Org. Chem. 1998, 63, 222-223. (i) Sakaguchi, S.; Takase,
T.; Iwahama, T.; Ishii, Y. Chem. Commun. 1998, 2037-2038. (j)
Iwahama, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 1998, 39, 9059-
9062.
(5) For reviews on the chemistry of isobenzofurans, see: (a) Friedrich-
sen, W. Adv. Heterocycl. Chem. 1980, 26, 135-241. (b) Rodrigo, R.
Tetrahedron 1988, 44, 2093-2135.
(6) Enantiomeric purity of 6a and 6b has been estimated by 1H NMR
at 200 MHz. Mixing racemic 6a with 1 equiv optically pure R-meth-
ylbenzylamine led to an efficient splitting of the sharp singlet at 8.68
ppm. The same effect was observed with 6b on the 8.50 ppm singlet.
Levorotatory diacid 6a , obtained from the crystalline salt formed with
brucine, has been isolated with a 24% yield (theoretical yield 50%); ee
> 99%. [R]20.7D -43.7° (c ) 2, MeOH). Levorotatory diacid 6b has been
obtained with a 45% yield from the crystalline salt formed with brucine;
ee > 99%. [R]21.7D -3.35° (c ) 0.4, MeOH). Dextrorotatoty 6b has been
isolated from the mother liquors; ee ) 97%. [R]21.7 +3.25° (c ) 0.4,
D
MeOH).
(3) Einhorn, C.; Einhorn, J .; Marcadal, C.; Pierre, J . L. Chem.
Commun. 1997, 447-448.
(4) Lemaire, H.; Rassat, A. J . Chem. Phys. 1964, 61, 1580-1588.
(7) Splitting of the OMe singlet at 3.71 ppm was observed in the 1H
NMR spectrum of racemic 1a when 1 equiv of optically pure R-meth-
ylbenzylamine was added.
10.1021/jo982527o CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/15/1999

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4543
Sch em e 1a
Sch em e 2a
Sch em e 3a
Sch em e 4a
recrystallization from ethanol. No loss of optical purity
was observed after storage for several weeks at room
temperature.
With optical pure 1a and 1b in hand, we have at-
tempted to catalyze some asymmetric oxidations. Indane
is readily oxidized into 1-indanone in good yields by
NHPI-mediated oxidations.2a,3 Indanes bearing two dif-
ferent substituents on carbon 2 are interesting substrates
for asymmetric oxidations, as they have two enantiotopic
benzylic carbons (Scheme 2). 2-Methylindane 7a , when
oxidized by molecular oxygen/acetaldehyde3 catalyzed by
optically pure 1a or 1b, gave as expected 2-methylindan-
1-one 8a in good yields but with only negligible asym-
metric inductions (2% and 4% ee).9 Likewise, 2-methoxy-
2-phenylindane 7b gave ketone 8b; in this case, the
difference of induction between catalyst 1a and 1b was
more pronounced: 2% and 8% ee.10 When the same
transformation (7b into 8b) was performed at -20 °C,
ee has been raised to 12% with catalyst 1b. A lower
temperature (-78 °C) led to an exceedingly slow reaction.
As NHPI is able to effect oxidative deprotection of
acetal protecting groups,1e kinetic resolutions could pos-
sibly be observed on chiral racemic acetals with catalysts
1a or 1b. Commercially available racemic 4-phenyl-1,3-
dioxane 9 was therefore submitted to our standard
oxidation conditions using optically pure catalyst 1b
(Scheme 3). At half completion, remaining 9 was isolated,
and its enantiomeric composition determined.11 In this
case, chiral recognition was very low (ee < 2%).
Better results were observed with dioxolanes 10a and
10b (Scheme 4). When oxidation of 10a mediated by 1b
was run to half completion, remaining 10a was isolated
with an ee of 7%.11 With dioxolane 10b, an 8% ee of
remaining 10b was measured with catalyst 1a and 18%
was found with catalyst 1b at half completion.12 We have
also carried out the oxidation of substrate 10b using CuCl
as a cocatalyst in the absence of acetaldehyde.13 Slightly
better results were observed, as catalyst 1a led to 12%
and 1b led to 24% ee (krel ≈ 2) at half completion.
Experiments have been attempted at -20 °C with CuCl
as cocatalyst, but virtually no oxidation has been ob-
served after one week. In all of the cases studied here,
(8) Compound 1b was first transformed into its OMe derivative
(excess diazomethane, see: Santos, P. F.; Lobo, A. M.; Prabhakar, S.
Synth. Commun. 1995, 25, 3509-3518), whose optical purity has been
determined by HPLC on a Chiralpak AD column; elution, cyclohexane/
i-PrOH (1/1), 0.5 mL min-1
.
(9) Determined by polarimetry, by comparison with literature data
for optically pure 8a (see: Meyers, A. I.; Williams, D. R.; Erickson, G.
W.; White, S.; Druelinger, M. J . Am. Chem. Soc. 1981, 103, 3081-
3087).
(11) Enantiomeric composition has been determined by GLC on a
Chiraldex B-PM capillary column, with an oven temperature of 130
°C.
(10) Determined by 1H NMR at 200 MHz, adding increasing
amounts of tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphora-
to]europium (Eu(hfc)3) to a dilute solution of ketone 8b. Splitting of
the OMe singlet was observed for racemic 8b.
(12) Enantiomeric composition has been determined by HPLC on a
Chiralpak AD column; elution, cyclohexane/i-PrOH (1/1), 0.5 mL min-1
.
(13) Einhorn, C.; Einhorn, J .; Marcadal, C.; Pierre, J . L., unpub-
lished results.

4544 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
Si 60 silica gel (0.040-0.063 mm) with the indicated solvent
system. GLC analyses were performed with a flame ionization
detector using a 0.2 mm × 30 m OV 17 capillary column. 1H
NMR spectra were recorded at 200 or 250 MHz. Chemical shifts
are reported in ppm on the δ scale relative to tretramethylsilan
(TMS) as an internal standard. 13C NMR spectra were recorded
at 50 or 62.5 MHz with complete proton decoupling. Chemical
shifts are reported in ppm relative to tetramethylsilan on the δ
scale. Mass spectra were recorded under chemical ionization
using NH3 + isobutane. Melting points have been determined
in unsealed capillary tubes and are uncorrected.
(2-Dim e t h oxym e t h yl-p h e n yl)-(2-m e t h oxy-1-n a p h t h a -
len yl)-m eth a n ol (3a ). To a solution of dimethylacetal of 2-bro-
mobenzaldehyde 2 (1.155 g, 5 mmol) in THF (20 mL) was added
a 2 M solution of n-BuLi in hexanes (2.5 mL, 5 mmol) at -78
°C. The temperature was progressively raised to 0 °C, and the
mixture was stirred at this temperature for 30 min. To this
solution was added 2-methoxy-1-naphthaldehyde (931 mg, 5
mmol) in THF (10 mL). The mixture was stirred for an additional
3 h at room temperature. It was then poured into cold water
(30 mL) and extracted with EtOAc. The organic extract was
washed with brine and dried over Na2SO4. The solvent was
removed under reduced pressure, leaving a slightly yellow solid.
Recrystallization from toluene gave pure 3a (1.52 g, 90%) as
colorless crystals. Mp 136-138 °C. IR (KBr) 3469 cm-1. 1H NMR
(200 MHz, CDCl3) δ 3.42 (s, 3H), 3.51 (s, 3H), 3.93 (s, 3H), 4.76
(d, J ) 8 Hz, 1H), 6.09 (s, 1H), 6.92-8.11 (m, 11H).15 13C NMR
(50 MHz, CDCl3) δ 53.0, 54.2, 56.4, 68.3, 101.5, 113.3, 122.0,
123.7, 124.2, 126.6, 127.0, 127.3, 127.6, 128.4, 128.6, 128.9, 129.4,
132.4, 136.3, 140.5, 155.1.
catalyst 1b exhibits chiral recognition noticeably higher
than that of catalyst 1a .
Although modest, these first results clearly indicate
that asymmetric catalysis mediated by optically active
N-hydroxyimides is possible. How do these catalysts lead
to asymmetric induction? At this stage, a response to this
question is necessarily speculative, as detailed reaction
paths for these oxidations are lacking. A possible ratio-
nalization can be formulated as follows: The active
species of these catalytic processes are most likely imide
N-oxyl radicals obtained by one-electron oxidation of
N-hydroxyimides. The first event of the substrate oxida-
tion is probably benzylic atom abstraction by these highly
reactive radicals. Imide N-oxyl radicals are nitroxydes
and, as so, are π-radicals,14 i.e., the unpaired electron
occupies a molecular orbital whose medium plane is
orthogonal to those of the phthalimide subunit. For
hydrogen atom abstraction, a facial approach of the
substrate can therefore be assumed. In the case of an
axially chiral radical like 11 (derived from 1b if R ) Ph),
the status of each face of the phthalimide subunit is very
different. Substrate approaching from face 1 will be
Dim eth yl 2′-Meth oxy-1,4-ep oxy-1,2,3,4-tetr a h yd r o-[1,1′]-
bin a p h th a len yl-2,3-d ica r boxyla te (4a ). To a suspension of
3a (338 mg, 1 mmol) in 1 mL of toluene was added p-
toluenesulfonic acid monohydrate (5 mg). The solids solubilized
progressively. After complete solubilization, dimethylfumarate
(433 mg, 3 mmol) was added, and the mixture was refluxed
under argon for 3 days. After the mixture cooled, solid Na2CO3
(about 100 mg) was added, and the mixture was stirred for 5
min. The solid was filtered, and the solvent was removed at
reduced pressure. The crude product was purified by column
chromatography (20% EtOAc/hexanes) to give 4a as a 1:3
mixture of diastereomers16 (238 mg, 57%). After several days at
room temperature, the oily residue crystallized partially. Addi-
tion of 2 mL of pentane allowed the isolation of the less abundant
isomer as a white crystalline solid. Mp 74-75 °C. IR (ΚBr) 1750
positionned in a chiral environment induced by stereo-
electronic effects of substituent R, allowing chiral dis-
crimination. Face 2, however, is comparatively unhin-
dered. Substrate approach from this face should therefore
be favored, but with poor chiral discrimination. Following
the preceding hypothesis, global chiral discrimination
capacities of radical 11 should remain modest even with
an optimal choice of substituent R.
In summary, we have prepared two original axially
chiral N-hydroxyimides by a synthetic approach based
on an isobenzofuran Diels-Alder reaction as the key step.
Optically pure N-hydroxyimides, obtained via resolution
of intermediate diacids, have been used as catalysts for
some asymmetric oxidations. Although our catalysts
display only modest chiral discrimination, these prelimi-
nary results are nevertheless promising as they consti-
tute the first examples of asymmetric catalysis by
optically active N-hydroxyimides. We are now investigat-
ing other catalysts, especially axially chiral N-hydroxy-
imides with C2 symmetry, to improve the selectivity and
to extend the scope of this type of oxidation to other
substrates.
cm-1 1H NMR (200 MHz), CDCl3) δ 2.80 (d, J ) 4.8 Hz, 1H),
.
3.60 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H), 4.66 (d, J ) 4.8 Hz, 1H),
5.77 (s, 1H), 6.90-8.90 (m, 10H). The more abundant isomer
has not been obtained in a pure form. Its 1H NMR spectrum
has been deduced from the spectrum of the mixture of isomers:
δ 3.33 (s, 3H), 3.62 (s, 3H), 3.76 (dd, J ) 5.4, 4.8 Hz, 1H), 3.97
(s, 3H), 4.02 (d, J ) 4.8 Hz, 1H), 5.88 (d, J ) 5.5 Hz, 1H), 6.90-
8.90 (m, 10H).
Dim eth yl 2′-Meth oxy-[1,1′]bin a p h th a len yl-2,3-d ica r box-
yla te (5a ). To a solution of Diels-Alder adduct 4a (mixture of
diastereomers) (1.1 g, 2.63 mmol) in 2 mL of CH2Cl2 under argon
was added methanesulfonic acid (341 µL, 5.26 mmol) at 0 °C.
The mixture was stirred at the same temperature for 15 min.
The reaction was quenched by addition of water (2 mL). The
mixture was extracted with CH2Cl2; the organic extract was
washed with saturated NaHCO3 solution and with brine, dried
(Na2SO4), and filtered; and the solvent was removed at reduced
pressure. The remaining solid was recrystallized from ethyl
acetate to give 1.5 g of 5a (100%). Mp 178 °C. IR (ΚBr) 1715
cm-1 1H NMR (200 MHz, CDCl3) δ 3.30 (s, 3H), 3.77 (s, 3H),
.
Exp er im en ta l Section
3.96 (s, 3H), 6.99-8.69 (m, 11H). 13C NMR (50 MHz, CDCl3) δ
51.7, 52.5 56.7, 113.4, 118.9, 123.6, 124.9, 125.3, 126.4, 126.6,
127.5, 127.6, 128.6, 129.1, 129.4, 130.4, 132.2, 132.4, 133.8, 134.1,
134.6, 155.1, 166.4, 168.9. Anal. Calcd for C23H20O5: C, 74.98;
H, 5.04; O, 19.99. Found: C, 74.49; H, 5.11; O, 18.89.
Gen er a l Meth od s. Organometallic reactions were performed
under an oxygen-free atmosphere of argon with exclusion of
moisture from reagents and glassware. The solvents were dried
using standard methods prior to use. Analytical thin-layer
chromatography (TLC) was performed using Merck 60F 254
plates. Visualization of the developed chromatogram was per-
formed by UV absorbance or ethanolic phosphomolybdic acid.
Column chromatography was performed using Merk Geduran
2′-Meth oxy-[1,1′]bin a p h th a len yl-2,3-d ica r boxylic Acid
(6a ). Diester 5a (1.44 g, 3.6 mmol) was dissolved in 50 mL of a
(15) Doublet at 4.76 ppm (J ) 8 Hz) was exchangeable with D2O.
After exchange, a doublet located at 7.12 ppm (J ) 8 Hz) appeared as
a singlet.
(14) Aurich, H. G. In Nitrones, Nitronates and Nitroxides Patai, S.,
Rappoport, Z., Eds; J ohn Wiley & Sons: New York, 1989; p 314.
(16) Determined by 1H NMR of the crude mixture.

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4545
2 M solution of potassium hydroxide in MeOH, and the solution
was refluxed for 24 h. The solution was cooled, and the methanol
was removed under reduced pressure. The remaining solid was
dissolved in water (50 mL). The aqueous solution was made
acidic (pH 1-2) with dilute HCl. The white precipitate that
formed was collected by filtration, washed with water, and dried.
Diacid 6a so obtained (1.34 g, 100%) was analytically pure. Mp
the elution rate of the diastereomers allowed isolation of pure
samples. First eluted diastereomer (most abundant): mp 94 °C.
1H NMR (250 MHz, CDCl3) δ 2.97 (d, J ) 3.8 Hz, 1H), 3.30 (s,
3H), 3.66 (s, 3H), 4.19 (d, J ) 3.8 Hz, 1H), 5.59 (s, 1H), 6.77-
8.06 (m, 13H). Second eluted diastereomer (less abundant): mp
177-178 °C. H NMR (250 MHz, CDCl3) δ 3.36 (d, J ) 4.8 Hz,
1H), 3.42 (s, 3H), 3.53 (s, 3H), 3.61 (dd, J ) 5.1, 4.8 Hz, 1H),
5.46 (d, J ) 5.1 Hz, 1H), 7.09-7.65 (m, 13H).
Dim et h yl 1-(2-P h en yl-p h en yl)-n a p h t h a len e-2,3-d ica r -
boxyla te (5b). The reaction was performed as for the prepara-
tion of 5a . Starting from 4b (mixture of diastereomers) (3.21
g, 7.75 mmol) 5b was obtained as white crystals (2.58 g, 84%)
after recrystallization from ethyl acetate. Mp 150-154 °C. IR
(KBr) 1740 cm-1. 1H NMR (200 MHz, CDCl3) δ 3.64 (s, 3H), 3.90
(s, 3H), 6.92-8.45 (m, 14H). 13C NMR (50 MHz, CDCl3) δ 52.1,
52.5, 124.6, 126.5, 126.9, 127.1, 127.2, 127.5, 128.6, 128.7, 128.9,
129.1, 130.0, 131.9, 133.4, 134.8, 138.3, 140.8, 142.3, 166.5, 169.4.
Anal. Calcd for C26H20O4: C, 78.76; H, 5.09; O, 16.15. Found:
C, 78.91; H, 5.28; O, 15.81.
1
1
274 °C. IR (KBr) 3500, 1702 cm-1. H NMR (200 MHz, Me2SO-
d6) δ 3.70 (s, 3H), 6.84-8.68 (m, 11H). MS (CI, NH3 + isobutane)
m/z 372 (M+, 100%).
2-Hyd r oxy-4-(2-m eth oxy-1-n a p h th a len yl)-ben zo[f]isoin -
d ole-1,3-d ion e (1a ). A solution of diacid 6a (744 mg, 2 mmol)
in acetic anhydride (2 mL) was refluxed for 15 min. The solvent
was removed under reduced pressure. The yellow residue was
dissolved in
3 mL of anhydrous pyridine. Hydroxylamine
hydrochloride (153 mg, 2.2 mmol) was added, and the mixture
was stirred overnight at room temperature under argon and then
for 4 h at 95 °C. The solvent was removed at reduced pressure,
and water (5 mL) was added. The mixture was acidified with
diluted HCl (pH 1-2). The yellow precipitate was collected by
filtration, washed with water, and dried. Crystallization from
ethanol gave 1a as a yellow powder (487 mg, 66%). Mp 250-
1-(2-P h en yl-p h en yl)-n a p h th a len e-2,3-d ica r boxylic Acid
(6b). Saponification of 5b (396 mg, 1 mmol) was performed with
15 mL of a 10 M solution of KOH in MeOH, at reflux for 24 h.
Workup as described for the preparation of 6a gave 327 mg (89%)
of diacid 6b as a white powder. Mp 174-179 °C. IR (KBr) 3500,
251 °C. IR (KBr) 3300, 1783, 1721 cm-1 1H NMR (200 MHz,
.
Me2SO-d6) δ 3.71 (s, 3H), 6.85-8.58 (m, 11H), 10.79 (s, 1H). 13
C
NMR (50 MHz, Me2SO-d6) δ 56.2, 113.7, 116.3, 122.9, 123.5,
1690 cm-1
H).
.
1H NMR (200 MHz, Me2SO-d6) δ 6.94-8.51 (m, 14
123.8, 124.3, 125.1, 126.9, 127.2, 128.2, 128.4, 129.1, 129.5, 130.5,
132.9, 134.1, 135.1, 136.2, 154.4, 162.8, 163.3. MS (CI, NH3
+
isobutane) m/z 387 (MH+ + NH3, 100%). Anal. Calcd for C23H15
-
2-Hyd r oxy-4-(2-p h en yl-p h en yl)-ben zo[f]isoin d ole-1,3-d i-
on e (1b). General procedure applied for the synthesis of 1a was
used, starting from diacid 6b (552 mg, 1.5 mmol) and leading
to 307 mg (56%) of 1b after recrystallization from ethanol. Mp
NO4: C, 74.78; H, 4.10; N, 3.79; O, 17.33. Found: C, 74.20; H,
3.97; N, 3.71; O, 17.12.
Resolu tion of Dia cid 6a . Anhydrous brucine (394 mg, 1
mmol) was dissolved in 11 mL of acetone at reflux. A solution
of racemic diacid 6a (372 mg, 1 mmol) in 3 mL of acetone was
added. After cooling, the mixture was left in the refrigerator (4
°C) overnight. The solid that formed was collected by filtration
and air-dried, giving 490 mg of white crystals. They were
redissolved in a mixture of 12 mL of MeOH and 10 mL of acetone
at reflux. After the mixture stood overnight in the freezer (-18
°C), a crystalline solid was formed which was collected by
filtration and air-dried, giving 224 mg of white crystals. They
were added to a mixture of 5 mL of EtOAc and 5 mL of 2 N
HCl. After complete dissolution of the solid, the organic phase
was separated, washed twice with brine, dried over Na2SO4, and
filtered. Removal of the solvent left 91 mg of levorotatory diacid
227 °C. IR (KBr) 3200, 1780, 1715 cm-1 1H NMR (200 MHz,
.
Me2SO-d6) δ 7.34-8.39 (m, 14H); 10.86 (s, 1H). 13C NMR (50
MHz, Me2SO-d6) δ 121.8, 123.9, 124.4, 126.8, 127.2, 127.7, 128.4,
128.9, 129.4, 129.7, 130.6, 132.9, 134.6, 138.5, 140.5, 141.4. MS
(DCI, NH3 + isobutane) m/z 366 (MH+, 100%). Anal. Calcd for
C
24H15NO3: C, 78.88; H, 4.14; N, 3.84; O, 13.14. Found: C, 78.98;
H, 4.20; N, 3.54; O, 13.28.
Resolu tion of Dia cid 6b. Anhydrous brucine (1,183 g, 3
mmol) was dissolved in 33 mL of acetone at reflux. A solution
of 1.1 g (3 mmol) of racemic diacid 6b was added. Solvent was
removed at reduced pressure, leaving a partially crystallized
yellow residue. A 20 mL portion of MeOH was added, and the
mixture was refluxed for 10 min and then cooled at room
temperature. The solid was collected by filtration, washed with
MeOH, and air-dried, providing 1.00 g of white cristalline solid.
It was added to a mixture of 20 mL of EtOAc and 20 mL of 2N
HCl. After complete dissolution of the solid, the organic phase
was separated, washed twice with brine, dried over Na2SO4, and
filtered. Removal of the solvent under reduced pressure left 497
mg of levorotatory diacid 6b (45%, theoretical yield 50%). ee >
6a (24%, theoretical yield 50%). ee > 99%.6 [R]20.7 -43.7° (c )
D
2, MeOH).
Op tica lly Active N-Hyd r oxyim id e 1a . General procedure
applied for the synthesis of racemic 1a was used starting with
optically pure levorotatory diacid 6a . Dextrorotatory 1a was
obtained as a yellow powder. ee > 99%.7 Mp 259 °C. [R]21.4
+88.3° (c ) 0.2, THF).
D
(2-Dim eth oxym eth yl-p h en yl)-(2-p h en yl-p h en yl)-m eth a -
n ol (3b). The reaction was performed as for the preparation of
3a , replacing 2-methoxy-1-naphthaldehyde by biphenyl-2-car-
boxaldehyde (1.285 g, 40 mmol). Workup gives 9.85 g of 3b (74%)
as white crystals after recrystallization from toluene. Mp 110-
99%.6 Mp 138 °C. [R]21.7 -3.35° (c ) 0.4, MeOH). The filtrate
D
was concentrated at reduced pressure and treated as above,
giving 515 mg of dextrorotatory diacid 6b (47%). ee ) 97%.6 Mp
137 °C. [R]21.7 +3.25° (c ) 0.4, MeOH).
D
Op tica lly Active N-Hyd r oxyim id e 1b. General procedure
applied for the synthesis of 1a was used, starting with optically
active diacid 6b. Dextrorotatory 6b (ee ) 97%) gave levorotatory
1
112 °C. IR (KBr) 3600 cm-1. H NMR (250 MHz, CDCl3) δ 3.08
(s, 3H), 3.20 (s, 3H), 3.22 (d, J ) 2.9 Hz, 1H), 4.92 (s, 1H), 6.08
(d, J ) 2.9 Hz, 1H), 7.01-7.81(m, 13H).17 13C NMR (62.5 MHz,
CDCl3) δ 52.4, 54.8, 68.6, 101.9, 126.4, 126.8, 127.1, 127.4, 127.7,
128.2, 128.7, 129.1, 129.8, 135.0, 139.5, 140.9, 142.0.
1b, ee ) 80%.8 Mp 235 °C. [R]21.3 -11.6° (c ) 0.2, THF); 338
D
mg of this sample of 1b was recrystallized from 2.5 mL of
ethanol, giving 245 mg of 1b, ee >99%. Mp 251 °C. [R]20.9D -14.9°
(c ) 0.2, THF).
Dim eth yl 1-(2-P h en yl-p h en yl)-1,4-ep oxy-1,2,3,4-tetr a h y-
d r on a p h th a len e-2,3-d ica r boxyla te (4b). To a suspension of
3b (6.68 g, 20 mmol) in 20 mL of xylenes was added p-
toluenesulfonic acid monohydrate (50 mg). After complete solu-
bilization, dimethyl fumarate (8.64 g, 60 mmol) was added, and
the mixture was refluxed under argon for 4 days. After the
mixture cooled, solid Na2CO3 (about 200 mg) was added, and
the mixture was stirred for 5 min. The solid was filtered, and
the solvent was removed at reduced pressure. The crude product
contains Diels-Alder adduct 4b as 9:1 mixture of diastereo-
mers.16 Column chromatography (10% EtOAc/hexanes) allows
isolation of globally 5.25 g (63%) of 4b. Slight differences between
Gen er a l P r oced u r es of N-Hyd r oxyim id es-Med ia ted Oxi-
d a tion s. (1) In th e P r esen ce of Aceta ld eh yd e.3 To 1 mmol
of substrate dissolved in 3 mL of anhydrous acetonitrile was
added 0.1 mmol of N-hydroxyimide. The mixture was vigorously
stirred under an oxygen atmosphere while a solution of 56 µL
(1 mmol) of acetaldehyde in 3 mL of anhydrous acetonitrile was
added via a syringe pump over 5 h. Progress of the reaction was
followed by TLC and/or GLC.
(2) In th e P r esen ce of Cu Cl. To a solution of 1 mmol of
substrate dissolved in 5 mL of anhydrous acetonitrile were added
0.1 mmol of N-hydroxyimide and 0.1 mmol of CuCl. The mixture
was vigorously stirred under an oxygen atmosphere, and progress
of the reaction was followed by TLC and/or GLC.
(17) Doublet at 3.22 ppm (J ) 2.9 Hz) was exchangeable with D2O.
After exchange, doublet at 6.08 ppm (J ) 2.9 Hz) appeared as a singlet.

4546 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
Su bstr a tes for Asym m etr ic Oxid a tion s. 2-Meth ylin d a n e
(7a ). Prepared according to literature procedure.18
dimethyl acetal (2.28 g, 10 mmol) and 1-phenyl-1,2-ethanediol
(1.38 g, 10 mmol) were dissolved in 100 mL of toluene. After
addition of a catalytic amount of p-toluenesulfonic acid mono-
hydrate, the mixture was refluxed for 1 h. After cooling at room
temperature, the solution was washed with a saturated solution
of NaHCO3 and dried over Na2SO4. The solvent was removed
under reduced pressure, and the solid residue was recrystallized
from hexanes, giving 2.42 g (80%) of 10b as colorless crystals.
2-Meth oxy-2-p h en ylin d a n e (7b). A commercial 35 wt %
dispersion in oil of potassium hydride (1.6 g, 14 mmol) was
washed twice with anhydrous pentane, and 14 mL of anhydrous
THF was added. While the mixture stirred under argon, a
solution of 2-phenylindan-2-ol19 (2.51 g, 12 mmol) in 24 mL of
THF was added dropwise, and the temperature of the reaction
medium was maintained below 20 °C. After the end of hydrogen
evolution, a solution of iodomethane (0.82 mL, 13.2 mmol) in
14 mL of THF was added dropwise. The mixture was stirred for
6 h at room temperature. It was quenched with 5 mL of MeOH
followed by 50 mL of water and extracted with ether. The organic
extract was washed with brine and dried over Na2SO4. The
solvents were removed under reduced pressure. The crude
product was purified by column chromatography (5% EtOAc/
hexanes), giving 1.72 g of 7b (64%) as a colorless liquid. IR (neat)
Mp 98 °C. IR (KBr) 1453 cm-1 1H NMR (200 MHz, CDCl3) δ
.
3.85-3.93 (m, 1H), 4.32-4.40 (m, 1H), 5.08-5.16 (m, 1H), 7.28-
7.63 (m, 15H). 13C NMR (50 MHz, CDCl3) δ 72.2, 78.5, 110.4,
126.2, 126.6, 128.1, 128.2, 128.6, 138.8, 142.4, 142.6.
Oxid a tion P r od u cts. 2-Meth ylin d a n -1-on e (8a ). Identified
by comparison with literature data.9
2-Meth oxy-2-p h en ylin d a n -1-on e (8b). After completion of
the oxidation of 7b (method 1 or 2), the solvent was removed at
reduced pressure. The residue was purified by column chroma-
tography (10% EtOAc/hexanes), and 8b was isolated as a
1480 cm-1 1H NMR (250 MHz, CDCl3) δ 3.08 (s, 3H), 3.23-
.
3.54 (m, 4H), 7.10-7.68 (m, 9H). 13C NMR (62.5 MHz, CDCl3) δ
44.1, 51.6, 89.7, 124.4, 126.6, 127.3, 128.3, 141.0, 143.0.
2-Dim eth yl-4-p h en yl-1,3-d ioxola n e (10a ). Prepared ac-
cording to literature procedure.20
colorless oil. IR (neat) 1739, 1450 cm-1 1H NMR (250 MHz,
.
CDCl3) δ 3.34 (s, 3H), 3.59 (s, 2H), 7.23-7.69 (m, 9H). 13C NMR
(62.5 MHz, CDCl3) 40.5, 52.8, 86.3, 125.2, 126.0, 126.4, 127.5,
127.8, 128.1, 128.6, 130.0, 134.1, 134.7, 138.4, 150.8, 202.4.
2,2-Dip h en yl-4-p h en yl-1,3-d ioxola n e (10b). Benzophenone
J O982527O
(18) Adamczyk, M.; Watt, D. S. J . Org. Chem. 1984, 49, 4226-4237.
(19) Greifenstein, L. G.; Lambert, J . B.; Nienhuis, R. J ., Fried, H.
E.; Pagani, G. A. J . Org. Chem. 1981, 46, 5125-5132.
(20) Hanzlik, R. P.; Leinwetter, M. J . Org. Chem. 1978, 43, 438-
440.