Synthesis of α-oxygenated ketones and substituted catechols via the rearrangement of N-enoxy- and N-aryloxyphthalimides

Article abstract of DOI:10.1016/j.tet.2017.01.061

A common approach to the synthesis of α-oxygenated carbonyl compounds and catechols is the treatment of a carbonyl compound or a phenol with an electrophilic oxygen source. As an alternative approach to these important structures, formal [3,3]-rearrangements of N-enoxyphthalimides, N-enoxyisoindolinones, and N-aryloxyphthalimides have been explored. When used in combination with an initial Chan-Lam coupling, these transformations facilitate the dioxygenation of alkenylboronic acids for the synthesis of α-oxygenated ketones and the dioxygenation of arylboronic acids for the synthesis of catechols. The rearrangements of N-enoxyisoindolinones have also been shown to be diastereoselective.

Full text of DOI:10.1016/j.tet.2017.01.061

Accepted Manuscript
Synthesis of α-oxygenated ketones and substituted catechols via the rearrangement
of N-enoxy- and N-aryloxyphthalimides
Michelle A. Kroc, Aditi Patil, Anthony Carlos, Josiah Ballantine, Stephanie Aguilar,
Dong-Liang Mo, Heng-Yen Wang, Daniel S. Mueller, Donald J. Wink, Laura L.
Anderson
PII:
S0040-4020(17)30096-0
10.1016/j.tet.2017.01.061
TET 28431
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 September 2016
Revised Date: 16 December 2016
Accepted Date: 26 January 2017
Please cite this article as: Kroc MA, Patil A, Carlos A, Ballantine J, Aguilar S, Mo D-L, Wang H-Y,
Mueller DS, Wink DJ, Anderson LL, Synthesis of α-oxygenated ketones and substituted catechols
via the rearrangement of N-enoxy- and N-aryloxyphthalimides, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.01.061.
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Synthesis of α-oxygenated ketones and
substituted catechols via the rearrangement
of N-enoxy- and N-aryloxyphthalimides
Leave this area blank for abstract info.
Michelle A. Kroc, Aditi Patil, Anthony Carlos, Josiah Ballantine, Stephanie Aguilar, Dong-Liang Mo, Heng-
Yen Wang, Daniel S. Mueller, Donald J. Wink, Laura L. Anderson
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607 USA

1
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Tetrahedron
journal homepage: www.elsevier.com
Synthesis of α-oxygenated ketones and substituted catechols via the rearrangement of
N-enoxy- and N-aryloxyphthalimides
Michelle A. Kroc, Aditi Patil, Anthony Carlos, Josiah Ballantine, Stephanie Aguilar, Dong-Liang Mo,
Heng-Yen Wang, Daniel S. Mueller, Donald J. Wink, and Laura L. Anderson*
aAffiliation 1, Address, City and Postal Code, Country
bAffiliation 2, Address, City and Postal Code, Country
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A common approach to the synthesis of α-oxygenated carbonyl compounds and catechols is the
treatment of a carbonyl compound or a phenol with an electrophilic oxygen source. As an
alternative approach to these important structures, formal [3,3]-rearrangements of N-
enoxyphthalimides, N-enoxyisoindolinones, and N-aryloxyphthalimides have been explored.
When used in combination with an initial Chan-Lam coupling, these transformations facilitate
the dioxygenation of alkenylboronic acids for the synthesis of α-oxygenated ketones and the
dioxygenation of arylboronic acids for the synthesis of catechols. The rearrangements of N-
enoxyisoindolinones have also been shown to be diastereoselective.
Available online
Keywords:
α-oxygenation
catechol
[3,3]-rearrangement
Chan-Lam
2009 Elsevier Ltd. All rights reserved
.
Boronic acid
1. Introduction
mechanistic pathway to provide access to these important
compounds.
Oxygenation reactions of ketones, aldehydes, and phenols are
important processes for the synthesis of α-oxygenated carbonyl
compounds and catechols. Common methods for the α-
oxygenation of ketones and aldehydes rely on the addition of
enolate derivatives to electrophilic sources of oxygen.1 These
transformations include the Rubottom oxidation, oxidations of
carbonyl compounds with Koser’s reagent or the Davis
oxaziridine, enamine-catalyzed additions of aldehydes to
nitrosobenzene or benzoyl peroxide, Lewis-acid catalyzed
additions of carbonyl compounds to nitrosobenzene, and
transition metal catalyzed aerobic oxidation at the α-position of
carbonyl compounds (Scheme 1A).2-6 Alternative approaches to
α-oxygenated
carbonyl
compounds
include
benzoin
condensations and displacement reactions of α-halogenated
precursors, but retain the common theme of carbonyl compound
functionalization (Scheme 1B and 1C).7,8 Similarly, traditional
methods for phenol oxidation involve treatment of phenols or
ortho-formyl phenols with stoichiometric oxidants to form ortho-
quinones that can be reduced to the corresponding catechols
(Scheme 1D and 1E).9,10 Recent advances have shown that the
regioselectivity of these processes can be controlled by transition
metal catalyzed C–H bond oxidation using appropriate directing
groups and through the careful selection of a copper catalyst and
reaction conditions for aerobic oxidation (Scheme 1D and
1F).11,12 We wondered if hydroxamic acid rearrangements could
provide a new approach to both ketone and phenol oxygenation
Scheme 1. Common approaches to the synthesis of α-
oxygenated ketones and catechols.
reactions by utilizing alternative reagents and
a unique

2
Tetrahedron
ACCEPTED MANUSCRIPT
The rearrangements of O-carbonylated oximes for the
synthesis of α-oxygenated ketones were initially reported by
House and coworkers and have been investigated in detail by the
Tomkinson group.13 Tomkinson and coworkers showed that
condensation of benzoyl-, acetyl-, sulfonyl-, or carbonate-
protected hydroxylamines with aldehydes or ketones gives the
corresponding α-oxygenated products through a spontaneous
[3,3]-rearrangement.14 Regioselectivity can be controlled by the
choice of protecting group (Scheme 2A). Initial studies with
chiral
scalemic
hydroxylamines
showed
that
these
transformations are diastereoselective (Scheme 2B).15 Similarly,
N-aryl-O-protected hydroxylamines have been prepared via a
nitroarene reduction or C–N bond coupling and shown to
undergo analogous rearrangements for the synthesis of
aminophenols (Scheme 2C).16 The simplicity of these
transformations, and the use of a pericyclic reaction to form a
new C–O bond, makes them appealing from a practical
standpoint and intriguing from a retrosynthetic perspective. We
wondered if a similar concept could be used to design a method
for the synthesis of α-oxygenated ketones and catechols from
alkenyl- or arylboronic acids, respectively.
Scheme 3. Dioxygenation of alkenylboronic acids via N-
enoxyphthalimide rearrangements
coworkers 2012.
–
Anderson and
2. Results and Discussion
2.1. Rearrangements of N-enoxyphthalimides for the synthesis of
α-oxygenated ketones
Scheme 2. α-Oxygenation reactions and 1,2-aminophenol
synthesis
using
hydroxylamine
condensation
and
In order to explore the rearrangements of N-
enoxyphthalimides for the synthesis of α-oxygenated carbonyl
compounds, a modular and facile synthesis was required for these
precursors. The preparation of N-enoxyphthalimides 3 from N-
hydroxyphthalimide 1 and alkenyl boronic acids 2 was achieved
through the optimization of a Chan-Lam reaction.17,18 Both
stoichiometric and catalytic conditions were optimized for the C–
O coupling and gave the highest yields with Cu(OAc)2 and
pyridine in DCE (Scheme 4). A variety of boronic acids were
tolerated for the transformation including linear disubstituted,
linear monosubstituted, and cyclic alkenylboronic acids. The
breadth of N-enoxyphthalimide substrates that could be accessed
from alkenylboronic acids provided a broad scope to test the
rearrangements of these compounds.
rearrangement reactions – Tomkinson and coworkers.
Recently, we communicated a two-step method for the
dioxygenation of alkenylboronic acids and the synthesis of α-
oxygenated ketones (Scheme 3A).17 A Chan-Lam reaction
provided access to N-enoxyphthalimides 3, which underwent
formal [3,3]-rearrangements to give α-oxygenated ketones 4.
Imidate-protected ketones 4 were then hydrolyzed to give α-
hydroxyketones 5 or α-benzoyloxyketones 6. This procedure for
forming α-oxygenated ketones is retrosynthetically distinct from
transformations that rely on electrophilic sources of oxygen and
carbonyl compound precursors. Instead, this transformation
allows for the conversion of alkenylboronic acids 2 to α-
oxygenated ketones 4 – 6 through a dioxygenation process, and
the conversion of alkynes to α-oxygenated ketones without a
carbonyl intermediate when combined with an initial
hydroboration process. Further exploration of these
rearrangements has shown that they can be rendered
diastereoselective and can be extended to arylboronic acids.
Herein, we highlight the development of our original
alkenylboronic acid dioxygenation process, describe our design
of an analogous diastereoselective rearrangement of N-
enoxyisoindolinones (Scheme 3B), and discuss our discovery of
a related arylboronic acid dioxygenation process for the synthesis
of substituted catechols (Scheme 3C).

3
rearrangement, and hydrolysis process in hand, a robust and
ACCEPTED MANUSCRIPT
versatile method for the synthesis of α-oxygenated ketones from
alkenylboronic acids was developed.
2.2. Diastereoselective rearrangements of N-enoxyphthalimides
Having established that N-enoxyphthalimides 3 undergo
formal [3,3]-rearrangements to α-oxygenated ketones 4, we
wondered if this transformation could be rendered
diastereoselective. Substituted cyclohexenyl substrates 3q and 3r
provided initial insight into the design of a diastereoselective
process (Scheme 6).17 When 4-t-Bu-cyclohexenyl hydroxylamine
ether 3q was subjected to thermal rearrangement conditions, a
60:40 ratio of diastereomers were observed in favor of the
thermodynamic product cis-4q. The low selectivity of the
rearrangement of 3q to 4q suggested that there was little
energetic difference for the approach of the terminal end of the
alkenyl hydroxylamine ether towards the carbonyl of the
phthalimide. Hydrolysis and benzoylation of 4q to 6q further
increased the diastereomeric ratio to favor the thermodynamic
product, most likely through epimerization. In contrast, when 2-
Me-cyclohexenyl hydroxylamine ether 3r was subjected to
thermal rearrangement conditions,
a
15:85 mixture of
diastereomers was observed to favor the kinetic product trans-4r.
This suggested a greater kinetic preference for the approach of
the terminal position of the alkenyl hydroxylamine ether towards
the carbonyl group in comparison to the 3q. Hydrolysis and
benzoylation of 4r to 6r decreased the diastereomeric ratio
towards the thermodynamic product. The difference in selectivity
between the rearrangements of 3q and 3r indicated that
substituents positioned closer to the reactive 6-atom fragment
have a larger influence on the kinetic selectivity of the
transformation.
Scheme 4. Preparation of N-enoxyphthalimides.17
The thermal rearrangement of N-enoxyphthalimides 3 was
determined to be optimal in a 0.1 M solution of toluene or
benzene at 80 – 90 °C.17 These transformations exhibited clean
conversion to the rearrangement products 4 and were essentially
quantitative for 3e – 3s. Although imidates 4 were sensitive to
silica gel, hydrolysis conditions for the conversion of 4 to α-
hydroxyketones 5 and α-benozyloxy ketones 6, provided α-
oxygenated ketones that could be purified by traditional methods
(Scheme 5).17 While N-enoxyphthalmides 3a – 3d derived from
monosubstituted alkenylboronic acids smoothly underwent
analogous rearrangements to form α-imidoyl aldehydes 4,
hydrolysis of these intermediates led to decomposition via
polymerization.17 Attempts at a single-flask conversion of
alkenylboronic acids to α-hydroxyketones showed that rigorous
purification of 3 is not required for the rearrangement process,
but that Cu(OAc)2 is not tolerated in the rearrangement reaction
mixture and that 3 needs to be separated from the copper residue
of the Chan-Lam C–O bond coupling prior to heating and
hydrolysis.17 With the optimized C–O bond coupling,
Scheme 6. Diastereoselectivity of 2- and 6-substituted
cyclohexenyl hydroxylamine ether rearrangements.17
Continuing of our efforts towards the development of a
diastereoselective N-enoxyphthalimide rearrangement, we
decided to test the installation of a stereocenter on the
phthalimide backbone (Scheme 7). N-Siloxyphthalimide 7 was
reduced to siloxy-substituted N-hydroxyisoindolinone 8, which
underwent a Chan-Lam reaction with 2m under the optimized
conditions for N-enoxyphthalimide synthesis.19 Surprisingly, in
addition to C–O bond formation, a spontaneous, and highly
diastereoselective, formal [3,3]-rearrangement occurred in the
same flask at 25 °C to give imidate 10m. This experiment
indicated that the substituent on the N-hydroxyisoindolinone
Scheme 5. Rearrangement and hydrolysis of N-
enoxyphthalimides.17

4
Tetrahedron
ACCEPTED MANUSCRIPT
backbone was more effective at controlling the
diastereoselectivity of the formal [3,3]-rearrangement of
intermediate 9m than the cyclohexenyl ether substituents of 3q
and 3r. The single-flask process at ambient temperature also
suggested that N-enoxyisodindolinone rearrangements occur at
lower temperatures than N-enoxyphthalimide rearrangements.20
O
O
H
=
N
OTBS
Scheme 9. X-ray crystal structure of 10t.
A variety of alkenylboronic acids successfully underwent the
Chan-Lam coupling and diastereoselective rearrangement
reaction to give imidates 10 in good yield and high
diastereoselectivity (Scheme 10A). This transformation tolerated
cyclic alkenylboronic acids of different ring sizes, as well as
linear alkenylboronic acids with both aryl- and alkyl-substituents.
3-Methyl-substituted cyclohexenylboronic acid 2s gave imidate
10s as a mixture of only two diastereomers arising from the two
Scheme 7. Diastereoselective 3-substituted isoindolinone
rearrangements.
adjacent
stereocenters
on
the
cyclohexanone
ring.
Monosubstituted boronic acid 2a was also tested but required
separation of intermediate 9a from Cu(OAc)2 and elevated
temperatures for the rearrangement reaction to occur to give 10a
(Scheme 10B). Surprisingly, trisubstituted alkenylboronic acid
2w, which was unreactive with N-hydroxyphthalimide 1,
smoothly underwent the coupling and rearrangement process
with N-hydroxyisoindolinones to form tertiary α-imidoyl ketone
10w. These results describe the generality of diastereoselective
Further exploration of the diastereoselective rearrangement of
in situ generated N-enoxyisoindolinones was pursued by varying
the 3-substituent of several N-hydroxyisoindolinones and testing
their C–O bond coupling and rearrangement reactivity with
indenyl boronic acid 2t. Silyloxy, alkoxy, and allyl substituents
were similarly effective at promoting diastereoselective
rearrangements to give imidates 10t and 16t – 20t (Scheme 8);
however, siloxy- and allyl-substituted isoindolinones provided
10t, 16t and 20t, in higher yield than 17t – 19t. Due to the
simplicity in handling and removing silyloxy protecting groups,
we decided to further explore the scope of the single-flask C–O
bond coupling and diastereoselective rearrangement with N-
hydroxyisoindolinone 8.
Optimization of the Chan-Lam
coupling and rearrangement reaction conditions for 8 and 2t
showed that the conditions determined for the N-
hydroxyphthalimide Chan-Lam reactions illustrated in Scheme 4
were
equally
efficient
for
the
and
single-flask
N-
hydroxyisoindolinone
synthesis
rearrangement.21
Crystallization of 10t from CDCl3 provided a single crystal and
an X-ray diffraction study indicated that C–O bond formation
occurs from the opposite face of the heterocycle to the OTBS
group (Scheme 9).
(HO)2B
O
O
2t
O
N
OH
N
Cu(OAc)2, Py, Na2SO4
DCE, 25 °C, air
R
R
10, 16 – 20
8, 11 – 15
O
O
O
O
N
O
N
O
N
OMe
OTBS
OTIPS
16t
17t
10t
(64%, dr = >95:5)
(50%, dr = 92:8)
(61%, dr = >95:5)
O
O
O
O
N
O
N
O
N
OEt
Oi-Pr
19t
20t
18t
(48%, dr = >95:5)
(66%, dr = >95:5)
(53%, dr = 92:8)
Scheme 10. Scope of alkenylboronic acids for N-
hydroxyisoindolinone
rearrangement reactions.
C–O
bond
coupling
and
Scheme 8. Isoindolinone substituent screen for N-
hydroxyisoindolinone single-flask C–O bond coupling and
rearrangement reactions.

5
rearrangements of N-enoxyisoindolinones 9 and indicate that the
1).18b As shown in Table 1, only moderate reactivity was
ACCEPTED MANUSCRIPT
C–O bond coupling and rearrangement conditions for
isoindolinone 8 (Scheme 10) tolerate an even broader selection of
alkenylboronic acids than the original N-enoxyphthalimide
synthesis and rearrangements described in Schemes 4 and 5.22
observed in PhMe or C6H5Cl at or below 120 °C, but good
conversion to the desired product was observed at 140 °C in
these solvents. The reaction temperature could be decreased to
120 °C when MeCN was used as the reaction medium and 24a
was isolated in quantitative yield. Isolated imidate 24a could also
be alkylated as shown in Scheme 13 to form methyl ether 27a or
allyl ether 28a.
While the conditions shown in Table 1, entry 6 were optimal
for the rearrangement of N-aryloxyphthalimide 23a, 23b and 23c
required further optimization. While testing conditions for the
conversion of 23a to 24a, we observed that when Ac2O was used
as an additive or a solvent, acetate-protected catechol 26a could
also be generated in excellent yield (Table 1, entries 7 and 8).
When Ac2O was tested as a solvent for the rearrangement of 23b
and 23c, 26b and 26c were obtained in high yield (entries 10 and
12). Due to the greater sensitivity of halogenated 23 to the
reaction conditions, we decided to further explore the scope of
the N-aryloxyphthalimide rearrangement using the conditions
shown in Table 1, entries 8, 10, and 12.
Scheme 11. Hydrolysis of imidate 10t.
Hydrolysis of imidate rearrangement products 10, required
alternative conditions to those described in Scheme 5 for
imidates 4. When imidate 10t was treated with Amberlite resin,
no reaction was observed. In contrast when imidate 10t was
treated with NH4Cl in a mixture of MeOH and H2O, hydrolysis to
the α-hydroxyketone occurred in moderate yield. Surprisingly,
halogenation provided a more efficient method for imidate
removal. When 10t was treated with oxayl chloride and heated
to 90 °C, α-chloroketone 21t was isolated in good yield. These
transformations showed that the isoindolinone fragment can be
separated from the rearrangement product after dioxygenation of
the alkenylboronic acid with 3-siloxy-N-hydroxyisoindolinone 8.
Table 1
Optimization of conditions for the rearrangement of N-
aryloxyphthalimides
2.3. Rearrangements of N-aryloxyphthalimides
# Yield (%)a
24a (51)
24a (76)
24a (59)
24a (87)
24a (68)
24a (>99)
26a (>99)
26a (98)
24b (45)
26b (85)
24c (40)
26c (68)
Expansion of the use of N-hydroxyphthalimide 1 as a
dioxygenation reagent was further investigated with arylboronic
acids 22. In light of our previous studies on the rearrangements of
N-enoxyphthalimides 4 and N-enoxyisoindolinones 9 to α-
Entry
1
X
Solvent
PhMe
Additive
none
none
none
none
none
none
Ac2O
none
none
none
none
none
T (°C)
120
140
120
140
100
120
120
140
120
140
120
140
Me
Me
Me
Me
Me
Me
Me
Me
F
2
PhMe
oxygenated ketones
aryloxyphthalimides
5
23
and 6, we wondered if N-
would undergo analogous
3
C6H5Cl
C6H5Cl
MeCN
MeCN
PhMe:DMFb
Ac2O
rearrangements to give substituted catechols 24 (Scheme 12).
Pairing this process with an N-hydroxyphthalimide aryl
etherification and a final hydrolysis step would allow for the
conversion of arylboronic acids to substituted catechols in three
simple steps without requiring oxidation to the ortho-
quinone.9,10,11b The optimization of this process and the
development of a new way to approach catechol synthesis from
arylboronic acids is described below.
4
5
6
7
8
9
MeCN
Ac2O
10
11
12
F
Cl
MeCN
Cl
Ac2O
a Conditions: 0.1 M solution of 23a, 18 h. b PhMe:DMF = 1:1.
Scheme 12. Catechol synthesis via dioxygenation of
arylboronic acids.
Scheme 13. Rearrangement product alkylation.
N-Aryloxyphthalimide, 23a was prepared via a Chan-Lam
reaction and the thermal rearrangement reactivity of this
compound was tested in a variety of different solvents (Table
The scope of the formal [3,3]-rearrangement of N-
aryloxyphthalimides 23 for the synthesis of acetate and imidate
protected catechols 24 was explored with a variety of different

6
Tetrahedron
ACCEPTED MANUSCRIPT
substrates prepared from the corresponding arylboronic acids
(Scheme 14).18b N-Aryloxyphthalimides with alkyl, halogen, aryl,
and alkenyl substituents at the 4-position smoothly underwent the
rearrangement to give the corresponding protected catechols 26.
Substrates with electron-withdrawing substituents such as 23h
and 23i were unreactive, presumably due to the electronic
requirements of the fundamentally oxidative process. 3,5-
Dimethylaryl-substituted 23j was smoothly converted to 26j and
3-OMe-substituted 23k was regioselectively converted to 26k
indicating tolerance and selectivity for meta-substituted aryl
ethers. While N-aryloxyphthalimides with substituents at the
ortho-position could not be prepared, naphthalene ether 23l was
easily accessed from
1
and smoothly underwent the
rearrangement to give imidate 26l. These studies clearly show
that the N-hydroxyphthalimide-mediated alkenylboronic acid
dioxygenation reactions described above can be extended to
electron-rich and electron-neutral arylboronic acids for the
synthesis of substituted catechols.
Scheme 15. Scope of imidate hydrolysis and catechol
synthesis.
3. Conclusion
Our initial discovery that N-enoxyphthalimides 3 can be
generated via a Chan-Lam reaction and undergo thermal
rearrangement to form imidates 4, led to the development of a
method for the dioxygenation of alkenylboronic acids to give α-
hydroxyketones 5, using N-hydroxyphthalimide 1 as an oxidant.
Further study of this transformation has shown that
a
diastereoselective version is accessible through reduction of one
of the phthalimide amide groups and installation of a stereocenter
close to the N–O bond. This diastereoselective rearrangement of
N-enoxyisoindolinones was shown to occur at lower temperature
than the N-enoxyphthalimide rearrangement and as a two-step
single-flask process with a C–O bond forming Chan-Lam
reaction. The scope of this transformation has surpassed the N-
enoxyphthalimide rearrangement and tolerates trisubstituted
alkenylboronic acids. The reaction sequence that was originally
designed to convert alkenylboronic acids to α-oxygenated
ketones was also optimized for arylboronic acids and the
analogous synthesis of substituted catechols.
These
transformations have provided new routes to two different types
of oxygenated compounds through novel, formal [3,3]-
rearrangements of alkenyl and aryl ethers of N-
hydroxyphthalimide, and have expanded the scope and
application of N–O bond rearrangements in organic synthesis.
Scheme 14. Scope of N-aryloxyphthalimide rearrangement.
With several imidate-protected catechols in hand, we decided
to test deprotection conditions for the imidate and acetate
functionalities to release the corresponding catechols. Gabriel-
deprotection conditions were optimized for a simultaneous
deprotection of both functional groups. The majority of the
imidates 24 prepared in Scheme 14 were smoothly converted to
their corresponding catechols 25 in good yield using these
conditions (Scheme 15). These studies illustrate how the
rearrangements of N-aryloxyphthalimides can be used to form
catechols from arylboronic acids. These types of manipulations
are unique in comparison to other types of phenol oxidations and
provide new opportunities for selectively protecting and
deprotecting catechols.9, 11, 12
4. Experimental Section
4.1. General experimental information
1H NMR and 13C NMR spectra were recorded at ambient
temperature using 500 MHz spectrometers. The data is reported
as follows: chemical shift in ppm from internal tetramethylsilane
on the δ scale, multiplicity (br = broad, s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet), coupling constants (Hz), and
integration. High resolution mass spectra were acquired on an
LTQ FT spectrometer, and were obtained by peak matching.
Melting points are reported uncorrected. Analytical thin layer
chromatography was performed on 0.25 mm extra hard silica gel
plates with UV254 fluorescent indicator. Medium pressure liquid
chromatography was performed using force flow of the indicated
solvent system down columns packed with 60 Å (40-60 ꢀm)
mesh silica gel (SiO2) or Florisil®. Unless otherwise noted, all
reagents and solvents were obtained from commercial sources
and, where appropriate, purified prior to use. Saturated solutions
of ammonia in methanol were prepared by bubbling anhydrous
NH3(g) through cold (0 ºC), anhydrous MeOH for 20 min.23

7
Alkenyl boronic acids 2, N-enoxyphthalimides 3, imidates 4,
α-hydroxyketones 5, and α-benzoyloxyketones 6 were prepared
as described previously.17 N-Aryloxyphthalimides 23 were made
as described previously or prepared by an analogous method.18b,
4.3.1 General procedure A. A scintillation vial was charged
ACCEPTED MANUSCRIPT
with the 3-substituted-N-hydroxyisoindolinones 8, 11, 12, 13, 14,
or 15 (1 equiv),24 indenyl boronic acid 2t (2 equiv), Cu(OAc)2 (1
equiv), and anhydrous Na2SO4 (4-6 equiv). These solids were
then diluted with 1,2-dichloroethane to form a 0.1 M solution of
the N-hydroxyisoindolinone. Pyridine (3 equiv) was added to the
resulting slurry via syringe. The scintillation vial was capped
with a septum, pierced with a ventilation needle, and the reaction
mixture was allowed to stir at 25 °C for 12 h. The reaction
mixture was then filtered through a plug of Florisil® with EtOAc
(5.0 mL) to remove the Cu(OAc)2. The filtrate was concentrated
under vacuum and the crude product mixture was purified by
flash chromatography on Florisil® (1:4 - 1:2; EtOAc:hexanes) to
give imidates 10t, 16t, 17t, 18t, 19t, or 20t. Diastereomeric ratios
were determined by 1H NMR spectroscopy.
24
Aryl boronic acids 22 were made as described previously or
purchased from commercial sources.25
4.2. Reduction of siloxyphthalimide 7 and treatment with
cyclohexenylboronic acid 2m for the synthesis of 10m.
4.2.1 Preparation of 8. A 50 mL round bottom flask was charged
with 2-((t-butyldimethylsilyl)oxy)isoindoline-1,3-dione 724 (4.00
g, 14.4 mmol) and MeOH (30 mL) and cooled to 0 ºC with an ice
bath. NaBH4 (0.818 g, 21.6 mmol, 1.5 equiv) was then added as
a solid. After the evolution of H2 was complete, the reaction
mixture was warmed to 25 °C and stirred for 4 h. The reaction
mixture was then concentrated under vacuum and the residue was
dissolved in EtOAc (30 mL) and extracted with sat. NH4Cl(aq) (30
mL). The aqueous layer was then back extracted with EtOAc (3 x
20 mL). The organic layers were combined and washed with H2O
(3 x 20 mL), brine (1 x 20 mL), dried with MgSO4 and
concentrated under vacuum. The crude reaction mixture was then
purified by medium pressure chromatography on silica gel (1:1
EtOAc:hexanes) to give 8 as a white solid (3.30 g, 82 %). 1H
NMR (500 MHz; CDCl3): δ 10.08 (bs, 1H), 7.68-7.67 (m, 1H),
7.58-7.54 (m, 1H), 7.46-7.43 (m, 2H), 5.97 (s, 1H), 1.00 (s, 9H),
0.34 (s, 3H), 0.30 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.5,
141.9, 132.5, 129.5, 129.3, 123.2, 122.9, 83.2, 25.7, 18.2, -4.1, -
4.8; IR (thin film) 3114, 2928, 2886, 2858, 1701, 1616, 1505,
1467, 1398, 1356, 1255, 1158 cm-1; HRMS (ESI) m/z calcd. for
C14H22NO3Si (M+H)+ 280.1369, found 280.1371; mp 147 ºC.
4.3.2 Imidate 10t. Prepared using general procedure A with 3-
silyloxy-N-hydroxyisoindolinone 8 (0.100 g; 0.357 mmol),
indenyl boronic acid 2t (0.114 g, 0.714 mmol), Cu(OAc)2 (0.065
g, 0.36 mmol), Na2SO4 (0.373 g, 2.62 mmol), and pyridine (86.6
ꢀL, 1.07 mmol). Flash chromatography (1:4; EtOAc: hexanes) on
Florisil® afforded 10t as a white solid (0.086 g, 61%, dr =
1
>95:5). H NMR (500 MHz; CDCl3): δ 7.84-7.83 (m, 1H), 7.65-
7.62 (m, 1H), 7.53-7.37 (m, 6H), 5.95 (s, 1H), 5.54-5.52 (m, 1H),
3.76 (dd, J = 16.7, 7.8 Hz, 1H), 3.43 (dd, J = 16.7, 4.5 Hz, 1H),
0.87 (s, 9H), 0.08 (s, 3H), -0.07 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 200.5, 167.7, 152.6, 150.3, 135.6, 135.1, 131.6, 130.0,
128.5, 127.9, 126.7, 124.3, 122.7, 120.8, 90.7, 77.9, 33.1, 25.8,
18.1, -4.1, -4.6; IR (thin film) 2927, 2854, 1727, 1629, 1609,
1579, 1469, 1396, 1329, 1272, 1186 cm-1; HRMS (ESI) m/z
calcd. for C23H28NO3Si (M+H)+ 394.1838, found 394.1846;
decomposed at 84-85 °C. Crystallized from CDCl3 with hexane
diffusion. CCDC 1504598.
4.2.2 Preparation of Imidate 10m. A scintillation vial was
charged with 3-silyloxy-N-hydroxyisoindolinone 8 (0.133 g;
0.476 mmol), 1-cyclohexenyl boronic acid 2m (0.120 g, 0.950
mmol), Cu(OAc)2 (0.086 g, 0.48 mmol), and anhydrous Na2SO4
(0.500 g, 3.52 mmol). These solids were then diluted with 1,2-
dichloroethane to form a 0.1 M solution of 8. Pyridine (110.0
ꢀL, 1.428 mmol) was added to the resulting slurry via syringe.
The scintillation vial was then capped with a septum, pierced
with a ventilation needle, and the reaction mixture was allowed to
stir at 25 °C for 8 h. The reaction mixture was filtered through a
plug of Florisil® with EtOAc (5.0 mL) to remove the Cu(OAc)2.
The filtrate was concentrated under vacuum and the crude
product mixture was purified by flash chromatography on
Florisil® (1:3; EtOAc:hexanes) to give imidate 10m as a white
4.3.3 Imidate 16t. Prepared using general procedure A with 3-
siloxy-N-hydroxyisoindolinone 11 (0.080 g; 0.25 mmol), indenyl
boronic acid 2t (0.080 g, 0.50 mmol), Cu(OAc)2 (0.045 g, 0.25
mmol), Na2SO4 (0.299 g, 2.11 mmol), and pyridine (60.0 ꢀL,
0.744 mmol). Flash chromatography (1:3; EtOAc: hexanes) on
Florisil® afforded 16t as a white solid (0.069 g, 64%, dr =
>95:5). 1H NMR (500 MHz; CDCl3): δ 7.84-7.83 (m, 1H), 7.65-
7.64 (m, 1H), 7.55-7.52 (m, 2H), 7.48-7.38 (m, 4H), 5.98 (s, 1H),
5.37 (dd, J = 5.0, 5.0 Hz, 1H), 3.70 (dd, J = 10.0, 5.0 Hz, 1H),
3.53 (dd, J = 10.0, 5.0 Hz, 1H) 1.05-0.97 (m, 21H); 13C NMR
(125 MHz, CDCl3): δ 200.4, 167.0, 152.7, 150.2, 135.4, 135.2,
131.6, 129.8, 128.4, 127.7, 126.6, 124.3, 122.6, 120.6, 90.3, 78.1,
32.6, 17.8, 17.7, 12.1; IR (thin film) 2942, 2864, 1727, 1628,
1606, 1576, 1465, 1396, 1272, 1191 cm-1; HRMS (ESI) m/z
calcd. for C26H34NO3 (M+H)+ 436.2308, found 436.2306;
decomposed at 114-115 °C.
1
solid (0.121 g, 71%, dr = 89:11). H NMR major diastereomer
(500 MHz; CDCl3): δ 7.56-7.50 (m, 2H), 7.41-7.37 (m, 2H), 5.97
(s, 1H), 5.58 (dd, J = 11.7, 5.9 Hz, 1H), 2.56-2.44 (m, 2H), 2.12-
1.94 (m, 4H), 1.87-1.65 (m, 2H), 0.90 (s, 9H), 0.09 (s, 3H), -0.01
(s, 3H); 13C NMR major diastereomer (125 MHz, CDCl3): δ
204.7, 168.2, 152.6, 131.8, 129.9, 128.4, 122.7, 120.8, 91.1, 79.9,
40.7, 33.7, 27.5, 25.8, 23.8, 18.1, -3.9, -4.1; 1H NMR minor
diastereomer (500 MHz; CDCl3): δ 7.66-7.48 (m, 4H), 6.10 (s,
1H), 5.58 (dd, J = 11.7, 5.9 Hz, 1H), 2.45-2.41 (m, 2H), 2.03-
1.82 (m, 4H), 1.68-1.51 (m, 2H), 0.91 (s, 9H), 0.15 (s, 3H), 0.02
(s, 3H); 13C NMR minor diastereomer (125 MHz, CDCl3): δ
204.7, 169.5, 152.6, 132.5, 129.9, 128.4, 123.5, 120.8, 91.1, 79.2,
40.7, 33.7, 27.5, 25.8, 23.8, 18.1, -3.9, -4.1; IR (thin film) 2929,
2857, 1731, 1626, 1575, 1471, 1361, 1328, 1288, 1120, 1025 cm-
1; HRMS (ESI) m/z calcd. for C20H30NO3Si (M+H)+ 360.1995,
found 360.1988; decomposed at 91 °C.
4.3.4 Imidate 17t. Prepared using general procedure A with N-
hydroxyisoindolinone 12 (0.060 g; 0.33 mmol), indenyl boronic
acid 2t (0.107 g, 0.668 mmol), Cu(OAc)2 (0.061 g, 0.33 mmol),
Na2SO4 (0.224 g, 1.57 mmol), and pyridine (81.0 ꢀL, 1.00
mmol). Flash chromatography (1:4; EtOAc: hexanes) on
Florisil® afforded 17t as a white solid (0.049 g, 50%, dr = 92:8).
1H NMR major diastereomer (500 MHz; CDCl3): δ 7.85-7.83 (m,
1H), 7.65-7.64 (m, 1H), 7.57-7.55 (m, 2H), 7.48-7.40 (m, 4H),
5.86 (s, 1H), 5.81 (dd, J = 7.2, 5.24 Hz, 1H), 3.87 (dd, J = 16.98,
7.23 Hz, 1H), 3.32-3.25 (m, 3H); 13C NMR major diastereomer
(125 MHz, CDCl3): δ 200.4, 169.4, 150.6, 149.0, 135.8, 134.8,
132.4, 130.2, 129.1, 128.1, 126.7, 124.5, 123.2, 121.0, 95.8, 77.6,
1
4.3. General procedure A for the single-flask alkenylation and
rearrangement of isoindolinones 8 and 11 – 15 with
indenylboronic acid 2t. Characterization of 10, 16 – 20.
53.7, 33.6; H NMR minor diastereomer (500 MHz; CDCl3): δ
7.89-7.88 (m, 1H), 7.76-7.73 (m, 1H), 7.57-7.55 (m, 2H), 7.48-
7.40 (m, 4H), 5.97 (s, 1H), 5.80 (m, 1H), 3.56 (dd, J = 16.2, 7.9
Hz, 1H), 3.14 (s, 3H), 3.00 (dd, J = 16.2, 4.6 Hz, 1H); 13C NMR

8
Tetrahedron
ACCEPTED MANUSCRIPT
minor diastereomer (125 MHz, CDCl3): δ 200.4, 164.8, 163.1,
153.7, 150.8, 135.7, 134.9, 134.4, 132.3, 129.1, 128.0, 127.3,
149.0, 135.8, 134.8, 132.4, 130.2, 129.1, 128.1, 126.7, 124.5,
123.2, 121.0, 95.8, 77.6, 53.7, 26.7; IR (thin film) 2965, 2930,
1736, 1625, 1603, 1570, 1459, 1395, 1333, 1274, 1189 cm-1;
HRMS (ESI) m/z calcd. for C18H16NO3 (M+H)+ 294.1130, found
294.1127; decomposed at 101 °C.
126.7, 124.5, 122.3, 120.9, 117.4, 68.3, 77.2, 37.6, 33.9; IR (thin
film) 2953, 2934, 2855, 1774, 1714, 1600, 1571, 1467, 1381,
1290, 1188 cm-1; HRMS (ESI) m/z calcd. for C20H18NO2 (M+H)+
304.1338, found 304.1343.
4.4. General procedure for the single-flask alkenylation and
rearrangement of 8 with alkenylboronic acids 2.
Characterization of 10f, 10g, 10l, 10n, 10s, 10u – 10w.
4.3.5 Imidate 18t. Prepared using general procedure A with N-
hydroxyisoindolinone 13 (0.080 g; 0.41 mmol), indenyl boronic
acid 2t (0.132 g, 0.820 mmol), Cu(OAc)2 (0.074 g, 0.41 mmol),
Na2SO4 (0.298 g, 2.09 mmol), and pyridine (100 ꢀL, 1.23 mmol).
Flash chromatography (1:4; EtOAc: hexanes) on Florisil®
4.4.1 General procedure B. A scintillation vial was charged with
3-silyloxy-N-hydroxyisoindolinone 8 (1 equiv), alkenyl boronic
acid 2 (2 equiv), Cu(OAc)2 (1 equiv), and anhydrous Na2SO4 (4-6
equiv). These solids were then diluted with 1,2-dichloroethane to
form a 0.1 M solution of 8. Pyridine (3 equiv) was added to the
resulting slurry via syringe. The scintillation vial was then
capped with a septum, pierced with a ventilation needle, and the
reaction mixture was allowed to stir at 25 °C for 8 h. The reaction
mixture was filtered through a plug of Florisil® with EtOAc (5.0
mL) to remove the Cu(OAc)2. The filtrate was concentrated
under vacuum and the crude product mixture was purified by
flash chromatography on Florisil® (1:4 - 1:2; EtOAc:hexanes) to
1
afforded 18t as a white solid (0.067 g, 53%, dr = 92:8). H NMR
major diastereomer (500 MHz; CDCl3): δ 7.85-7.84 (m, 1H),
7.87-7.84 (m, 1H), 7.58-7.55 (m, 2H), 7.48-7.41 (m, 4H), 5.90 (s,
1H), 5.79 (dd, J = 6.9, 5.3 Hz, 1H), 3.87 (dd, J = 17.0, 6.9 Hz,
1H), 3.61 (m, 1H), 3.26 (dd, J = 17.0, 5.3 Hz, 1H), 1.21 (t, J =
6.9, 3H); 13C NMR major diastereomer (125 MHz, CDCl3): δ
200.5, 169.2, 150.6, 149.6, 135.8, 134.8, 132.3, 130.1, 129.0,
128.1, 126.7, 124.5, 123.2, 120.9, 95.1, 77.5, 62.0, 33.7, 15.4; 1H
NMR minor diastereomer (500 MHz; CDCl3): δ 7.93-7.92 (m,
1H), 7.75-7.74 (m, 1H), 7.58-7.55 (m, 2H), 7.48-7.41 (m, 4H),
5.87 (s, 1H), 5.51-5.50 (m, 1H), 3.79-3.71 (m, 1H), 3.61-3.60 (m,
1H), 3.52-3.50 (m, 1H), 3.31-3.29 (m, 1H), 1.29 (t, J = 6.9 Hz,
3H); 13C NMR minor diastereomer (125 MHz, CDCl3): δ 200.5,
169.2, 150.6, 149.6, 134.3, 134.8, 132.3, 130.1, 129.0, 128.1,
126.7, 124.0, 123.5, 120.9, 95.1, 77.5, 62.0, 33.7, 15.4; IR (thin
film) 2972, 2906, 2871, 1726, 1622, 1571, 1470, 1388, 1328,
1261, 1183 cm-1; HRMS (ESI) m/z calcd. for C19H18NO3Si
(M+H)+ 308.1287, found 308.1279; decomposed at 110 °C.
1
give imidates 10. Diastereomeric ratios were determined by H
NMR spectroscopy.
4.4.2 Imidate 10f. Prepared by general procedure B using 8
(0.080 g; 0.287 mmol), alkenyl boronic acid 2f (0.100 g, 0.574
mmol), Cu(OAc)2 (0.052 g, 0.287 mmol), Na2SO4 (0.300 g, 2.11
mmol), and pyridine (70.0 ꢀL, 0.861 mmol). Flash
chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10f
1
as a white solid (0.077 g, 66%, dr = >95:5). H NMR (500 MHz;
CDCl3): δ 8.08-8.06 (m, 1H), 7.61-7.60 (m, 1H), 7.55-7.51 (m,
2H), 7.46-7.39 (m, 2H), 7.37-7.34 (m, 1H), 7.30-7.29 (m, 1H),
6.07 (s, 1H), 5.94 (dd, J = 13.1, 4.7 Hz, 1H), 3.32-3.26 (m, 1H),
3.16-3.13 (m, 1H), 2.68-2.64 (m, 1H), 2.50-2.42 (m, 1H), 0.92 (s,
9H), 0.14(s, 3H), -0.05 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
192.9, 168.4, 152.7, 143.1, 133.7, 132.1, 131.9, 129.9, 128.6,
128.5, 127.8, 126.9, 122.7, 120.9, 91.1, 78.1, 29.4, 28.0, 25.9,
18.1, -3.8, -4.1; IR (thin film) 2952, 2928, 2854, 1704, 1626,
1603, 1575, 1471, 1460, 1327, 1249 cm-1; HRMS (ESI) m/z
calcd. for C24H30NO3Si (M+H)+ 408.1995, found 408.1985;
decomposed at 128 °C.
4.3.6 Imidate 19t. Prepared using general procedure A with N-
hydroxyisoindolinone 14 (0.080 g; 0.39 mmol), indenyl boronic
acid 2t (0.123 g, 0.772 mmol), Cu(OAc)2 (0.070 g, 0.39 mmol),
Na2SO4 (0.298 g, 2.09 mmol), and pyridine (93.0 ꢀL, 1.16
mmol). Flash chromatography (1:4; EtOAc: hexanes) on
Florisil® afforded 19t as a white solid (0.060 g, 48%, dr = 97:3).
1H NMR major diastereomer (500 MHz; CDCl3): δ 7.86-7.84 (m,
1H), 7.66-7.63 (m, 1H), 7.55-7.54 (m, 2H), 7.47-7.40 (m, 4H),
5.83 (s, 1H), 5.69 (dd, J = 7.6, 4.7 Hz, 1H), 3.91-3.90 (m, 1H),
3.83 (dd, J = 16.4, 7.6 Hz, 1H), 3.32 (dd, J = 16.4, 4.7 Hz, 1H),
1.26 (d, J = 5.9 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H); 13C NMR
major diastereomer (125 MHz, CDCl3): δ 200.5, 168.7, 150.5,
135.6, 134.8, 132.2, 130.0, 128.8, 127.9, 126.6, 124.4, 124.0,
4.4.3 Imidate 10g. Prepared by general procedure B using 8
(0.087 g; 0.31 mmol), Z-1-phenyl-1-buten-1-yl boronic acid 2g
(0.110 g, 0.624 mmol), Cu(OAc)2 (0.057 g, 0.31 mmol), Na2SO4
(0.320 g, 2.25 mmol), and pyridine (90.0 ꢀL, 0.936 mmol). Flash
chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10g
1
123.1, 120.8, 94.2, 77.6, 70.3, 33.5, 23.4, 22.7; H NMR minor
diastereomer (500 MHz; CDCl3): δ 7.94-7.92 (m, 2H), 7.60-7.59
(m, 2H), 7.35-7.29 (m, 4H), 5.87 (s, 1H), 5.44-5.41 (m, 1H), 3.83
(dd, J = 16.4, 7.6 Hz, 1H), 3.70-3.63 (m, 1H), 3.05 (dd, J = 16.4,
3.9 Hz, 1H), 1.35 (d, J = 5.0 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H);
13C NMR minor diastereomer (125 MHz, CDCl3): δ 200.5,
168.7, 150.3, 135.0, 134.8, 132.2, 130.1, 128.8, 127.9, 126.6,
124.2, 124.0, 123.1, 120.8, 94.2, 77.6, 70.3, 33.9, 23.4, 22.7; IR
(thin film) 2968, 2930, 2855, 1726, 1629, 1577, 1463, 1404,
1372, 1274, 1151 cm-1; HRMS (ESI) m/z calcd. for C20H20NO3
(M+H)+ 322.1443, found 322.1436; decomposed at 120 °C.
1
as a white solid (0.075 g, 59%, dr = >95:5). H NMR (500 MHz;
CDCl3): δ 8.07-8.05 (m, 2H), 7.60-7.57 (m, 2H), 7.49-7.40 (m,
5H), 6.17 (t, J = 5.0 Hz, 1H), 5.94 (s, 1H), 2.09-2.04 (m, 2H),
1.14 (t, J = 5.0 Hz, 3H), 0.80 (s, 9H), -0.06 (s, 3H), -0.26 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 196.9, 168.5, 152.6, 135.4,
133.2, 131.7, 129.9, 128.6, 128.5, 128.4, 122.7, 120.7, 91.1, 79.5,
25.7, 25.4, 18.0, 10.1, -4.3, -4.7; IR (thin film) 2928, 2855, 1699,
1627, 1598, 1576, 1471, 1403, 1218, 1117, 1027 cm-1; HRMS
(ESI) m/z calcd. for C24H32NO3Si (M+H)+ 410.2151, found
410.2157; decomposed at 68 °C.
4.3.7 Imidate 20t. Prepared using general procedure A with N-
hydroxyisoindolinone 15 (0.055 g; 0.29 mmol), indenyl boronic
acid 2t (0.093 g, 0.58 mmol), Cu(OAc)2 (0.053 g, 0.29 mmol),
Na2SO4 (0.205 g, 1.44 mmol), and pyridine (70.0 ꢀL, 0.870
mmol). Flash chromatography (1:3; EtOAc: hexanes) on
Florisil® afforded 20t as an amorphous white solid (0.058 g,
4.4.4 Imidate 10l. Prepared by general procedure B using 8
(0.140 g; 0.50 mmol), Z-2-buten-2-yl boronic acid 2l (0.100 g,
1.00 mmol), Cu(OAc)2 (0.091 g, 0.50 mmol), Na2SO4 (0.470 g,
3.30 mmol), and pyridine (120 ꢀl, 1.50 mmol). Flash
chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10l
1
66%, dr = >95:5). H NMR (500 MHz; CDCl3): δ 7.86-7.84 (m,
1
1H), 7.67-7.64 (m, 1H), 7.60-7.59 (m, 1H), 7.50-7.35 (m, 5H),
5.81-5.72 (m, 2H), 5.07-5.01 (m, 2H), 4.75 (t, J = 6.4 Hz, 1H),
3.86 (dd, J = 17.0, 7.7 Hz, 1H), 3.23 (dd, J = 17.0, 4.6 Hz, 1H),
2.60-2.57 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 201.0, 168.0,
as a colorless liquid (0.108 g, 65%, dr = >95:5). H NMR (500
MHz; CDCl3): δ 7.54-7.44 (m, 2H), 7.43-7.39 (m, 2H), 5.96 (s,
1H), 5.35 (q, J = 5.0 Hz, 1H), 2.24 (s, 3H), 1.54 (d, J = 5.0 Hz,
3H), 0.93 (s, 9H), 0.18 (s, 3H), 0.02 (s, 3H); 13C NMR (125

9
MHz, CDCl3): δ 207.2, 168.3, 152.6, 131.6, 130.1, 128.6, 122.8,
120.5, 90.9, 78.5, 25.7, 25.4, 18.1, 16.6, -4.0, -4.6; IR (thin film)
2956, 2928, 2858, 1729, 1625, 1581, 1470, 1401, 1255, 1192,
1116 cm-1; HRMS (ESI) m/z calcd. for C18H28NO3Si (M+H)+
334.1838, found 334.1844.
4.4.8 Imidate 10v. Prepared by general procedure B using 8
ACCEPTED MANUSCRIPT
(0.060 g; 0.21 mmol), boronic acid 2v (0.076 g, 0.43 mmol),
Cu(OAc)2 (0.039 g, 0.21 mmol), Na2SO4 (0.224 g, 1.57 mmol),
and pyridine (50.0 ꢀL, 0.642 mmol). Flash chromatography (1:4;
EtOAc: hexanes) on Florisil® afforded 10v as a white solid
(0.053 g, 61%, dr = >95:5). 1H NMR (500 MHz; CDCl3): δ 7.60-
7.51 (m, 4H), 7.44-7.39 (m, 5H), 6.30 (s, 1H), 5.98 (s, 1H), 2.70-
2.62 (m, 1H), 2.63-2.53 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H), 0.95 (s,
9H), 0.19 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
205.6, 168.3, 152.6, 134.4, 131.5, 130.1, 128.9, 128.8, 128.5,
127.7, 122.8, 120.7, 91.1, 83.5, 31.5, 25.9, 18.1, 7.1, -4.0, -4.5;
IR (thin film) 2930, 2858, 1729, 1625, 1570, 1469, 1388, 1326,
1258, 1193, 1125 cm-1; HRMS (ESI) m/z calcd. for C24H32NO3Si
(M+H)+ 410.2151, found 410.2144; decomposed at 80 °C.
4.4.5 Imidate 10n. Prepared by general procedure B using 8
(0.175 g; 0.625 mmol), 1-cyclopentenyl boronic acid 2n (0.140 g,
1.25 mmol), Cu(OAc)2 (0.114 g, 0.625 mmol), Na2SO4 (0.650 g,
4.57 mmol), and pyridine (150 ꢀL, 1.87 mmol). Flash
chromatography (1:3; EtOAc: hexanes) on Florisil® afforded
1
10n as a colorless liquid (0.138 g, 64%, dr = 80:20). H NMR
major diastereomer (500 MHz; CDCl3): δ 7.51-7.48 (m, 2H),
7.41-7.35 (m, 2H), 6.00 (s, 1H), 5.32 (t, J = 5.0 Hz, 1H), 2.65-
2.60 (m, 1H), 2.41-2.38 (m, 2H), 2.18-2.13 (m, 2H), 1.93-1.88
(m, 1H), 0.94 (s, 9H), 0.19 (s, 3H), 0.01 (s, 3H); 13C NMR major
diastereomer (125 MHz, CDCl3): δ 212.3, 168.0, 152.4, 131.7,
129.9, 128.5, 122.7, 120.7, 90.8, 79.2, 35.2, 28.2, 25.8, 18.1,
17.1, -3.8, -4.2; 1H NMR minor diastereomer (500 MHz; CDCl3):
δ 7.43-7.35 (m, 4H), 6.00 (s, 1H), 5.32 (t, J = 5.0 Hz, 1H), 2.65-
2.60 (m, 1H), 2.41-2.38 (m, 2H), 2.18-2.13 (m, 2H), 1.93-1.88
(m, 1H), 0.91 (s, 9H), 0.19 (s, 3H), 0.09 (s, 3H); 13C NMR minor
diastereomer (125 MHz, CDCl3): δ 212.3, 168.0, 152.4, 131.7,
129.9, 128.5, 122.7, 120.7, 90.8, 79.2, 35.2, 28.2, 25.7, 18.1,
17.1, -3.8, -4.2; IR (thin film) 2929, 2856, 1706, 1576, 1470,
1401, 1361, 1255, 1099, 1072 cm-1; HRMS (ESI) m/z calcd. for
C19H28NO3Si (M+H)+ 346.1828, found 346.1842.
4.4.9 Imidate 10w. Prepared by general procedure B using 8
(0.049 g; 0.18 mmol), alkenyl boronic acid 2w (0.0.40 g, 0.35
mmol), Cu(OAc)2 (0.032 g, 0.18 mmol), Na2SO4 (0.183 g, 1.29
mmol), and pyridine (40.0 ꢀL, 0.525 mmol). Flash
chromatography (1:3; EtOAc: hexanes) on Florisil® afforded
1
10w as a colorless liquid (0.038 g, 68 %). H NMR (500 MHz;
CDCl3): δ 7.51-7.39 (m, 4H), 5.94 (s, 1H), 2.18 (s, 3H), 1.68 (s,
3H), 1.67 (s, 3H), 0.94 (s, 9H), 0.22 (s, 3H), 0.10 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 207.7, 166.7, 152.2, 132.4, 129.9,
128.5, 122.6, 120.5, 90.8, 85.9, 25.9, 24.1, 23.6, 23.4, 18.2, -4.1,
-5.0; IR (thin film) 2953, 2926, 2884, 2854, 1719, 1626, 1605,
1578, 1470, 1390, 1255, 1194 cm-1; HRMS (ESI) m/z calcd. for
C19H30NO3Si (M+H)+ 348.1995, found 348.1994.
4.4.6 Imidate 10s. Prepared by general procedure B using 8
(0.100 g; 0.357 mmol), alkenyl boronic acid 2s (0.100 g, 0.714
mmol), Cu(OAc)2 (0.065 g, 0.71 mmol), Na2SO4 (0.373 g, 2.62
mmol), and pyridine (90.0 ꢀL, 1.07 mmol). Flash
chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10s
as a semi-solid (0.085 g, 64%, dr = 69:31) 1H NMR major
diastereomer (500 MHz; CDCl3): δ 7.54-7.51 (m, 2H), 7.43-7.41
(m, 2H), 5.98 (s, 1H), 5.27 (d, J = 10.0 Hz, 1H), 2.54-2.47 (m,
3H), 2.09-1.95 (m, 4H), 1.18 (d, J = 5.0 Hz, 3H), 0.89 (s, 9H),
0.05 (s, 3H), -0.16 (s, 3H); 13C NMR major diastereomer (125
MHz, CDCl3): δ 204.2, 168.6, 152.7, 133.0, 129.9, 128.4, 122.8,
120.7, 91.2, 85.0, 40.4, 40.0, 32.8, 26.0, 25.8, 25.6, 18.8, -3.9, -
4.5. Alkenylation and thermal rearrangement of 8 with
alkenylboronic acid 3a. Characterization of 9a and 10a.
4.5.1 N-Enoxyisoindolinone 9a. A scintillation vial was charged
with 3-siloxy-N-hydroxyisoindolinone 8 (0.164 g; 0.586 mmol),
E-1-hexen-1-yl boronic acid 1d (0.150 g, 1.17 mmol), Cu(OAc)2
(0.106 g, 0.586 mmol), and anhydrous Na2SO4 (0.507 g, 3.56
mmol). These solids were then diluted with 1,2-dichloroethane to
form a 0.1 M solution of 8. Pyridine (143 ꢀl, 1.76 mmol) was
added to the resulting slurry via syringe. The scintillation vial
was then capped with a septum pierced with a ventilation needle
and the reaction mixture was allowed to stir at 25 °C for 12 h.
The reaction mixture was then concentrated under vacuum and
the crude product was purified by medium pressure
chromatography (1:4; EtOAc:hexanes) to give 9a as a colorless
1
4.0; H NMR minor diastereomer (500 MHz; CDCl3): δ 7.58-
7.57 (m, 2H), 7.41-7.38 (m, 2H), 6.01 (s, 1H), 5.54 (d, J = 10.0
Hz, 1H), 2.20-2.07 (m, 4H), 1.72-1.62 (m, 3H), 1.10 (d, J = 5.0
Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), -0.11 (s, 3H); 13C NMR
minor diastereomer (125 MHz, CDCl3): δ 205.6, 168.2, 152.7,
133.0, 129.9, 129.7, 123.8, 123.1, 82.9, 82.2, 37.4, 31.1, 29.8,
25.8, 23.2, 18.0, 13.6, -3.9, -4.0; IR (thin film) 2928, 2855, 1733,
1626, 1471, 1319, 1249, 1194, 1121, 1046 cm-1; HRMS (ESI)
m/z calcd. for C21H32NO3Si (M+H)+ 374.2151, found 374.2153.
1
liquid (0.174 g, 82%). H NMR (500 MHz; CDCl3): δ 7.79 (d, J
= 7.4 Hz, 1H), 7.61 (dd, J = 7.6, 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz,
1H), 7.44 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 12.3 Hz, 1H), 5.98 (s,
1H), 5.26 (td, J = 12.3, 7.4 Hz, 1H), 1.96-1.92 (m, 2H), 1.33-1.29
(m, 4H), 0.95 (s, 9H), 0.86 (t, J = 6.9 Hz, 3H), 0.27 (s, 3H), 0.20
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.1, 147.1, 142.1,
133.2, 129.8, 128.7, 123.8, 123.1, 107.4, 82.5, 32.0, 26.5, 25.6,
22.1, 18.0, 13.8, -4.3, -4.5; IR (thin film) 2955, 2928, 2857, 1740,
1667, 1466, 1361, 1252, 1203, 1117 cm-1; HRMS (ESI) m/z
calcd. for C20H32NO3Si (M+H)+ 362.2151, found 362.2142.
4.4.7 Imidate 10u. Prepared by general procedure B using 8
(0.127 g; 0.454 mmol), cyclooctenyl boronic acid 2u (0.140 g,
0.909 mmol), Cu(OAc)2 (0.082 g, 0.45 mmol), Na2SO4 (0.470 g,
3.30 mmol), and pyridine (110.0 ꢀL, 1.362 mmol). Flash
chromatography (1:4; EtOAc: hexanes) on Florisil® afforded
1
4.5.2 Imidate 10a. A J-Young tube was charged with a 0.1 M
solution of N-enoxyisoindolinone 9a (0.040 g, 0.130 mmol) in
toluene-d8. The reaction mixture was heated to 50 °C for 3 h. At
this time, the reaction mixture was concentrated under vacuum to
afford imidate 10a as a yellow oil (0.040 g, >99%, dr = >95:5).
1H NMR (500 MHz; C6D6): δ 9.51 (s, 1H), 7.28-7.37 (m, 1H),
7.38-6.99 (m, 3H), 5.92 (s, 1H), 5.11-5.08 (m, 1H), 1.68-1.66 (m,
2H), 1.24-1.21 (m, 4H), 1.03 (s, 9H), 0.83 (t, J = 5.0 Hz, 3H),
0.29 (s, 3H), 0.16 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 198.6,
168.6, 152.3, 131.5, 129.8, 128.7, 122.7, 120.2, 91.1, 81.7, 29.2,
27.1, 25.7, 22.4, 18.1, 13.6, -4.0, -4.9; IR (thin film) 2955, 2929,
2858, 1738, 1576, 1400, 1379, 1254, 1122, 1075 cm-1; HRMS
10u as a colorless liquid (0.101 g, 57%, dr = >95:5). H NMR
(500 MHz; CDCl3): δ 7.56-7.54 (m, 1H), 7.50-7.48 (m, 1H),
7.43-7.37 (m, 2H), 5.95 (s, 1H), 5.48 (dd, J = 8.5, 3.8 Hz, 1H),
2.74-2.69 (m, 1H), 2.52-2.39 (m, 1H), 2.25-2.19 (m, 1H), 2.15-
2.08 (m, 1H), 2.02-2.01 (m, 2H), 1.87-1.83 (m, 1H), 1.61-1.53
(m, 4H), 1.45-1.37 (m, 1H), 0.92 (s, 9H), 0.14 (s, 3H), -0.05 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 212.7, 168.3, 152.5, 131.7,
129.9, 128.5, 122.7, 120.7, 91.0, 80.3, 41.2, 33.3, 28.1, 25.9,
25.8, 24.9, 23.2, 21.4, -4.0, -4.4; IR (thin film) 2933, 2852, 1724,
1622, 1573, 1466, 1395, 1326, 1241, 1186, 1125 cm-1; HRMS
(ESI) m/z calcd. for C22H34NO3Si (M+H)+ 388.2308, found
388.2300.

10
Tetrahedron
(ESI) m/z calcd. for C20H32NO3Si (M+H)+ 362.2151, found
organic layer was separated and the aqueous layer was extracted
ACCEPTED MANUSCRIPT
362.2139.
with EtOAc (2 x 10.0 mL). The combined organic layers were
washed with brine, dried with MgSO4, and filtered. The filtrate
was concentrated under vacuum and the crude product was
purified by flash column chromatography on Florisil® (10%
Ethyl Acetate, 2% TEA, pentane) to afford methyl-protected
4.6. Hydrolysis and chlorination of 10t. Characterization of 5t
and 21t.
4.6.1 α-Hydroxyketone 5t.25 A 10 mL round bottom flask was
charged with a solution of imidate 10t (0.030 g, 0.076 mmol) in
MeOH:H2O (2.0 mL, 1:1). NH4Cl (0.007 g, 0.125 mmol) was
added to the solution as a solid and the reaction mixture was
heated to 90 °C for 2 h. The reaction mixture was then
concentrated under vacuum and the residue was extracted with
EtOAc (3 x 7.0 mL). The organic layer was then dried with
MgSO4 and concentrated under vacuum. The crude product
mixture was purified by medium pressure chromatography on
silica gel (1:2 EtOAc:hexanes) to give 5t as an amorphous white
1
imidate 27a (0.0570 g, 72%) as an amorphous solid. H NMR
(500 MHz; CDCl3): δ 7.83-7.81 (m, 1H), 7.58-7.56 (m, 1H),
7.51-7.49 (m, 1H), 6.84-6.83 (m, 1H), 6.74-6.73 (m, 1H), 6.73-
6.72 (m, 1H), 2.93 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 165.8, 146.6, 144.5, 144.4, 140.3, 132.9, 132.0, 131.4,
130.7, 123.2, 121.9, 109.6, 109.4, 180.0, 23.1, 21.2; HRMS (ESI)
m/z calcd. for C16H14NO3 (M+H)+ 268.0974, found 268.0977.
4.8.2 Allylated Catechol 28a. A scintillation vial was charged
with imidate 24a (0.0751 g, 0.297 mmol, 1 equiv) and DMF (5.0
mL). This solution was then treated with K2CO3 (0.124 g, 0.900
mmol, 3 equiv) and allyl bromide (0.0390 mL, 0.450 mmol, 1.5
equiv) and then heated to 50 ºC for 18 h. At this time, the
reaction mixture was diluted with EtOAc (10.0 mL) and H2O (5.0
mL). The organic layer was separated and the aqueous layer was
extracted with EtOAc (2 x 10.0 mL). The combined organic
layers were washed with brine, dried with MgSO4, and filtered.
The filtrate was concentrated under vacuum and the crude
product was purified by flash column chromatography on
Florisil® (10% Ethyl Acetate, 2% TEA, pentane) to afford
methyl-protected imidate 28a (0.0501 g, 57%) as an amorphous
1
solid (0.0060 g, 53%). H NMR (500 MHz; CDCl3): δ 7.78-7.76
(m, 1H), 7.66-7.64 (m, 1H), 7.47-7.46 (m, 1H), 7.42-7.39 (m,
1H), 4.54 (dd, J = 7.8, 5.1 Hz, 1H), 3.58 (dd, J = 16.5, 7.8 Hz,
1H), 3.02 (dd, J = 16.5, 5.1 Hz, 1H), 2.92 (s, 1H); 13C NMR (125
MHz, CDCl3): δ 206.3, 150.8, 135.8, 134.0, 128.1, 126.8, 124.4,
74.3, 35.1; IR (thin film) 3469, 2982, 1732, 1609, 1470, 1366,
1299, 1252, 1154, 1047 cm-1; HRMS (ESI) m/z calcd. for
C9H8O2 (M)+ 148.0524, found 148.0531.
4.6.2 α-Chloroketone 5t.26 A 10 mL round bottom flask was
charged with imidate 10t (0.040 g, 0.10 mmol) in CCl4 (2.0 mL).
Oxalyl chloride (8.0 ꢀl, 0.10 mmol) was added via syringe and
the reaction mixture was allowed to stir at 25 °C for 12 h. The
reaction mixture was then concentrated under vacuum and the
crude product was purified by medium pressure chromatography
on silica gel (1:4 EtOAc:hexanes) to give 21t as an amorphous
white solid (0.012 g, 74%). 1H NMR (500 MHz; CDCl3): δ 7.84-
7.83 (m, 1H), 7.68-7.66 (m, 1H), 7.47-7.43 (m, 2H), 4.56 (dd, J =
7.3, 3.8 Hz, 1H), 3.78 (dd, J = 17.4, 7.3 Hz, 1H), 3.30 (dd, J =
17.4, 3.8 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 199.2, 150.7,
136.1, 133.8, 128.3, 126.4, 125.1, 55.7, 37.5; ; IR (thin film)
2956, 2954, 1767, 1726, 1609, 1578, 1470, 1429, 1324, 1277,
1158 cm-1; HRMS (ESI) m/z calcd. for C9H8OCl (M+H)+
167.0264, found 167.0273.
1
solid. H NMR (500 MHz; CDCl3): δ 7.84-7.82 (m, 1H), 7.59-
7.57 (m, 2H), 7.51-7.49 (m, 1H), 6.81-6.79 (m, 1H), 6.76-6.73
(m, 1H), 6.73-6.71 (m, 1H), 5.85-5.80 (m, 1H), 5.02-4.99 (m,
2H), 4.02-4.01 (m, 2H), 2.33 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 165.7, 146.5, 144.4, 140.4, 133.0, 132.9, 131.9, 131.4,
130.5, 123.3, 122.0, 121.9, 117.2, 109.6, 109.4, 108.0, 40.9, 21.2;
IR (thin film) 3084, 2922, 1731, 1495, 1468, 1433, 1384, 1338,
1248, 1214; HRMS (ESI) m/z calcd. for C18H16NO3 (M+H)+
294.1119, found 294.1130.
4.9. General procedure for rearrangement and acetoxylation of
N-aryloxyphthalimides and characterization data
4.9.1 General procedure C. A 5 mL conical vial was charged
with 0.1 M solution of N-aryloxyphthalimide 23 (1 equiv) in
Ac2O and sealed with a Teflon-lined cap. The solution was then
allowed to stir for 18-30 h at 140 °C. The reaction mixture was
then cooled to 25 °C, transferred to a scintillation vial, and
concentrated under vacuum. The crude reaction mixture was then
purified by medium-pressure chromatography on Florisil®, to
give protected imidate 26 as white solid.
4.7. Synthesis of imidate 24a and characterization data.
A 5 mL conical vial was charged with 0.1 M solution of N-
aryloxyphthalimide 23a (0.0767 g, 0.302 mmol, 1 equiv) in
MeCN (3.0 mL), sealed with a Teflon-lined cap, and allowed to
stir for 18 h at 140 °C. The reaction mixture was then cooled to
25 °C, transferred to a scintillation vial, and concentrated under
vacuum. The crude product was purified by medium pressure
chromatography on Florisil® (10% EtOAc, 2% NEt3, pentane) to
afford imidate 24a as white solid (0.0664 g, 89%). 1H NMR (500
MHz; CDCl3): δ 7.83-7.82 (m, 1H), 7.64-7.59 (m, 2H), 7.54-7.52
(m, 1H), 6.85 (m, 1H), 6.83-6.82 (m, 1H), 6.78 (s, 1H), 6.74-6.72
(m, 1H), 2.33 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.7,
146.1, 144.0, 141.4, 133.5, 132.1, 131.5, 130.3, 123.6, 122.3,
122.0, 118.6, 110.0, 108.4, 21.2; IR (thin film) 3249, 2923, 2865,
1727, 1635, 1613, 1494, 1469,1417, 1306 cm-1; HRMS (ESI) m/z
calcd. for HRMS (ESI) m/z calcd. for C15H12NO3 (M+H)+
254.0817, found 254.0810; m.p. 130-132 °C.
4.9.2 Imidate 26a. Prepared by general procedure C using N-
aryloxyphthalimide 23a (0.0767 g, 0.302 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
NEt3, pentane) afforded 26a as white solid (0.0806 g, 91%). H
NMR (500 MHz; CDCl3): δ 7.94-7.92 (m, 1H), 7.76-7.73 (m,
1H), 7.70-7.67 (m, 1H), 7.59-7.58 (m, 1H), 6.81-6.79 (m, 1H),
6.77-6.75 (m, 2H) 2.63 (s, 3H), 2.35 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 169.8, 165.2, 147.1, 145.1, 140.8, 140.6, 135.4,
132.5, 131.9, 128.0, 124.0, 122.7, 122.0, 108.7, 107.2, 26.1, 21.3;
IR (thin film) 3077, 3038, 2924, 1773, 1750, 1725, 1496, 1371,
1343, 1254 cm-1; HRMS (ESI) m/z calcd. for C17H13NO4Na
(M+Na+) 318.0742, found 318.0740; m.p. 129-130 ºC.
4.8. Alkylation of imidate 24a and characterization data for 27a
and 28a.
4.8.1 Methylated catechol 27a. A scintillation vial was charged
with imidate 24a (0.0753 g, 0.297 mmol, 1 equiv) and DMF (7.5
mL). This solution was then treated with K2CO3 (0.099 g, 0.72
mmol, 2.4 equiv) and MeI (0.022 mL, 0.36 mmol, 1.2 equiv) and
then heated to 50 ºC for 18 h. At this time, the reaction mixture
was diluted with EtOAc (10.0 mL) and H2O (5.0 mL). The
4.9.3 Imidate 26b. Prepared using general procedure C using N-
aryloxyphthalimide 23b (0.0773 g, 0.301 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
NEt3, pentane) afforded 26b as white solid (0.0766 g, 85%). H

11
NMR (500 MHz; CDCl3): δ 7.95-7.93 (m, 1H), 7.79-7.75 (m,
C2 H15NO4Na (M+Na+) 380.0899, found 380.0900; m.p. 74-
75 ºC.
ACCEPTED MANUSCRIPT
2
1H), 7.72-7.69 (m, 1H), 7.60-7.59 (m, 1H), 6.82-6.80 (m, 1H),
6.69-6.63 (m, 2H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
169.8, 164.9, 159.0, 157.1, 147.5 (d, JCF = 13.9 Hz), 143.4,
140.1, 135.5, 132.5, 127.9, 124.5, 122.8, 107.3 (d, JCF = 18.5
Hz), 107.2 (d, JCF = 3.4 Hz), 97.6 (d, JCF = 37.5), 26.1; IR (thin
film) 3080, 1774, 1750, 1713, 1488, 1470, 1416, 1314, 1155,
1127; HRMS (ESI) m/z calcd. for C16H10NO4NaF (M+Na+)
322.0492, found 322.0483; m.p. 147-148 ºC.
4.9.8 Imidate 26g. Prepared by general procedure C using N-
aryloxyphthalimide 23g (0.0955 g, 0.300 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 30 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
NEt3, pentane) afforded 26g as white solid (0.0608 g, 53%). H
NMR (500 MHz; CDCl3): δ 7.95-7.93 (m, 1H), 7.78-7.75 (m,
1H), 7.73-7.70 (m, 1H), 7.58-7.57 (m, 1H), 7.10-7.09 (m, 1H),
7.06-7.02 (m, 1H), 6.80-6.78 (m, 1H), 2.63 (s, 1H); 13C NMR
(125 MHz, CDCl3): δ 169.8, 164.9, 147.9, 146.6, 140.9, 139.9,
135.5, 132.5, 127.9, 124.7, 124.5, 122.8, 113.6, 111.6, 108.9,
26.1; IR (thin film) 2921, 2865, 1773,1750, 1713, 1477, 1370,
1349, 1155, 1135; HRMS (ESI) m/z calcd. for C16H10NO4NaBr
(M+Na+) 381.9691, found 381.9679; m.p 156-157 ºC.
4.9.4 Imidate 26c. Prepared by general procedure C using N-
aryloxyphthalimide 23c (0.0832 g, 0.304 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 30 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
NEt3, pentane) afforded 26c as white solid (0.0641 g, 68%). H
NMR (500 MHz; CDCl3): δ 7.94-7.93 (m, 1H), 7.78-7.75 (m,
1H), 7.72-7.69 (m, 1H), 7.58-7.57 (m, 1H), 6.95- 6.92 (m, 2H),
6.83-6.81 (m, 1H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
169.8, 164.9, 147.7, 146.1, 140.7, 140.0, 135.6, 132.6, 128.0,
126.8, 124.6, 122.8, 121.7, 109.0, 108.2, 26.1; IR (thin film)
3097, 2939, 2854, 1774, 1752, 1726, 1482, 1317, 1252, 801;
HRMS (ESI) m/z calcd. for C16H10NO4ClNa (M+Na+) 338.0196,
found 338.0191; m.p 106-107 ºC.
4.9.9 Imidate 26j. Prepared by general procedure C using N-
aryloxyphthalimide 23j (0.0807 g, 0.303 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
NEt3, pentane) afforded 26j as white solid (0.0774 g, 83%). H
NMR (500 MHz; CDCl3): δ 7.93-7.92 (m, 1H), 7.76-7.73 (m,
1H), 7.69-7.67 (m, 1H), 7.61-7.59 (m, 1H), 6.59 (s, 2H), 2.63 (s,
3H), 2.31 (s, 3H), 2.21 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
169.6, 165.3, 146.6, 143.5, 141.5, 140.8, 135.4, 132.2, 131.4,
128.1 124.3, 124.0, 122.8, 117.6, 106.1, 26.2, 21.3, 14.6; IR (thin
film) 2921, 2865, 1748, 1724, 1494, 1218, 1370, 1344, 1313,
1247; HRMS (ESI) m/z calcd. for C18H15NO4Na (M+Na+)
332.0899, found 332.0889; m.p. 149-151 ºC.
4.9.5 Imidate 26d. Prepared by general procedure C using N-
aryloxyphthalimide 23d (0.0795 g, 0.300 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
NEt3, pentane) afforded 26d as white solid (0.0586 g, 64%). H
NMR (500 MHz; CDCl3): δ 7.94-7.93 (m, 1H), 7.76-7.74 (m,
1H), 7.71-7.68 (m, 1H), 7.59-7.58 (m, 1H), 7.07-7.05 (m, 1H),
6.98-6.97 (m, 1H), 6.87- 6.85 (m, 1H), 6.68 (dd, J = 10.0, 15.0
Hz, 1H), 6.62 (d, J = 15.0 Hz, 1H), 5.17 (d, J = 15.0 Hz, 1H),
2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 169.8, 165.1, 147.6,
146.9, 140.5, 140.3, 136.3, 135.5, 132.6, 132.4, 128.0, 124.5,
122.7, 121.3, 112.4, 107.5, 104.7, 26.1; IR (thin film) 3085,
3015, 1773, 1749, 1723, 1494, 1444, 1415; HRMS (ESI) m/z
calcd. for C18H13NO4Na (M+Na+) 330.0742, found 330.0740;
m.p. 145-147 ºC.
4.9.10 Imidate 26k. Prepared by general procedure C using N-
aryloxyphthalimide 23k (0.0815 g, 0.302 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was and heated to 140 °C for
18 h. Medium-pressure chromatography on Florisil® (5%
EtOAc, 2% NEt3, pentane) afforded 26k as white solid (0.0807 g,
1
80%). H NMR (500 MHz; CDCl3): (major isomer) δ 7.94-7.92
(m, 1H), 7.77-7.74 (m, 1H), 7.71-7.68 (m, 1H), 7.60-7.59 (m,
1H), 6.81-6.79 (m, 1H), 6.59-6.58 (m, 1H), 6.47-6.45 (m, 1H),
3.79 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): (major
isomer) δ 169.8, 165.2, 155.3, 147.7, 141.4, 140.6, 140.5, 135.4,
4.9.6 Imidate 26e. Prepared by general procedure C using N-
aryloxyphthalimide 23e (0.0897 g, 0.303 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
132.3, 128.0, 124.4, 122.7, 107.1, 105.2, 96.6, 56.0, 26.1; H
NMR (500 MHz; CDCl3): (minor isomer, diagnostic peaks) δ
7.63-7.62 (m, 1H), 6.94-6.91 (m, 1H), 6.67-6.61 (m, 1H), 3.90 (s,
3H); 13C NMR (125 MHz, CDCl3): (minor isomer, diagnostic
peaks) δ 122.9, 107.4, 101.4, 56.4; IR (thin film) 3077, 3009,
2845, 1779, 1755, 1711, 1492. 1465, 1346, 1315; HRMS (ESI)
m/z calcd. for C17H13NO5Na (M+Na+) 334.0691, found
334.0690; m.p. 98-100 ºC.
1
NEt3, pentane) afforded 26e as white solid (0.0942 g, 92%). H
NMR (500 MHz; CDCl3): δ 7.94-7.92 (m, 1H), 7.76-7.73 (m,
1H), 7.70-7.67 (m, 1H), 7.62-7.60 (m, 1H), 6.98-6.96 (m, 2H),
6.83-6.81 (m, 1H), 2.64 (s, 3H), 1.33 (s, 9H); 13C NMR (125
MHz, CDCl3): δ 169.8, 165.3, 147.0, 145.6, 144.7, 140.9, 140.7,
135.4, 132.2, 128.0, 124.4, 122.8, 118.3, 106.8, 105.5, 34.8, 31.7,
26.1; IR (thin film) 2905, 2874, 1773, 1749, 1713, 1506, 1490,
1429, 1370, 1312; HRMS (ESI) m/z calcd. for C20H19NO4Na
(M+Na+) 360.1212, found 360.1203; m.p. 70-72 ºC.
4.9.11 Imidate 26l. Prepared by general procedure C using N-
aryloxyphthalimide 23l (0.085g, 0.31 mmol) and Ac2O (3.0 mL,
0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
1
4.9.7 Imidate 26f. Prepared by general procedure C using N-
aryloxyphthalimide 23f (0.0948 g, 0.301 mmol) and Ac2O (3.0
mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h.
Medium-pressure chromatography on Florisil® (5% EtOAc, 2%
NEt3, pentane) afforded 26l as white solid (0.0.077 g, 76%). H
NMR (500 MHz; CDCl3): δ 7.98-7.97 (m, 1H), 7.87-7.85 (m,
1H), 7.79-7.69 (m, 3H), 7.63-7.61 (m, 1H), 7.57-7.55 (m, 1H),
7.46-7.43 (m, 1H), 7.37-7.34 (m, 1H), 7.29-7.27 (m, 1H); 13C
NMR (125 MHz, CDCl3): δ 169.6, 165.3, 142.7, 140.7, 140.6,
135.5, 132.3, 130.1, 128.5, 128.0, 126.3, 124.4, 124.0, 122.9,
122.1, 119.5, 119.0, 109.6, 109.5, 26.2; IR (thin film); HRMS
(ESI) m/z calcd. for C18H15NO4Na (M+Na+) 354.0742, found
354.0739; m.p. 198-201 ºC.
1
NEt3, pentane) afforded 26f as white solid (0.0731 g, 69%). H
NMR (500 MHz; CDCl3): δ 7.96-7.95 (m, 1H), 7.78-7.75 (m,
1H), 7.72-7.69 (m, 1H), 7.65-7.63 (m, 1H), 7.57-7.56 (m, 2H),
7.44-7.41 (m, 2H), 7.34-7.32 (m, 1H), 7.21-7.19 (m, 1H), 7.16-
7.14 (m, 1H), 6.99-6.98 (m, 1H), 2.66 (s, 3H); 13C NMR (125
MHz, CDCl3): δ 169.8, 165.2, 147.7, 146.6, 140.9, 140.7, 140.4,
136.0, 135.5, 132.4, 128.8, 128.7, 128.0, 127.0, 124.5, 122.8,
121.0, 107.8, 107.0, 26.1; IR (thin film) 3062, 3035, 1772, 1749,
1723, 1479, 1345, 1314; HRMS (ESI) m/z calcd. for
4.10. General procedure for catechol synthesis via imidate
hydrolysis and characterization data
4.10.1 General procedure D. A scintillation vial was charged
with a 0.3 M solution of imidate (1 equiv) in EtOH, treated with

12
Tetrahedron
ACCEPTED MANUSCRIPT
hydrazine hydrate (2 equiv), and sealed with a Teflon-lined
4.10.7 Catechol 25g.27 Prepared by general procedure D using
cap. The solution was then allowed to stir for 12 h at 25 °C. The
reaction mixture was then concentrated under vacuum, dissolved
in EtOAc (10.0 mL), and filtered through glass fiber filter paper.
The filtrate was diluted with H2O (6.0 mL). The aqueous layer
was extracted with EtOAc (6.0 mL x 3). The organic layers were
combined and washed with sat. NH4Cl(aq) (6.0 mL), water (6.0
ml), and brine (6.0 mL), and dried over Na2SO4. The crude
product mixture was then concentrated under vacuum and
imidate 26g (0.109 g, 0.302 mmol), EtOH (3.0 mL, 0.10 M), and
N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography afforded 25g as an amorphous solid (0.0438 g,
77%). 1H NMR (500 MHz; CDCl3): δ 7.02 (s, 1H), 6.93 (d, J = 5,
1H), 6.75 (d, J = 5, 1H), 5.35 (br, 2H); 13C NMR (125 MHz,
CDCl3): δ 144.4, 142.7, 124.0, 118.7, 116.7, 112.6; IR (thin film)
3331, 2923, 2851, 1597, 1651, 1445, 1427, 1327, 882, 851;
HRMS (ESI) m/z calcd. for C6H5O2Br (M+H)+ 187.9473, found
187.9470.
purified by medium-pressure chromatography (1%
- 3%,
NH3•MeOH/CH2Cl2) to give catechol 25.
4.10.8 Catechol 25j.30 Prepared by general procedure D using
imidate 26j (0.0921 g, 0.298 mmol), EtOH (3.0 mL, 0.10 M), and
N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography affored 25j as an amorphous solid (0.0316 g,
4.10.2 Catechol 25a.12c, 27 Prepared by general procedure D using
imidate 26a (0.0891 g, 0.302 mmol), EtOH (3.00 mL, 0.10 M),
and N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography afforded 25a as an amorphous solid (0.0334 g,
1
76%). H NMR (500 MHz; CDCl3): δ 6.54 (s, 1H), 6.53 (s, 1H),
1
90%). H NMR (500 MHz; CDCl3): δ 6.76 (d, J = 10 Hz, 1H),
5.19 (br, 2H), 2.22 (s, 3H), 2.21 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 143.0, 139.6, 130.8, 124.3, 123.4, 113.7, 20.7, 15.5; IR
(thin film) 3357, 2919, 2858, 1603, 1518, 1461, 1302, 1184,
1140, 1034; HRMS (ESI) m/z calcd. for C8H10O2 (M+H)+
138.0681, found 138.0679.
6.70 (s, 1H), 6.61 (d, J = 10 Hz, 1H), 5.29 (br, 2H), 2.24 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 143.3, 141.0, 131.1, 121.5,
116.3, 115.4, 20.7; IR (thin film) 3339, 2920, 2865, 1603, 1518,
1433, 1352, 1281, 1108, 941; HRMS (ESI) m/z calcd. for
C7H8O2 (M+H)+ 124.0524, found 124.0525.
4.10.9 Catechol 25k.12c, 27 Prepared by general procedure D using
imidate 26k (0.0945g, 0.303 mmol), EtOH (3.0 mL, 0.10 M), and
N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography afforded 25k as an amorphous solid (0.0368g,
85%). 1H NMR (500 MHz; CDCl3): (major isomer) δ 6.75 (d, J =
10.0, 1H), 6.49 (s, 1H), 6.32 (d, J = 10.0, 1H), 5.73 (br, 2H), 3.70
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 154.1, 144.7, 137.4,
4.10.3 Catechol 25b.12c, 28 Prepared by general procedure D using
imidate 26b (0.0910g, 0.304 mmol), EtOH (3.0 mL, 0.10 M), and
N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography afforded 25b as an amorphous solid (0.026g,
1
70%). H NMR (500 MHz; CDCl3): δ 6.80-6.77 (m, 1H), 6.66-
6.64 (m, 1H), 6.52-6.49 (m, 1H), 4.93 (br, 2H); 13C NMR (125
MHz, CDCl3): δ 158.2, 144.4 (d, JCF = 11.8 Hz), 139.9, 115.6 (d,
JCF = 9.7 Hz), 106.8 (d, JCF = 22.9), 103.4 (d, JCF = 26.6 Hz); IR
(thin film) 3297, 2923, 2828, 1627, 1518, 1480, 1450, 794, 731,
598; HRMS (ESI) m/z calcd. for C6H5O2F (M+H)+ 128.0274,
found 128.0272.
1
116.0, 105.5, 102.6, 55.8; H NMR (500 MHz; CDCl3): (minor
isomer, diagnostic peaks) δ 6.59 (d, J = 5, 1H), 3.84 (s, 3H); IR
(thin film) 3339, 2938, 2838, 1608, 1516, 1465, 1439, 1358,
1305, 833; HRMS (ESI) m/z calcd. for C7H8O3 (M+H)+
140.0473, found 140.0471.
4.10.4 Catechol 25c.12c, 27 Prepared by general procedure D using
imidate 26c (0.0956 g, 0.302 mmol), EtOH (3.0 mL, 0.10 M),
and N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography afforded 25c as yellow solid (0.0297 g, 69%).
1H NMR (500 MHz; CDCl3): δ 6.93 – 6.89 (m, 1H), 6.81 – 6.75
(m, 2H), 5.30 (br, 2H); 13C NMR (125 MHz, CDCl3): δ 144.2,
142.2, 125.7, 121.0, 116.2, 115.9; IR (thin film) 3346, 1603,
1507, 1432, 1348, 853, 803, 780, 657; HRMS (ESI) m/z calcd.
for C6H5O2Cl (M+H)+ 143.9978, found 143.9981.
4.10.10 Catechol 25l.9d Prepared by general procedure D using
imidate 26l (0.106 g, 0.302 mmol), EtOH (EtOH (3.0 mL, 0.10
M), and N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography afforded 25l as an amorphous solid (0.0366 g,
1
75%). H NMR (500 MHz; CDCl3): δ 8.04-8.02 (m, 1H), 7.76-
7.74 (m, 1H), 7.46-7.45 (m, 1H), 7.37-7.36 (m, 2H), 7.16-7.13
(m, 1H), 5.59 (br, 2H); 13C NMR (125 MHz, CDCl3): δ 138.6,
137.1, 127.9, 125.7, 125.6, 123.9, 120.9, 120.8, 120.2, 117.3; IR
(thin film) 3362, 3057, 2930, 2843, 1604, 1583, 1515, 1476,
1451, 1357; HRMS (ESI) m/z calcd. for C10H7O2 (M+H)-
159.0446, found 156.0450.
4.10.5 Catechol 25e.29 Prepared by general procedure D with
imidate 26e (0.1001 g, 0.297 mmol), EtOH (3.0 mL, 0.10 M),
and N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography affored 25e as an amorphous solid (0.0405 g,
Acknowledgments
1
83%). H NMR (500 MHz; CDCl3): δ 6.95-6.92 (m, 1H), 6.81-
We are grateful to the National Science Foundation (NSF-CHE
1212895 and 1464115), the ACS PRF (DNI 50491), and the
University of Illinois at Chicago for their generous financial
support. We thank Mr. Furong Sun (UIUC) for high resolution
mass spectrometry data.
6.79 (m, 2H), 1.26 (s, 9H), the OH resonances were too broad to
be observed; 13C NMR (125 MHz, CDCl3): δ 144.8, 143.0, 140.9,
117.8, 115.1, 113.1, 34.2, 31.5; IR (thin film) 3346, 2962, 2903,
2868, 1602, 1524, 1432, 1392, 865, 809; HRMS (ESI) m/z calcd.
for C10H14O2 (M+H)+ 166.0994, found 166.0991.
Author information
4.10.6 Catechol 25f.11a Prepared by general procedure D using
imidate 26f (0.1069 g, 0.299 mmol), EtOH (3.0 mL, 0.10 M), and
N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure
chromatography affored 25f as a yellow solid (0.0429 g, 77%).
1H NMR (500 MHz; CDCl3): δ 7.52-7.51 (m, 2H), 7.42-7.39 (m,
2H), 7.32-7.29 (m, 1H), 7.13 (br, 1H), 7.07-7.05 (m, 1H), 6.95-
6.93 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 143.7, 143.1,
140.6, 134.8, 128.7, 126.9, 126.7, 119.9, 115.7, 114.3; IR (thin
film) 3306, 3060, 3037, 2923, 2852, 1488, 1463, 1422; HRMS
(ESI) m/z calcd. for C12H10O2 (M+H)+ 186.0681, found 186.0681;
m.p 132-134.
Corresponding Author
*E-mail: lauralin@uic.edu.
Notes
The authors declare no competing financial interest.
Supplementary Material
Supplementary data associated with this article can be found in
the online version.

13
Tetrahedron Lett. 2005, 46, 3541. (e) Uyanik, M.; Mutsuga,
T.; Ishihara, K. Molecules 2012, 17, 8604.
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ACCEPTED MANUSCRIPT
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