DAST-mediated preparation of N-substituted 3-alkoxyisoindolinones

Article abstract of DOI:10.24820/ark.5550190.p010.809

3-Alkoxy-2-phenylethylisoindolinones are conveniently prepared by reacting the corresponding hydroxylactams with diethylaminosulfur trifluoride (DAST) in the presence of a range of alcohols. The DAST-mediated reaction did not result in any reactant fluori

Full text of DOI:10.24820/ark.5550190.p010.809

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Arkivoc 2019, part v, 0-0
DAST-mediated preparation of N-substituted 3-alkoxyisoindolinones
Jarrid M. Ronnebaum and Frederick A. Luzzio*
Department of Chemistry, University of Louisville, 2320 South Brook St., Louisville, KY 40292, USA
Email: faluzz01@louisville.edu
Dedicated to Professor E. J. Corey on the occasion of his 90th birthday
Received 11-10-2019
Accepted 05-21-2019
Published on line 06-02-2019
Abstract
3-Alkoxy-2-phenylethylisoindolinones are conveniently prepared by reacting the corresponding hydroxylactams
with diethylaminosulfur trifluoride (DAST) in the presence of a range of alcohols. The DAST-mediated reaction
did not result in any reactant fluorination but smooth installation of the alkoxy group derived from the reactant
alcohol on the benzylic position of the heterocycle. The central starting hydroxylactam substrate was prepared
from the corresponding chiral phthalimide, 2-((S)-1-phenylethyl)-isoindoline-1,3-dione, by selective reduction
using either aluminum amalgam or sodium borohydride. The resultant diasteriomeric mixture of
hydroxylactams were used in the DAST alkoxylation reaction and were compared with a more conventional
method of alkoxylation using the protic acid camphorsulfonic acid.
O
O
DAST/DCM
ROH
N
N
H
H
OH
OR
71-91%
Keywords: DAST, imides, iminium ions, isoindolinones
DOI: https://doi.org/10.24820/ark.5550190.p010.809
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1. Introduction
Isoindolinones form a central heterocyclic scaffold in natural products and medicinal chemistry. A number of
compounds bearing the isoindolinone core are of interest as antivirals,1 inhibitors of protein-protein
interaction,2,3 muscarinic receptor ligands,4 cytotoxins and cytostatic agents.5 Substitution on the isoindolinone
core, both heteroatom and carbon, may take the form of bonds to the aromatic ring, the heterocyclic nitrogen
and the benzylic positions. During the course of our studies of substituted isoindolinones as chiral auxiliaries,
we examined methods of mild bond formation to the benzylic position of N-substituted isoindolinones.
Normally, nucleophiles such as alcohols or thiols work very well when used in conjunction with a method which
generates the corresponding acyliminium ions from the corresponding hydroxylactams.6-10 In turn,
hydroxylactams are easily accessed by selective reduction of the corresponding phthalimides with sodium
borohydride, diisobutylaluminum hydride or aluminum amalgam.11 Given the usual starting materials, which
comprise both hydroxylactams and alcohols, the formation of the corresponding alkoxylactams can be
accomplished through the agency of acid or metal catalysts.12-15 While they are harsh and often involve the
release of acid, halogenating agents such as thionyl chloride also work well to facilitate the formation of
alkoxyisoindolinones from hydroxylactams.2,3 Diethylaminosulfur trifluoride (DAST) is a mild fluorinating agent
which can be used to prepare a distinct array of fluorinated analogues of natural products and medicinal
compounds from the corresponding alcohols. While the preparation of the monofluorides and gem-difluorides
using DAST has been well-documented, the preparation of ethers with this reagent has been also explored and
is the topic of several early reports.16-18 Inasmuch as ether formation from alcohols using DAST is most notably
a consequence of mechanistic variation, the diversion of pathway may be preponderant with some substrates
over others. For example, with the use of DAST and some highly reactive substrates such as allylic or benzylic
alcohols, fluorination of the alcohols may preclude ether formation. We report herein that hydroxylactam 1
used in conjunction with simple alcohols and DAST leads to the corresponding alkoxylactams
(alkoxyisoindolinones) 3-13 (Scheme 1) in good to excellent yields.
Scheme 1. DAST-mediated alkoxylation of hydroxylactam 1.
The yields are comparable to or greater than those which utilize the very commonly-used p-toluenesulfonic
acid or camphorsulfonic acids, however the reaction does afford diastereomeric mixtures of the corresponding
3-alkoxyisoindolinones. The product distribution of the alkoxylation reaction is not surprising given that the
benzylic position which is occupied by the hydroxyl group offers unique reactivity toward the reagent in
preference to the substrate alcohols.
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Results and Discussion
Phthaloylation of the chiral amine (S)-(-)--methylbenzylamine ([]D -39°, neat)19,20 with phthalic anhydride
followed by reduction of the resultant chiral phthalimide 2 with sodium borohydride gave the substrate
hydroxylactam 1 as a diastereomeric mixture (Scheme 2). While the hydroxylactam mixture could be separated
by crystallization, the mixture was used directly in the alkoxylation reaction.7 The alkoxylation entails addition
of DAST to a room-temperature solution of the hydroxylactam 1 (CH2Cl2), followed by stirring (16 h), then
addition of the reactant alcohol followed by stirring (4-8 h). All alkoxylated products were easily purified by flash
column chromatography on silica gel, whereby the ratios of diastereomers ranged from 55/45 to 65/35 as
determined by 1H NMR (Table 1). Although no diastereoselectivity was preferred, the highest ratio (80:20) was
derived from using 2,2,2-trichloroethanol as a reactant (See Entry 6, Table 1).
Scheme 2. Reduction of phthalimide 2 to hydroxylactam 1.
Table 1. Reaction of selected alcohols with hydroxylactam 1
Entry Substrate alcohol (ROH)/Equivalents Ratioa Compound/Yield (%)b
1
2
3
4
5
6
7
8
9
2-propanol/10
cyclopentanol/10
phenylmethanol/5
2-phenylethanol/5
(4-methoxyphenyl)methanol/5
2,2,2-trichloroethanol/5
2-propene-1-ol/5
60:40
60:40
55:45
65:35
55:45
80:20
65:35
65:35
65:35
60:40
65:35
3/89
4/88
5/80
6/91
7/60
8/85
9/71
10/77
11/83
12/79
13/71
1,4-butanediol/5
2,2-dimethyl-1-propanediol/5
Anthracen-9-ylmethanol/5
(2-bromophenyl)methanol/5
10
11
aRatios were determined by 1H NMR
bYields are for chromatographically pure products.
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For comparison, a subset of reactions using selected substrate alcohols and catalyzed by camphorsulfonic
acid (CSA), were performed with the hydroxylactam 1 and 1,4-butanediol, 2,2-dimethyl-1,3-propanediol and
anthracenylmethanol thereby affording products 10, 11 and 12 respectively after chromatographic purification
(Table 2, Entries 1,2,3). While acid-mediated alkoxylation of the isoindolinone core may occur through the
accepted acyliminium ion mechanism (Scheme 2), the DAST-mediated reaction may progress through the same
intermediate (A) which is enhanced by the benzylic position of the isoindolinone (Scheme 2).
Table 2. Reaction of selected alcohols with hydroxylactam 1 mediated by CSA
Entry Substrate alcohol (ROH)/Equivalents Ratioa Compound/Yield (%)b
1
2
3
1,4-butanediol/5
2,2-dimethyl-1-propanediol/5
anthracen-9-ylmethanol/5
65:35
65:35
60:40
10/80
11/75
12/75
aRatios were determined by 1H NMR
bYields are for chromatographically pure products.
With secondary alcohol substrates, fluorination by DAST gives the corresponding fluorinated compounds
with inversion of configuration, quite possibly through displacement of intermediate B.21,22 Consequently, one
may argue that if intermediate B did indeed exist in the alkoxylation reaction, a high diastereomeric ratio of
alkoxyisoindolinones may result, so it is highly likely that the reaction proceeds through intermediate A.
Scheme 3. Mechanistic pathways of DAST-mediated alkoxylation.
In theory, one may presume that the inverse sequence whereby the alkoxide of a typical hydroxylactam
followed by addition of an alkyl halide will give the desired alkoxyisoindolinones. As reported earlier by other
groups, the diastereomeric hydroxylactams 1 could be separated by crystallization after reduction of 2, and the
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separated diastereomers have been used in several reactions to explore diastereoselectivity.7 However,
generation of the alkoxide of 1 (NaH/THF) from diastereomerically pure 1, followed by addition of benzyl
bromide did not provide the desired benzyloxyisoindolinone, but only an epimeric mixture of hydroxylactams.
Presumably, formation of the alkoxide resulted in opening to the corresponding aldamide, which then
equlibrates on closing, resulting in epimerization.
Conclusions
We have detailed an efficient route to 3-alkoxyisoindolinones from hydroxylactams and alcohols which does not
require the use of acid but utilizes the mediation of the reactive fluorinating reagent DAST. The alkoxylation
proceeds by means of an acyliminium ion intermediate which is attacked by the reactant alcohol to yield the
product. Despite the fact that the substrate bears a chiral group derived from -phenethylamine,
diastereomeric mixtures result from the reaction.
Experimental Section
General. Solvents and reagents are ACS grade and were used as commercially supplied. Analytical thin-layer
chromatography (TLC) utilized 0.25 mm pre-cut glass-backed plates (Merck, Silica Gel 60 F254). Thin-layer
chromatograms were visualized during chromatographic and extraction runs by rapidly dipping the plates in
anisaldehyde/ethanol/sulfuric acid stain or phosphomolybdic acid/ethanol stain and heating (hot plate).
Gravity-column chromatography was carried out using silica gel 60 (E. Merck 7734, 70-230 mesh). Nuclear
magnetic resonance (1H and l3C NMR) spectra were recorded with Varian VNMRS 400 or 500 MHz instruments
using CDCl3 as a solvent and TMS as internal standard. Infrared spectra (FTIR) were recorded with a Perkin-Elmer
Spectrum 100 instrument and spectral values are reported as cm-1. High resolution mass spectrometry (HRMS)
were performed by the Indiana University Mass Spectrometry Facility, Bloomington, Indiana.
General procedure for synthesis of 3-alkoxy-2-((S)-1-phenylethyl)isoindolin-1-ones (3-13). 3-Hydroxy-2-((S)-1-
phenylethyl)isoindolin-1-one 1 (150 mg, 0.592 mmol, Entries 1-3, Table 1) or (100 mg, 0.395 mmol, (Entries 4-
11, Table 1) was dissolved in dichloromethane (3.0 mL) under an inert atmosphere (N2) while stirring followed
by the addition diethylaminosulfur trifluoride (DAST, 240 L, 1.776 mmol, 3 eq). Stirring was continued
overnight (16 hr) and the alcohol (10 or 5 eq) was added and stirring was continued until the reaction was
complete as indicated by TLC (4-8 hr). The crude reaction mixture was directly submitted to gravity-column
chromatography and the entire series of products were eluted with hexane/ethyl acetate, 4:1. Combination and
concentration of the individual fractions gave the pure products detailed in Table 1.
General procedure for synthesis of 3-alkoxy-2-((S)-phenylethyl)isoindolin-1-ones (10-12). 3-Hydroxy-2-((S)-1-
phenylethyl)isoindolin-1-one 1 (100 mg, 0.395 mmol, Entries 1-3, Table 2) was dissolved in dichloromethane
(3.0 mL) with alcohol (1.2 eq) in the presence of camphorsulfonic acid (20% eq). Stirring was continued overnight
(4-6 hr) until the reaction was complete as indicated by TLC (4-8 hr). The crude reaction mixture was directly
submitted to gravity-column chromatography and the entire series of products were eluted with hexane/ethyl
acetate, 4:1. Combination and concentration of the individual fractions gave the pure products detailed in Table
2.
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3-Isopropoxy-2-((S)-1-phenylethyl)isoindolin-1-one (3). Colorless oil (158 mg, 89%); Rf = 0.44 (hexane/ethyl
acetate, 4:1); IR 3029, 2976, 2927, 2886, 1702 cm -1 . 1H NMR (500 MHz, CDCl3, major)  7.81-7.84 (m, 1H), 7.25-
7.55 (m, 8H), 5.68 (q, J 7.0 Hz, 1H), 5.53 (s, 1H), 3.66-3.70 (m, 1H), 1.83 (d, J 6.5 Hz, 3H), 1.18 (d, J 6.0 Hz, 3H),
1.05 (d, J 6.0 Hz, 3H). H1 NMR (500 MHz, CDCl3, minor)  7.81-7.84 (m, 1H), 7.25-7.55 (m, 8H), 5.76 (s, 1H), 5.15
13
(q, J 7.0 Hz, 1H), 3.66-3.70 (m, 1H), 1.98 (d, J 7.5 Hz, 3H), 1.15 (d, J 6.5 Hz, 3H), 0.92 (d, J 6.5 Hz, 3H). C NMR
(125 MHz, CDCl3)  168.0, 127.7, 143.0, 142.3, 140.5, 132.9, 132.1, 131.9, 131.8, 129.7, 129.5, 128.5, 128.4,
128.2, 127.5, 127.2, 126.6, 123.5, 123.4, 123.3, 85.9 (major), 85.6 (minor), 69.4, 68.7, 52.0, 50.2, 23.9, 23.7, 23.2,
3.0, 18.9, 18.9. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C19H21O2NNa 318.1465, Found: 318.1468.
3-(Cyclopentyloxy)-2-((S)-1-phenylethyl)isoindolin-1-one (4). Colorless oil (167 mg, 88%); Rf = 0.48
(hexane/ethyl acetate, 4:1); IR 3030, 2999, 2959, 2871, 1697 cm -1. 1HNMR (500 MHz, CDCl3, major)  7.81-7.84
(m, 1H), 7.25-7.55 (m, 8H), 5.68 (q, J 7.5 Hz, 1H), 5.54 (s, 1H), 3.91-3.93 (m, 1H), 1.81 (d, J 7.0 Hz, 3H), 1.31-1.74
(m, 8H). 1H NMR (500 MHz, CDCl3, minor)  7.81-7.84 (m, 1H), 7.25-7.55 (m, 8H), 5.81 (s, 1H), 5.17 (q, J 7.0 Hz,
1H), 3.78-3.80 (m, 1H), 1.96 (d, J 7.0 Hz, 3H) 1.31-1.74 (m, 8H). 13C NMR (125 MHz, CDCl3)  168.1, 167.8, 142.6,
142.2, 140.5, 132.9, 132.3, 131.7, 129.7, 129.6, 128.6, 128.4, 127.7, 127.6, 127.3, 127.2, 126.6, 123.8, 123.8,
123.5, 123.3, 86.0 (major), 85.8 (minor), 51.7, 50.3, 33.7, 33.5, 33.4, 33.3, 23.6, 23.4, 23.2, 18.7, 18.3. HRMS
(FTMS + p ESI) m/z [M + Na]+; calculated for C21H23O2NNa 344.1621, Found 344.1624.
3-(Benzyloxy)-2-((S)-1-phenylethyl)isoindolin-1-one (5). Colorless oil (108 mg, 80%); Rf = 0.47 (hexane/ethyl
acetate, 4:1) IR 3031, 2928, 2886, 2875, 1698 cm -1. 1H NMR (500 MHz, CDCl3, major)  7.88-7.89 (m, 1H), 7.21-
7.60 (m, 12H), 6.92-6.94 (m, 1H), 5.79 (s, 1H), 5.73 (q, J 7.0 Hz, 1H), 4.32 (d, J 11.0 Hz, 1H), 3.97 (d, J 11.0 Hz, 1H),
1.84 (d, J 7.0 Hz, 3H). 1H NMR (500 MHz, CDCl3, minor)  7.88-7.89 (m, 1H), 7.21-7.60 (m, 12H), 6.92-6.94 (m,
1H), 6.19 (s, 1H), 5.47 (q, J 7.5 Hz, 1H), 3.73 (d, J 11.0 Hz, 1H), 3.62 (d, J 11.0 Hz, 1H), 1.91 (d, J 7.0 Hz, 3H). 13C
NMR (125 MHz, CDCl3)  167.8, 141.7, 141.0, 140.7, 140.3, 137.4, 137.2, 133.1, 132.6, 132.1, 130.0, 129.9, 128.7,
128.4, 127.8, 127.7, 127.6, 127.5, 123.7, 123.6, 123.4, 110.0, 85.8 (major), 85.6 (minor), 64.1, 63.9, 50.7, 50.6,
18.1, 17.5. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C23H21O2NNa 366.1465, Found 366.1469.
3-Phenethoxy-2-((S)-1-phenylethyl)isoindolin-1-one (6). Colorless oil (193 mg, 91%); Rf = 0.67 (hexane/ethyl
acetate, 4:1); IR 3066, 3028, 2937, 2875, 1698 cm -1. 1H NMR (500 MHz, CDCl3, major)  7.81-7.82 (m, 1H), 7.11-
7.59 (m, 12H), 6.94 (d, J 8.0 Hz, 1H), 5.64 (q, J 7.0 Hz, 1H), 5.61 (s, 1H) 3.47 (dd, J 16.0, 7.0 Hz, 1H), 3.09 (dd, J
16.0, 7.0 Hz, 1H), 2.79-2.88 (m, 2H), 1.72 (d, J 7.5 Hz, 3H). 1H NMR (500 MHz, CDCl3, minor)  7.81-7.82 (m, 1H),
7.11-7.59 (m, 13H), 6.03 (s, 1H), 5.35 (q, J 7.5 Hz, 1H), 2,79-2.88 (m, 2H) 2.40-2.46 (m, 1H), 2.28-2.32(m, 1H),
1.85 (d, J 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3)  167.7, 141.0, 140,4 138.40, 132.6, 131.9, 129.8, 129.7, 129.0,
128.9, 128.6, 128.4, 128.2, 127.8, 127.7, 127.6, 127.4, 126.4, 126.3, 123.6, 123.5, 123.2, 85.7 (major), 85.3
(minor), 62.9, 62.5, 50.7, 50.3, 26.1, 25.5, 17.9, 17.4. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for
C24H23O2NNa 380.1621, Found 380.1624.
3-((4-Methoxybenzyl)oxy)-2-((S)-1-phenylethyl)isoindolin-1-one (7). Colorless oil (88 mg, 60%); Rf = 0.37
(hexane/ethyl acetate, 4:1). IR 3063, 2989, 2941, 2843, 1702 cm -1. 1HNMR (500 MHz, CDCl3, major)  7.87-7.88
(m, 1H), 7.14-7.60 (m, 8H), 6.77-6.83 (m, 3H), 6.50-6.53 (m, 1H), 5.79 (s, 1H) 5.73 (q, J 8.0 Hz, 1H), 4.29 (d, J 11.5
Hz, 1H), 3.95 (d, J 11.5 Hz, 1H), 3.81 (s, 3H), 1.84 (d, J 7.0 Hz, 3H). 1H NMR (500 MHz, CDCl3, minor)  7.87-7.88
(m, 1H), 7.14-7.60 (m, 8H), 6.77-6.83 (m, 3H), 6.50-6.53 (m, 1H), 6.19 (s, 1H), 5.47 (q, J 7.0 Hz, 1H), 3.77 (s, 3H),
3.69 (d, J 11.0 Hz, 1H), 3.57 (d, J 11.0 Hz, 1H), 1.91 (d, J 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3)  167.5, 159.7,
141.7, 141.0, 140.7, 140.3, 139.0, 138.8, 133.1, 132.6, 132.1 123.0, 129.5, 129.2, 128.7, 128.4, 127.8, 127.7,
127.5, 123.7, 123.6, 123.4, 120.0, 119.8, 113.2, 113.1, 113.0, 85.8 (major), 85.6 (minor), 63.9, 63.8, 55.2, 30.7,
18.1, 17.5. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C24H23O3NNa 396.1570, Found 396.1573.
2-((S)-1-Phenylethyl)-3-(2,2,2-trichloroethoxy)isoindolin-1-one (8). Colorless oil (129 mg, 85%); Rf = 0.47
(hexane/ethyl acetate, 2:1) IR 3046, 3035, 2980, 2936, 1677 cm -1. 1H NMR (500 MHz, CDCl3, major)  7.87-7.88
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(m, 1H), 7.27-7.62 (m, 8H), 5.88 (s, 1H), 5.72 (q, J 7.5 Hz, 1H), 3.94 (d, J 10.5 Hz, 1H), 3.44 (d, J 10.5 Hz, 1H), 1.89
(d, J 7.0 Hz, 3H). 1H NMR (500 MHz, CDCl3, minor)  7.87-7.88 (m, 1H), 7.27-7.62 (m, 8H), 6.24 (s, 1H), 5.48 (q, J
13
7.5 Hz, 1H), 3.18 (d, J 10.5 Hz, 1H), 3.08 (d, J 10.5 Hz, 1H), 1.93 (d, J 7.0 Hz, 3H). C NMR (125 MHz, CDCl3) 
167.6, 141.1, 139.9, 139.5, 139.1, 132.9, 132.7, 132.5 130.6, 130.5, 128.8, 128.7, 128.0, 127.7, 127.6, 124.0,
123.9, 123.7, 95.9, 85.7 (major), 85.5 (minor), 74.2, 73.9, 50.9, 18.0, 17.4. HRMS (FTMS + p ESI) m/z [M + Na]+;
calculated for C18H16O2NCl3Na 406.0139, Found 406.0142.
3-(Allyloxy)-2-((S)-1-phenylethyl)isoindolin-1-one (9). Colorless oil (81 mg, 70%); Rf = 0.45 (hexane/ethyl
acetate, 9:1) IR 3041, 3010, 2976, 2942, 1700 cm -1. 1H NMR (500 MHz, CDCl3, major)  7.84-7.85 (m, 1H), 7.24-
7.58 (m, 8H), 5.80-5.84 (m, 1H), 5.70 (q, J 7.5 Hz, 1H), 5.67 (s, 1H) 4.94-4.99 (m, 1H), 3.54 (dd, J 11.0, 5.5 Hz, 1H),
1
3.45 (dd, J 11.0, 5.5 Hz, 1H), 1.80 (d, J 7.0 Hz, 3H). H NMR (500 MHz, CDCl3, minor)  7.84-7.85 (m, 1H), 7.24-
7.58 (m, 8H), 6.09 (s, 1H), 5.44 (q, J 7.0 Hz, 1H), 5.37-5.40 (m, 1H), 5.23 (d, J=7.0 Hz, 2H), 4.94-4.99 (m, 1H), 3.20
(dd, J 13.5, 7.5 Hz, 1H), 3.10 (dd, J 13.5, 7.5 Hz, 1H), 1.89 (d, J 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3)  167.7,
167.6, 141.7, 140.9, 140.6, 140.2, 133.8, 133.6, 133.0, 132.6, 132.0, 129.9, 129.8, 128.6, 128.4, 128.2, 127.9,
127.8, 127.7, 127.4, 126.6, 123.7, 123.5, 123.3, 117.1, 117.0, 85.5 (major), 85.3 (minor), 62.9, 62.8, 50.5, 50.4,
17.9, 17.4. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C19H19O2NNa 316.1308, Found 316.1304.
3-(4-Hydroxybutoxy)-2-((S)-1-phenylethyl)isoindolin-1-one (10). Colorless oil (103 mg, 80%); Rf = 0.19
(hexane/ethyl acetate, 2:1); IR 3405 br, 2940, 2874, 2836, 1683 cm -1. 1H NMR (500 MHz, CDCl3, major)  7.81-
7.83 (m, 1H), 7.22-7.24 (m, 8H), 5.65 (q, J 6.5 Hz, 1H), 5.62 (s, 1H), 3.86-3.89 (m, 1H), 3.60-3.71 (m, 3H), 3.41-
1
3.46 (m, 1H), 3.28-3.30 (m, 1H) 2.87-2.89 (m, 1H), 1.57-2.0 (4H), 1.23-1.34 (m, 2H). H NMR (500 MHz, CDCl3,
minor)  7.81-7.83 (m, 1H), 7.22-7.24 (m, 8H), 6.03 (s, 1H), 5.43 (q, J 6.0 Hz, 1H), 3.60-3.71 (m, 3H), 3.41-3.46
13
(m, 1H) 2.60-2.68 (m, 2H), 1.57-2.0 (m, 4H), 1.15-1.18 (m, 1H), 1.09-1.10 (m, 1H). C NMR (125 MHz, CDCl3) 
167.8, 141.8, 141.3, 140.9, 140.5, 133.1, 132.7, 132.2, 130.0, 129.9, 128.8, 128.5, 127.9, 127.8, 127.5, 123.8,
123.7, 123.3, 85.8 (major), 85.4 (minor), 62.7, 62.6, 61.9, 61.7, 50.8, 50.3, 29.7, 29.5, 26.2, 25.7, 18.1, 17.5.
HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C20H23O3NNa 348.1570, Found 348.1573.
3-(3-Hydroxy-2,2-dimethylpropoxy)-2-((S)-1-phenylethyl)isoindolin-1-one (11). Colorless oil (101 mg, 75%); Rf
= 0.25 (hexane/ethyl acetate, 2:1); IR 3449 br, 3061, 2973, 2870, 1686 cm -1. 1H NMR (500 MHz, CDCl3, major) 
7.84-7.85 (m, 1H), 7.27-7.58 (m, 8H), 5.66 (q, J 7.0 Hz, 1H), 5.64 (s, 1H), 3.36-3.44 (m, 2h) 3.22 (d, J 9.0 Hz, 1H),
1
2.68 (d, J 9.0 Hz, 1H), 2.02 (br s, 1H), 1.85 (d, J 7.5 Hz, 3H), 0.87 (s, 3H), 0.85 (s, 3H). H NMR (500 MHz, CDCl3,
minor)  7.84-7.85 (m, 1H), 7.27-7.58 (m, 8H), 6.00 (s, 1H), 5.36 (q, J 7.0 Hz, 1H), 3.15-3.17 (m, 2H), 2.59 (d, J 9.0
Hz, 1H), 2.54 (d, J 9.0 Hz, 1H), 1.89 (d, J 7.5 Hz, 3H), 1.76 (br s, 1H), 0.70 (s, 3H), 0.63 (s, 3H). 13C NMR (125 MHz,
CDCl3)  167.8, 141.7, 141.1, 140.7, 140.3, 133.1, 132.7, 132.2, 132.1, 130.0, 129.9, 128.7, 128.5, 127.8, 127.7,
127.5, 123.7, 123.5, 123.2, 123.0, 85.7 (major), 85.5 (minor), 70.8, 70.5, 69.8, 50.8, 50.7, 35.9, 35.6, 21.8, 21.6,
18.0, 17.8. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C21H25O3NNa 362.1727, Found 362.1730.
3-(Anthracen-9-ylmethoxy)-2-((S)-1-phenylethyl)isoindolin-1-one (12). Pale yellow solid (138mg, 78%); mp 85-
87 C; Rf = 0.25 (hexane/ethyl acetate, 2:1); IR 3056, 3035, 2927, 2854, 1696 cm -1. 1H NMR (400 MHz, CDCl3,
major)  8.43 (s, 1H), 7.95-7.96 (m, 3H), 7.86-7.89 (m, 1H), 7.26-7.72 (m, 12H), 6.98 (d, J 7.2 Hz, 1H), 5.86 (s, 1H),
5.80 (q, J 7.2 Hz, 1H), 5.34 (d, J 12.0 Hz, 1H), 5.12 (d, J 12.0 Hz, 1H), 1.90 (d, J 7.6 Hz, 3H). 1H NMR (400 MHz,
CDCl3, minor)  8.39 (s, 1H), 7.95-7.96 (m, 3H), 7.86-7.89 (m, 1H), 7.26-7.72 (m, 12H), 7.18 (d, J 7.2 Hz, 1H), 6.10
13
(s, 1H), 5.40 (q, J 7.2 Hz, 1H), 4.85 (q, J 7.6 Hz, 2H), 2.04 (d, J 7.2 Hz, 3H). C NMR (125 MHz, CDCl3)  168.4,
168.3, 142.0, 141.4, 140.9, 140.7, 133.2, 132.5, 132.0, 131.9, 131.4, 130.5, 130.4, 129.9, 129.8, 129.0, 128.9,
128.8, 128.6, 128.5, 128.3, 127.7, 127.6, 126.5, 126.1, 124.9, 124.9, 124.2, 124.0, 123.8, 123.7, 123.6, 86.3
(major), 86.0 (minor), 58.0, 57.1, 51.6, 51.0, 18.5, 18.3. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for
C31H25O2NNa 466.1778, Found 466.1780.
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3-((2-Bromobenzyl)oxy)-2-((S)-1-phenylethyl)isoindolin-1-one (13). Colorless oil (118 mg, 71%); Rf = 0.29
(hexane/ethyl acetate, 9:1) IR 3077, 3035, 2984, 2937, 1686 cm -1. 1H NMR (500 MHz, CDCl3, major)  7.88-7.90
(m, 1H), 7.10-7.56 (m, 12H), 5.89 (s, 1H), 5.75 (q, J 7.0 Hz, 1H), 4.40 (d, J 12.0 Hz, 1H), 4.07 (d, J 12.5 Hz, 1H), 1.83
(d, J 7.5 Hz, 1H). 1H NMR (500 MHz, CDCl3, minor)  7.88-7.90 (m, 1H), 7.10- 7.56 (m, 11H) 5.47 (q, J 7.0 Hz, 1H),
13
4.06 (d, J 12.5 Hz, 1H), 3.87 (d, J 12.5 Hz, 1H), 1.92 (d, J 7.5 Hz, 3H). C NMR (125 MHz, CDCl3)  167.9, 167.8,
141.6, 140.7, 140.4, 140.3, 136.9, 136.7, 132.9, 132.5, 132.3, 132.2, 132.1, 130.1, 130.0, 129.4, 129.2, 129.1,
128.9, 128.7, 128.4, 127.8, 127.5, 127.4, 127.3, 127.1, 123.8, 123.6, 123.5, 123.4, 122.8, 122.7, 85.7 (major),
85.5 (minor), 63.7, 63.6, 50.7, 50.6, 18.1, 17.6. HRMS (FTMS + p ESI) m/z [M + Na]+; calculated for C23H20O2NBrNa
444.0570, Found 444.0572.
Acknowledgements
Support for JMR through a Department of Chemistry Teaching Assistantship is acknowledged.
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