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

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

DOI:

10.1016/j.tet.2017.01.061

Reference:

TET 28431

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. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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

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Michelle A. Kroc, Aditi Patil, Anthony Carlos, Josiah Ballantine, Stephanie Aguilar, Dong-Liang Mo, HengYen Wang, Daniel S. Mueller, Donald J. Wink, Laura L. Anderson Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607 USA

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Tetrahedron journal homepage: www.elsevier.com

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

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Affiliation 1, Address, City and Postal Code, Country Affiliation 2, Address, City and Postal Code, Country

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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*

ABSTRACT

Article history: Received Received in revised form Accepted Available online

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 Nenoxyphthalimides, 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 Nenoxyisoindolinones have also been shown to be diastereoselective.

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1. Introduction

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Keywords: α-oxygenation catechol [3,3]-rearrangement Chan-Lam Boronic acid

mechanistic pathway to provide access to these important compounds.

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Oxygenation reactions of ketones, aldehydes, and phenols are important processes for the synthesis of α-oxygenated carbonyl compounds and catechols. Common methods for the αoxygenation 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 orthoquinones 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 reactions by utilizing alternative reagents and a unique

2009 Elsevier Ltd. All rights reserved.

Scheme 1. Common approaches to the synthesis of αoxygenated ketones and catechols.

Tetrahedron

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The rearrangements of O-carbonylatedACCEPTED oximes for the MANUSCRIPT 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 carbonateprotected 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.

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Scheme 3. Dioxygenation of alkenylboronic acids via Nenoxyphthalimide rearrangements – Anderson and coworkers 2012. 2. Results and Discussion

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Scheme 2. α-Oxygenation reactions and 1,2-aminophenol synthesis using hydroxylamine condensation and rearrangement reactions – Tomkinson and coworkers.

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Recently, we communicated a two-step method for the dioxygenation of alkenylboronic acids and the synthesis of αoxygenated 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 αhydroxyketones 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 αoxygenated 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 Nenoxyisoindolinones (Scheme 3B), and discuss our discovery of a related arylboronic acid dioxygenation process for the synthesis of substituted catechols (Scheme 3C).

2.1. Rearrangements of N-enoxyphthalimides for the synthesis of α-oxygenated ketones In order to explore the rearrangements of Nenoxyphthalimides 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 Nhydroxyphthalimide 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.

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rearrangement, and ACCEPTED MANUSCRIPT

hydrolysis process in hand, a robust and versatile method for the synthesis of α-oxygenated ketones from alkenylboronic acids was developed. 2.2. Diastereoselective rearrangements of N-enoxyphthalimides

Scheme 4. Preparation of N-enoxyphthalimides.17

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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 αhydroxyketones 5 and α-benozyloxy ketones 6, provided αoxygenated 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,

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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 2Me-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 5. Rearrangement enoxyphthalimides.17

and

Scheme 6. Diastereoselectivity of 2- and 6-substituted cyclohexenyl hydroxylamine ether rearrangements.17

hydrolysis

of

N-

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

4

Tetrahedron

backbone was more effective at ACCEPTED controlling the MANUSCRIPT diastereoselectivity of the formal [3,3]-rearrangement of O intermediate 9m than the cyclohexenyl ether substituents of 3q O and 3r. The single-flask process at ambient temperature also H suggested that N-enoxyisodindolinone rearrangements occur at N 20 lower temperatures than N-enoxyphthalimide rearrangements.

=

OTBS

Scheme 9. X-ray crystal structure of 10t.

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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 Nhydroxyisoindolinone 8. Optimization of the Chan-Lam coupling and rearrangement reaction conditions for 8 and 2t showed that the conditions determined for the Nhydroxyphthalimide Chan-Lam reactions illustrated in Scheme 4 were equally efficient for the single-flask Nhydroxyisoindolinone synthesis and 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).

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Scheme 7. Diastereoselective 3-substituted isoindolinone rearrangements.

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 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

(HO) 2B

O

O

2t

N OH

O N

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R 8, 11 – 15

O

O

OTBS

10t (61%, dr = >95:5)

O N

Cu(OAc)2, Py, Na 2SO 4 DCE, 25 °C, air

N

O

OTIPS

16t (64%, dr = >95:5)

O O

OEt 18t (53%, dr = 92:8)

N

N

O

R 10, 16 – 20

O N

O

OMe 17t (50%, dr = 92:8)

O O N

O

Oi-Pr 19t (48%, dr = >95:5)

20t (66%, dr = >95:5)

Scheme 8. Isoindolinone substituent screen for Nhydroxyisoindolinone single-flask C–O bond coupling and rearrangement reactions.

Scheme 10. Scope of alkenylboronic acids for Nhydroxyisoindolinone C–O bond coupling and rearrangement reactions.

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rearrangements of N-enoxyisoindolinones 9 and indicate that the MANUSCRIPT 1).18b As shown in Table 1, only moderate reactivity was ACCEPTED C–O bond coupling and rearrangement conditions for observed in PhMe or C6H5Cl at or below 120 °C, but good isoindolinone 8 (Scheme 10) tolerate an even broader selection of conversion to the desired product was observed at 140 °C in alkenylboronic acids than the original N-enoxyphthalimide these solvents. The reaction temperature could be decreased to synthesis and rearrangements described in Schemes 4 and 5.22 120 °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.

2.3. Rearrangements of N-aryloxyphthalimides

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Optimization of conditions for the rearrangement of Naryloxyphthalimides

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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.

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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 αoxygenated ketones 5 and 6, we wondered if Naryloxyphthalimides 23 would undergo analogous 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 orthoquinone.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.

Scheme 12. Catechol arylboronic acids.

synthesis

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Scheme 11. Hydrolysis of imidate 10t.

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.

a

dioxygenation

Entry

X

Solvent

Additive

T (°C)

# Yield (%)a

1

Me

PhMe

none

120

24a (51)

2

Me

PhMe

none

140

24a (76)

3

Me

C6H5Cl

none

120

24a (59)

4

Me

C6H5Cl

none

140

24a (87)

5

Me

MeCN

none

100

24a (68)

6

Me

MeCN

none

120

24a (>99)

7

Me

PhMe:DMFb

Ac2O

120

26a (>99)

8

Me

Ac2O

none

140

26a (98)

9

F

MeCN

none

120

24b (45)

10

F

Ac2O

none

140

26b (85)

11

Cl

MeCN

none

120

24c (40)

12

Cl

Ac2O

none

140

26c (68)

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Conditions: 0.1 M solution of 23a, 18 h. PhMe:DMF = 1:1.

of

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

Scheme 13. Rearrangement product alkylation. The scope of the formal [3,3]-rearrangement of Naryloxyphthalimides 23 for the synthesis of acetate and imidate protected catechols 24 was explored with a variety of different

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3. Conclusion

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substrates prepared from the corresponding ACCEPTED arylboronic acids MANUSCRIPT (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. 3,5Dimethylaryl-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 Scheme 15. Scope of imidate hydrolysis and catechol synthesis of substituted catechols. synthesis.

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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 αhydroxyketones 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 Nenoxyphthalimide 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 Nhydroxyphthalimide, and have expanded the scope and application of N–O bond rearrangements in organic synthesis.

Scheme 14. Scope of N-aryloxyphthalimide rearrangement.

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With several imidate-protected catechols in hand, we decided to test deprotection conditions for the imidate and acetate functionalities to release the corresponding catechols. Gabrieldeprotection 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 1

H 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 µm) 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

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4.3.1 General procedure A. A scintillation vial was charged Alkenyl boronic acids 2, N-enoxyphthalimides 3, imidates 4, MANUSCRIPT ACCEPTED with the 3-substituted-N-hydroxyisoindolinones 8, 11, 12, 13, 14, α-hydroxyketones 5, and α-benzoyloxyketones 6 were prepared or 15 (1 equiv),24 indenyl boronic acid 2t (2 equiv), Cu(OAc)2 (1 as described previously.17 N-Aryloxyphthalimides 23 were made 18b, as described previously or prepared by an analogous method. equiv), and anhydrous Na2SO4 (4-6 equiv). These solids were 24 Aryl boronic acids 22 were made as described previously or then diluted with 1,2-dichloroethane to form a 0.1 M solution of purchased from commercial sources.25 the N-hydroxyisoindolinone. Pyridine (3 equiv) was added to the resulting slurry via syringe. The scintillation vial was capped 4.2. Reduction of siloxyphthalimide 7 and treatment with with a septum, pierced with a ventilation needle, and the reaction cyclohexenylboronic acid 2m for the synthesis of 10m. mixture was allowed to stir at 25 °C for 12 h. The reaction mixture was then filtered through a plug of Florisil® with EtOAc 4.2.1 Preparation of 8. A 50 mL round bottom flask was charged (5.0 mL) to remove the Cu(OAc)2. The filtrate was concentrated with 2-((t-butyldimethylsilyl)oxy)isoindoline-1,3-dione 724 (4.00 under vacuum and the crude product mixture was purified by g, 14.4 mmol) and MeOH (30 mL) and cooled to 0 ºC with an ice flash chromatography on Florisil® (1:4 - 1:2; EtOAc:hexanes) to bath. NaBH4 (0.818 g, 21.6 mmol, 1.5 equiv) was then added as give imidates 10t, 16t, 17t, 18t, 19t, or 20t. Diastereomeric ratios a solid. After the evolution of H2 was complete, the reaction were determined by 1H NMR spectroscopy. mixture was warmed to 25 °C and stirred for 4 h. The reaction mixture was then concentrated under vacuum and the residue was 4.3.2 Imidate 10t. Prepared using general procedure A with 3dissolved in EtOAc (30 mL) and extracted with sat. NH4Cl(aq) (30 silyloxy-N-hydroxyisoindolinone 8 (0.100 g; 0.357 mmol), mL). The aqueous layer was then back extracted with EtOAc (3 x indenyl boronic acid 2t (0.114 g, 0.714 mmol), Cu(OAc)2 (0.065 20 mL). The organic layers were combined and washed with H2O g, 0.36 mmol), Na2SO4 (0.373 g, 2.62 mmol), and pyridine (86.6 (3 x 20 mL), brine (1 x 20 mL), dried with MgSO4 and µL, 1.07 mmol). Flash chromatography (1:4; EtOAc: hexanes) on concentrated under vacuum. The crude reaction mixture was then Florisil® afforded 10t as a white solid (0.086 g, 61%, dr = purified by medium pressure chromatography on silica gel (1:1 >95:5). 1H NMR (500 MHz; CDCl3): δ 7.84-7.83 (m, 1H), 7.651 EtOAc:hexanes) to give 8 as a white solid (3.30 g, 82 %). H 7.62 (m, 1H), 7.53-7.37 (m, 6H), 5.95 (s, 1H), 5.54-5.52 (m, 1H), NMR (500 MHz; CDCl3): δ 10.08 (bs, 1H), 7.68-7.67 (m, 1H), 3.76 (dd, J = 16.7, 7.8 Hz, 1H), 3.43 (dd, J = 16.7, 4.5 Hz, 1H), 7.58-7.54 (m, 1H), 7.46-7.43 (m, 2H), 5.97 (s, 1H), 1.00 (s, 9H), 0.87 (s, 9H), 0.08 (s, 3H), -0.07 (s, 3H); 13C NMR (125 MHz, 13 0.34 (s, 3H), 0.30 (s, 3H); C NMR (125 MHz, CDCl3): δ 165.5, CDCl3): δ 200.5, 167.7, 152.6, 150.3, 135.6, 135.1, 131.6, 130.0, 141.9, 132.5, 129.5, 129.3, 123.2, 122.9, 83.2, 25.7, 18.2, -4.1, 128.5, 127.9, 126.7, 124.3, 122.7, 120.8, 90.7, 77.9, 33.1, 25.8, 4.8; IR (thin film) 3114, 2928, 2886, 2858, 1701, 1616, 1505, 18.1, -4.1, -4.6; IR (thin film) 2927, 2854, 1727, 1629, 1609, 1467, 1398, 1356, 1255, 1158 cm-1; HRMS (ESI) m/z calcd. for 1579, 1469, 1396, 1329, 1272, 1186 cm-1; HRMS (ESI) m/z + C14H22NO3Si (M+H) 280.1369, found 280.1371; mp 147 ºC. calcd. for C H NO Si (M+H)+ 394.1838, found 394.1846; 23

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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 1,2dichloroethane to form a 0.1 M solution of 8. Pyridine (110.0 µL, 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 solid (0.121 g, 71%, dr = 89:11). 1H 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), 2.121.94 (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), 2.031.82 (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 cm1 ; HRMS (ESI) m/z calcd. for C20H30NO3Si (M+H)+ 360.1995, found 360.1988; decomposed at 91 °C. 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.

28

3

decomposed at 84-85 °C. Crystallized from CDCl3 with hexane diffusion. CCDC 1504598.

4.3.3 Imidate 16t. Prepared using general procedure A with 3siloxy-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 µL, 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), 7.657.64 (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.

4.3.4 Imidate 17t. Prepared using general procedure A with Nhydroxyisoindolinone 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 µL, 1.00 mmol). Flash chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 17t as a white solid (0.049 g, 50%, dr = 92:8). 1 H 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, 53.7, 33.6; 1H 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), 7.487.40 (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

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M AN U

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153.7, 150.8, 135.7, 134.9, 134.4, 132.3, 129.1, 128.0, 127.3, minor diastereomer (125 MHz, CDCl3): δ 200.4, 164.8, 163.1, MANUSCRIPT ACCEPTED 126.7, 124.5, 122.3, 120.9, 117.4, 68.3, 77.2, 37.6, 33.9; IR (thin 149.0, 135.8, 134.8, 132.4, 130.2, 129.1, 128.1, 126.7, 124.5, film) 2953, 2934, 2855, 1774, 1714, 1600, 1571, 1467, 1381, 123.2, 121.0, 95.8, 77.6, 53.7, 26.7; IR (thin film) 2965, 2930, 1290, 1188 cm-1; HRMS (ESI) m/z calcd. for C20H18NO2 (M+H)+ 1736, 1625, 1603, 1570, 1459, 1395, 1333, 1274, 1189 cm-1; + HRMS (ESI) m/z calcd. for C18H16NO3 (M+H) 294.1130, found 304.1338, found 304.1343. 294.1127; decomposed at 101 °C. 4.4. General procedure for the single-flask alkenylation and rearrangement of 8 with alkenylboronic acids 2. 4.3.5 Imidate 18t. Prepared using general procedure A with NCharacterization of 10f, 10g, 10l, 10n, 10s, 10u – 10w. 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), 4.4.1 General procedure B. A scintillation vial was charged with Na2SO4 (0.298 g, 2.09 mmol), and pyridine (100 µL, 1.23 mmol). 3-silyloxy-N-hydroxyisoindolinone 8 (1 equiv), alkenyl boronic Flash chromatography (1:4; EtOAc: hexanes) on Florisil® 1 acid 2 (2 equiv), Cu(OAc)2 (1 equiv), and anhydrous Na2SO4 (4-6 afforded 18t as a white solid (0.067 g, 53%, dr = 92:8). H NMR equiv). These solids were then diluted with 1,2-dichloroethane to major diastereomer (500 MHz; CDCl3): δ 7.85-7.84 (m, 1H), form a 0.1 M solution of 8. Pyridine (3 equiv) was added to the 7.87-7.84 (m, 1H), 7.58-7.55 (m, 2H), 7.48-7.41 (m, 4H), 5.90 (s, resulting slurry via syringe. The scintillation vial was then 1H), 5.79 (dd, J = 6.9, 5.3 Hz, 1H), 3.87 (dd, J = 17.0, 6.9 Hz, capped with a septum, pierced with a ventilation needle, and the 1H), 3.61 (m, 1H), 3.26 (dd, J = 17.0, 5.3 Hz, 1H), 1.21 (t, J = 13 reaction mixture was allowed to stir at 25 °C for 8 h. The reaction 6.9, 3H); C NMR major diastereomer (125 MHz, CDCl3): δ mixture was filtered through a plug of Florisil® with EtOAc (5.0 200.5, 169.2, 150.6, 149.6, 135.8, 134.8, 132.3, 130.1, 129.0, 1 mL) to remove the Cu(OAc)2. The filtrate was concentrated 128.1, 126.7, 124.5, 123.2, 120.9, 95.1, 77.5, 62.0, 33.7, 15.4; H under vacuum and the crude product mixture was purified by NMR minor diastereomer (500 MHz; CDCl3): δ 7.93-7.92 (m, flash chromatography on Florisil® (1:4 - 1:2; EtOAc:hexanes) to 1H), 7.75-7.74 (m, 1H), 7.58-7.55 (m, 2H), 7.48-7.41 (m, 4H), give imidates 10. Diastereomeric ratios were determined by 1H 5.87 (s, 1H), 5.51-5.50 (m, 1H), 3.79-3.71 (m, 1H), 3.61-3.60 (m, NMR spectroscopy. 1H), 3.52-3.50 (m, 1H), 3.31-3.29 (m, 1H), 1.29 (t, J = 6.9 Hz, 13 3H); C NMR minor diastereomer (125 MHz, CDCl3): δ 200.5, 4.4.2 Imidate 10f. Prepared by general procedure B using 8 169.2, 150.6, 149.6, 134.3, 134.8, 132.3, 130.1, 129.0, 128.1, (0.080 g; 0.287 mmol), alkenyl boronic acid 2f (0.100 g, 0.574 126.7, 124.0, 123.5, 120.9, 95.1, 77.5, 62.0, 33.7, 15.4; IR (thin mmol), Cu(OAc)2 (0.052 g, 0.287 mmol), Na2SO4 (0.300 g, 2.11 film) 2972, 2906, 2871, 1726, 1622, 1571, 1470, 1388, 1328, mmol), and pyridine (70.0 µL, 0.861 mmol). Flash 1261, 1183 cm-1; HRMS (ESI) m/z calcd. for C19H18NO3Si chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10f (M+H)+ 308.1287, found 308.1279; decomposed at 110 °C. as a white solid (0.077 g, 66%, dr = >95:5). 1H NMR (500 MHz; CDCl3): δ 8.08-8.06 (m, 1H), 7.61-7.60 (m, 1H), 7.55-7.51 (m, 4.3.6 Imidate 19t. Prepared using general procedure A with N2H), 7.46-7.39 (m, 2H), 7.37-7.34 (m, 1H), 7.30-7.29 (m, 1H), hydroxyisoindolinone 14 (0.080 g; 0.39 mmol), indenyl boronic 6.07 (s, 1H), 5.94 (dd, J = 13.1, 4.7 Hz, 1H), 3.32-3.26 (m, 1H), acid 2t (0.123 g, 0.772 mmol), Cu(OAc)2 (0.070 g, 0.39 mmol), 3.16-3.13 (m, 1H), 2.68-2.64 (m, 1H), 2.50-2.42 (m, 1H), 0.92 (s, Na2SO4 (0.298 g, 2.09 mmol), and pyridine (93.0 µL, 1.16 9H), 0.14(s, 3H), -0.05 (s, 3H); 13C NMR (125 MHz, CDCl3): δ mmol). Flash chromatography (1:4; EtOAc: hexanes) on 192.9, 168.4, 152.7, 143.1, 133.7, 132.1, 131.9, 129.9, 128.6, Florisil® afforded 19t as a white solid (0.060 g, 48%, dr = 97:3). 1 128.5, 127.8, 126.9, 122.7, 120.9, 91.1, 78.1, 29.4, 28.0, 25.9, H NMR major diastereomer (500 MHz; CDCl3): δ 7.86-7.84 (m, 18.1, -3.8, -4.1; IR (thin film) 2952, 2928, 2854, 1704, 1626, 1H), 7.66-7.63 (m, 1H), 7.55-7.54 (m, 2H), 7.47-7.40 (m, 4H), 1603, 1575, 1471, 1460, 1327, 1249 cm-1; HRMS (ESI) m/z 5.83 (s, 1H), 5.69 (dd, J = 7.6, 4.7 Hz, 1H), 3.91-3.90 (m, 1H), calcd. for C24H30NO3Si (M+H)+ 408.1995, found 408.1985; 3.83 (dd, J = 16.4, 7.6 Hz, 1H), 3.32 (dd, J = 16.4, 4.7 Hz, 1H), decomposed at 128 °C. 1.26 (d, J = 5.9 Hz, 3H), 1.09 (d, J = 6.0 Hz, 3H); 13C NMR

AC C

EP

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, 123.1, 120.8, 94.2, 77.6, 70.3, 33.5, 23.4, 22.7; 1H 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); 13 C 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. 4.3.7 Imidate 20t. Prepared using general procedure A with Nhydroxyisoindolinone 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 µL, 0.870 mmol). Flash chromatography (1:3; EtOAc: hexanes) on Florisil® afforded 20t as an amorphous white solid (0.058 g, 66%, dr = >95:5). 1H NMR (500 MHz; CDCl3): δ 7.86-7.84 (m, 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,

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 µL, 0.936 mmol). Flash chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10g as a white solid (0.075 g, 59%, dr = >95:5). 1H 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); 13 C 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. 4.4.4 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 µl, 1.50 mmol). Flash chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10l as a colorless liquid (0.108 g, 65%, dr = >95:5). 1H 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

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4.4.8 Imidate 10v. Prepared by general procedure B using 8 MHz, CDCl3): δ 207.2, 168.3, 152.6, 131.6, 130.1, 128.6, 122.8, MANUSCRIPT ACCEPTED (0.060 g; 0.21 mmol), boronic acid 2v (0.076 g, 0.43 mmol), 120.5, 90.9, 78.5, 25.7, 25.4, 18.1, 16.6, -4.0, -4.6; IR (thin film) Cu(OAc)2 (0.039 g, 0.21 mmol), Na2SO4 (0.224 g, 1.57 mmol), 2956, 2928, 2858, 1729, 1625, 1581, 1470, 1401, 1255, 1192, and pyridine (50.0 µL, 0.642 mmol). Flash chromatography (1:4; 1116 cm-1; HRMS (ESI) m/z calcd. for C18H28NO3Si (M+H)+ 334.1838, found 334.1844. EtOAc: hexanes) on Florisil® afforded 10v as a white solid (0.053 g, 61%, dr = >95:5). 1H NMR (500 MHz; CDCl3): δ 7.604.4.5 Imidate 10n. Prepared by general procedure B using 8 7.51 (m, 4H), 7.44-7.39 (m, 5H), 6.30 (s, 1H), 5.98 (s, 1H), 2.70(0.175 g; 0.625 mmol), 1-cyclopentenyl boronic acid 2n (0.140 g, 2.62 (m, 1H), 2.63-2.53 (m, 1H), 1.00 (t, J = 7.2 Hz, 3H), 0.95 (s, 1.25 mmol), Cu(OAc)2 (0.114 g, 0.625 mmol), Na2SO4 (0.650 g, 9H), 0.19 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 4.57 mmol), and pyridine (150 µL, 1.87 mmol). Flash 205.6, 168.3, 152.6, 134.4, 131.5, 130.1, 128.9, 128.8, 128.5, chromatography (1:3; EtOAc: hexanes) on Florisil® afforded 127.7, 122.8, 120.7, 91.1, 83.5, 31.5, 25.9, 18.1, 7.1, -4.0, -4.5; 1 10n as a colorless liquid (0.138 g, 64%, dr = 80:20). H NMR IR (thin film) 2930, 2858, 1729, 1625, 1570, 1469, 1388, 1326, major diastereomer (500 MHz; CDCl3): δ 7.51-7.48 (m, 2H), 1258, 1193, 1125 cm-1; HRMS (ESI) m/z calcd. for C24H32NO3Si 7.41-7.35 (m, 2H), 6.00 (s, 1H), 5.32 (t, J = 5.0 Hz, 1H), 2.65(M+H)+ 410.2151, found 410.2144; decomposed at 80 °C. 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 4.4.9 Imidate 10w. Prepared by general procedure B using 8 diastereomer (125 MHz, CDCl3): δ 212.3, 168.0, 152.4, 131.7, (0.049 g; 0.18 mmol), alkenyl boronic acid 2w (0.0.40 g, 0.35 129.9, 128.5, 122.7, 120.7, 90.8, 79.2, 35.2, 28.2, 25.8, 18.1, mmol), Cu(OAc)2 (0.032 g, 0.18 mmol), Na2SO4 (0.183 g, 1.29 mmol), and pyridine (40.0 µL, 0.525 mmol). Flash 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), 2.65chromatography (1:3; EtOAc: hexanes) on Florisil® afforded 2.60 (m, 1H), 2.41-2.38 (m, 2H), 2.18-2.13 (m, 2H), 1.93-1.88 10w as a colorless liquid (0.038 g, 68 %). 1H NMR (500 MHz; 13 (m, 1H), 0.91 (s, 9H), 0.19 (s, 3H), 0.09 (s, 3H); C NMR minor CDCl3): δ 7.51-7.39 (m, 4H), 5.94 (s, 1H), 2.18 (s, 3H), 1.68 (s, diastereomer (125 MHz, CDCl3): δ 212.3, 168.0, 152.4, 131.7, 3H), 1.67 (s, 3H), 0.94 (s, 9H), 0.22 (s, 3H), 0.10 (s, 3H); 13C 129.9, 128.5, 122.7, 120.7, 90.8, 79.2, 35.2, 28.2, 25.7, 18.1, 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, 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 -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 C19H28NO3Si (M+H)+ 346.1828, found 346.1842. C19H30NO3Si (M+H)+ 348.1995, found 348.1994. 4.4.6 Imidate 10s. Prepared by general procedure B using 8 4.5. Alkenylation and thermal rearrangement of 8 with (0.100 g; 0.357 mmol), alkenyl boronic acid 2s (0.100 g, 0.714 alkenylboronic acid 3a. Characterization of 9a and 10a. mmol), Cu(OAc)2 (0.065 g, 0.71 mmol), Na2SO4 (0.373 g, 2.62 mmol), and pyridine (90.0 µL, 1.07 mmol). Flash 4.5.1 N-Enoxyisoindolinone 9a. A scintillation vial was charged chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 10s with 3-siloxy-N-hydroxyisoindolinone 8 (0.164 g; 0.586 mmol), as a semi-solid (0.085 g, 64%, dr = 69:31) 1H NMR major E-1-hexen-1-yl boronic acid 1d (0.150 g, 1.17 mmol), Cu(OAc)2 diastereomer (500 MHz; CDCl3): δ 7.54-7.51 (m, 2H), 7.43-7.41 (0.106 g, 0.586 mmol), and anhydrous Na2SO4 (0.507 g, 3.56 (m, 2H), 5.98 (s, 1H), 5.27 (d, J = 10.0 Hz, 1H), 2.54-2.47 (m, mmol). These solids were then diluted with 1,2-dichloroethane to 3H), 2.09-1.95 (m, 4H), 1.18 (d, J = 5.0 Hz, 3H), 0.89 (s, 9H), form a 0.1 M solution of 8. Pyridine (143 µl, 1.76 mmol) was 0.05 (s, 3H), -0.16 (s, 3H); 13C NMR major diastereomer (125 added to the resulting slurry via syringe. The scintillation vial MHz, CDCl3): δ 204.2, 168.6, 152.7, 133.0, 129.9, 128.4, 122.8, was then capped with a septum pierced with a ventilation needle 120.7, 91.2, 85.0, 40.4, 40.0, 32.8, 26.0, 25.8, 25.6, 18.8, -3.9, 1 and the reaction mixture was allowed to stir at 25 °C for 12 h. 4.0; H NMR minor diastereomer (500 MHz; CDCl3): δ 7.58The reaction mixture was then concentrated under vacuum and 7.57 (m, 2H), 7.41-7.38 (m, 2H), 6.01 (s, 1H), 5.54 (d, J = 10.0 the crude product was purified by medium pressure Hz, 1H), 2.20-2.07 (m, 4H), 1.72-1.62 (m, 3H), 1.10 (d, J = 5.0 13 chromatography (1:4; EtOAc:hexanes) to give 9a as a colorless Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), -0.11 (s, 3H); C NMR liquid (0.174 g, 82%). 1H NMR (500 MHz; CDCl3): δ 7.79 (d, J minor diastereomer (125 MHz, CDCl3): δ 205.6, 168.2, 152.7, = 7.4 Hz, 1H), 7.61 (dd, J = 7.6, 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 133.0, 129.9, 129.7, 123.8, 123.1, 82.9, 82.2, 37.4, 31.1, 29.8, 1H), 7.44 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 12.3 Hz, 1H), 5.98 (s, 25.8, 23.2, 18.0, 13.6, -3.9, -4.0; IR (thin film) 2928, 2855, 1733, -1 1H), 5.26 (td, J = 12.3, 7.4 Hz, 1H), 1.96-1.92 (m, 2H), 1.33-1.29 1626, 1471, 1319, 1249, 1194, 1121, 1046 cm ; HRMS (ESI) + (m, 4H), 0.95 (s, 9H), 0.86 (t, J = 6.9 Hz, 3H), 0.27 (s, 3H), 0.20 m/z calcd. for C21H32NO3Si (M+H) 374.2151, found 374.2153. (s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.1, 147.1, 142.1, 4.4.7 Imidate 10u. Prepared by general procedure B using 8 133.2, 129.8, 128.7, 123.8, 123.1, 107.4, 82.5, 32.0, 26.5, 25.6, (0.127 g; 0.454 mmol), cyclooctenyl boronic acid 2u (0.140 g, 22.1, 18.0, 13.8, -4.3, -4.5; IR (thin film) 2955, 2928, 2857, 1740, 0.909 mmol), Cu(OAc)2 (0.082 g, 0.45 mmol), Na2SO4 (0.470 g, 1667, 1466, 1361, 1252, 1203, 1117 cm-1; HRMS (ESI) m/z 3.30 mmol), and pyridine (110.0 µL, 1.362 mmol). Flash calcd. for C20H32NO3Si (M+H)+ 362.2151, found 362.2142. chromatography (1:4; EtOAc: hexanes) on Florisil® afforded 4.5.2 Imidate 10a. A J-Young tube was charged with a 0.1 M 10u as a colorless liquid (0.101 g, 57%, dr = >95:5). 1H NMR solution of N-enoxyisoindolinone 9a (0.040 g, 0.130 mmol) in (500 MHz; CDCl3): δ 7.56-7.54 (m, 1H), 7.50-7.48 (m, 1H), toluene-d8. The reaction mixture was heated to 50 °C for 3 h. At 7.43-7.37 (m, 2H), 5.95 (s, 1H), 5.48 (dd, J = 8.5, 3.8 Hz, 1H), this time, the reaction mixture was concentrated under vacuum to 2.74-2.69 (m, 1H), 2.52-2.39 (m, 1H), 2.25-2.19 (m, 1H), 2.15afford imidate 10a as a yellow oil (0.040 g, >99%, dr = >95:5). 2.08 (m, 1H), 2.02-2.01 (m, 2H), 1.87-1.83 (m, 1H), 1.61-1.53 1 H NMR (500 MHz; C6D6): δ 9.51 (s, 1H), 7.28-7.37 (m, 1H), (m, 4H), 1.45-1.37 (m, 1H), 0.92 (s, 9H), 0.14 (s, 3H), -0.05 (s, 7.38-6.99 (m, 3H), 5.92 (s, 1H), 5.11-5.08 (m, 1H), 1.68-1.66 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 212.7, 168.3, 152.5, 131.7, 2H), 1.24-1.21 (m, 4H), 1.03 (s, 9H), 0.83 (t, J = 5.0 Hz, 3H), 129.9, 128.5, 122.7, 120.7, 91.0, 80.3, 41.2, 33.3, 28.1, 25.9, 0.29 (s, 3H), 0.16 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 198.6, 25.8, 24.9, 23.2, 21.4, -4.0, -4.4; IR (thin film) 2933, 2852, 1724, -1 168.6, 152.3, 131.5, 129.8, 128.7, 122.7, 120.2, 91.1, 81.7, 29.2, 1622, 1573, 1466, 1395, 1326, 1241, 1186, 1125 cm ; HRMS + 27.1, 25.7, 22.4, 18.1, 13.6, -4.0, -4.9; IR (thin film) 2955, 2929, (ESI) m/z calcd. for C22H34NO3Si (M+H) 388.2308, found 2858, 1738, 1576, 1400, 1379, 1254, 1122, 1075 cm-1; HRMS 388.2300.

10

Tetrahedron

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 solid. 1H NMR (500 MHz; CDCl3): δ 7.84-7.82 (m, 1H), 7.597.57 (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.

TE D

M AN U

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 µl, 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 7.847.83 (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.

SC

RI PT

organic layer was separated and the aqueous layer was extracted (ESI) m/z calcd. for C20H32NO3Si (M+H)+ACCEPTED 362.2151, found MANUSCRIPT with EtOAc (2 x 10.0 mL). The combined organic layers were 362.2139. washed with brine, dried with MgSO4, and filtered. The filtrate 4.6. Hydrolysis and chlorination of 10t. Characterization of 5t was concentrated under vacuum and the crude product was and 21t. purified by flash column chromatography on Florisil® (10% Ethyl Acetate, 2% TEA, pentane) to afford methyl-protected 4.6.1 α-Hydroxyketone 5t.25 A 10 mL round bottom flask was imidate 27a (0.0570 g, 72%) as an amorphous solid. 1H NMR charged with a solution of imidate 10t (0.030 g, 0.076 mmol) in (500 MHz; CDCl3): δ 7.83-7.81 (m, 1H), 7.58-7.56 (m, 1H), MeOH:H2O (2.0 mL, 1:1). NH4Cl (0.007 g, 0.125 mmol) was 7.51-7.49 (m, 1H), 6.84-6.83 (m, 1H), 6.74-6.73 (m, 1H), 6.73added to the solution as a solid and the reaction mixture was 6.72 (m, 1H), 2.93 (s, 3H), 2.34 (s, 3H); 13C NMR (125 MHz, heated to 90 °C for 2 h. The reaction mixture was then CDCl3): δ 165.8, 146.6, 144.5, 144.4, 140.3, 132.9, 132.0, 131.4, concentrated under vacuum and the residue was extracted with 130.7, 123.2, 121.9, 109.6, 109.4, 180.0, 23.1, 21.2; HRMS (ESI) EtOAc (3 x 7.0 mL). The organic layer was then dried with m/z calcd. for C16H14NO3 (M+H)+ 268.0974, found 268.0977. MgSO4 and concentrated under vacuum. The crude product mixture was purified by medium pressure chromatography on 4.8.2 Allylated Catechol 28a. A scintillation vial was charged silica gel (1:2 EtOAc:hexanes) to give 5t as an amorphous white with imidate 24a (0.0751 g, 0.297 mmol, 1 equiv) and DMF (5.0 solid (0.0060 g, 53%). 1H NMR (500 MHz; CDCl3): δ 7.78-7.76 mL). This solution was then treated with K2CO3 (0.124 g, 0.900 (m, 1H), 7.66-7.64 (m, 1H), 7.47-7.46 (m, 1H), 7.42-7.39 (m, mmol, 3 equiv) and allyl bromide (0.0390 mL, 0.450 mmol, 1.5 1H), 4.54 (dd, J = 7.8, 5.1 Hz, 1H), 3.58 (dd, J = 16.5, 7.8 Hz, equiv) and then heated to 50 ºC for 18 h. At this time, the 13 1H), 3.02 (dd, J = 16.5, 5.1 Hz, 1H), 2.92 (s, 1H); C NMR (125 reaction mixture was diluted with EtOAc (10.0 mL) and H2O (5.0 MHz, CDCl3): δ 206.3, 150.8, 135.8, 134.0, 128.1, 126.8, 124.4, mL). The organic layer was separated and the aqueous layer was 74.3, 35.1; IR (thin film) 3469, 2982, 1732, 1609, 1470, 1366, extracted with EtOAc (2 x 10.0 mL). The combined organic 1299, 1252, 1154, 1047 cm-1; HRMS (ESI) m/z calcd. for layers were washed with brine, dried with MgSO4, and filtered. + C9H8O2 (M) 148.0524, found 148.0531. The filtrate was concentrated under vacuum and the crude

4.7. Synthesis of imidate 24a and characterization data.

AC C

EP

A 5 mL conical vial was charged with 0.1 M solution of Naryloxyphthalimide 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. 4.8. 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. 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. 4.9.2 Imidate 26a. Prepared by general procedure C using Naryloxyphthalimide 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% NEt3, pentane) afforded 26a as white solid (0.0806 g, 91%). 1H 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. 4.9.3 Imidate 26b. Prepared using general procedure C using Naryloxyphthalimide 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% NEt3, pentane) afforded 26b as white solid (0.0766 g, 85%). 1H

11

AC C

EP

TE D

M AN U

SC

RI PT

NMR (500 MHz; CDCl3): δ 7.95-7.93 (m, 1H), 7.79-7.75 (m, MANUSCRIPT C22H15NO4Na (M+Na+) 380.0899, found 380.0900; m.p. 74ACCEPTED 1H), 7.72-7.69 (m, 1H), 7.60-7.59 (m, 1H), 6.82-6.80 (m, 1H), 75 ºC. 6.69-6.63 (m, 2H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 4.9.8 Imidate 26g. Prepared by general procedure C using N169.8, 164.9, 159.0, 157.1, 147.5 (d, JCF = 13.9 Hz), 143.4, aryloxyphthalimide 23g (0.0955 g, 0.300 mmol) and Ac2O (3.0 140.1, 135.5, 132.5, 127.9, 124.5, 122.8, 107.3 (d, JCF = 18.5 mL, 0.1 M). The reaction mixture was heated to 140 °C for 30 h. Hz), 107.2 (d, JCF = 3.4 Hz), 97.6 (d, JCF = 37.5), 26.1; IR (thin Medium-pressure chromatography on Florisil® (5% EtOAc, 2% film) 3080, 1774, 1750, 1713, 1488, 1470, 1416, 1314, 1155, NEt3, pentane) afforded 26g as white solid (0.0608 g, 53%). 1H + 1127; HRMS (ESI) m/z calcd. for C16H10NO4NaF (M+Na ) NMR (500 MHz; CDCl3): δ 7.95-7.93 (m, 1H), 7.78-7.75 (m, 322.0492, found 322.0483; m.p. 147-148 ºC. 1H), 7.73-7.70 (m, 1H), 7.58-7.57 (m, 1H), 7.10-7.09 (m, 1H), 4.9.4 Imidate 26c. Prepared by general procedure C using N7.06-7.02 (m, 1H), 6.80-6.78 (m, 1H), 2.63 (s, 1H); 13C NMR aryloxyphthalimide 23c (0.0832 g, 0.304 mmol) and Ac2O (3.0 (125 MHz, CDCl3): δ 169.8, 164.9, 147.9, 146.6, 140.9, 139.9, mL, 0.1 M). The reaction mixture was heated to 140 °C for 30 h. 135.5, 132.5, 127.9, 124.7, 124.5, 122.8, 113.6, 111.6, 108.9, Medium-pressure chromatography on Florisil® (5% EtOAc, 2% 26.1; IR (thin film) 2921, 2865, 1773,1750, 1713, 1477, 1370, NEt3, pentane) afforded 26c as white solid (0.0641 g, 68%). 1H 1349, 1155, 1135; HRMS (ESI) m/z calcd. for C16H10NO4NaBr NMR (500 MHz; CDCl3): δ 7.94-7.93 (m, 1H), 7.78-7.75 (m, (M+Na+) 381.9691, found 381.9679; m.p 156-157 ºC. 1H), 7.72-7.69 (m, 1H), 7.58-7.57 (m, 1H), 6.95- 6.92 (m, 2H), 4.9.9 Imidate 26j. Prepared by general procedure C using N6.83-6.81 (m, 1H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): δ aryloxyphthalimide 23j (0.0807 g, 0.303 mmol) and Ac2O (3.0 169.8, 164.9, 147.7, 146.1, 140.7, 140.0, 135.6, 132.6, 128.0, mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h. 126.8, 124.6, 122.8, 121.7, 109.0, 108.2, 26.1; IR (thin film) Medium-pressure chromatography on Florisil® (5% EtOAc, 2% 3097, 2939, 2854, 1774, 1752, 1726, 1482, 1317, 1252, 801; NEt3, pentane) afforded 26j as white solid (0.0774 g, 83%). 1H + HRMS (ESI) m/z calcd. for C16H10NO4ClNa (M+Na ) 338.0196, NMR (500 MHz; CDCl3): δ 7.93-7.92 (m, 1H), 7.76-7.73 (m, found 338.0191; m.p 106-107 ºC. 1H), 7.69-7.67 (m, 1H), 7.61-7.59 (m, 1H), 6.59 (s, 2H), 2.63 (s, 4.9.5 Imidate 26d. Prepared by general procedure C using N3H), 2.31 (s, 3H), 2.21 (s, 3H); 13C NMR (125 MHz, CDCl3): δ aryloxyphthalimide 23d (0.0795 g, 0.300 mmol) and Ac2O (3.0 169.6, 165.3, 146.6, 143.5, 141.5, 140.8, 135.4, 132.2, 131.4, mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h. 128.1 124.3, 124.0, 122.8, 117.6, 106.1, 26.2, 21.3, 14.6; IR (thin Medium-pressure chromatography on Florisil® (5% EtOAc, 2% film) 2921, 2865, 1748, 1724, 1494, 1218, 1370, 1344, 1313, NEt3, pentane) afforded 26d as white solid (0.0586 g, 64%). 1H 1247; HRMS (ESI) m/z calcd. for C18H15NO4Na (M+Na+) NMR (500 MHz; CDCl3): δ 7.94-7.93 (m, 1H), 7.76-7.74 (m, 332.0899, found 332.0889; m.p. 149-151 ºC. 1H), 7.71-7.68 (m, 1H), 7.59-7.58 (m, 1H), 7.07-7.05 (m, 1H), 4.9.10 Imidate 26k. Prepared by general procedure C using N6.98-6.97 (m, 1H), 6.87- 6.85 (m, 1H), 6.68 (dd, J = 10.0, 15.0 aryloxyphthalimide 23k (0.0815 g, 0.302 mmol) and Ac2O (3.0 Hz, 1H), 6.62 (d, J = 15.0 Hz, 1H), 5.17 (d, J = 15.0 Hz, 1H), mL, 0.1 M). The reaction mixture was and heated to 140 °C for 13 2.63 (s, 3H); C NMR (125 MHz, CDCl3): δ 169.8, 165.1, 147.6, 18 h. Medium-pressure chromatography on Florisil® (5% 146.9, 140.5, 140.3, 136.3, 135.5, 132.6, 132.4, 128.0, 124.5, EtOAc, 2% NEt3, pentane) afforded 26k as white solid (0.0807 g, 122.7, 121.3, 112.4, 107.5, 104.7, 26.1; IR (thin film) 3085, 80%). 1H NMR (500 MHz; CDCl3): (major isomer) δ 7.94-7.92 3015, 1773, 1749, 1723, 1494, 1444, 1415; HRMS (ESI) m/z (m, 1H), 7.77-7.74 (m, 1H), 7.71-7.68 (m, 1H), 7.60-7.59 (m, calcd. for C18H13NO4Na (M+Na+) 330.0742, found 330.0740; 1H), 6.81-6.79 (m, 1H), 6.59-6.58 (m, 1H), 6.47-6.45 (m, 1H), m.p. 145-147 ºC. 3.79 (s, 3H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3): (major 4.9.6 Imidate 26e. Prepared by general procedure C using Nisomer) δ 169.8, 165.2, 155.3, 147.7, 141.4, 140.6, 140.5, 135.4, 132.3, 128.0, 124.4, 122.7, 107.1, 105.2, 96.6, 56.0, 26.1; 1H 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. NMR (500 MHz; CDCl3): (minor isomer, diagnostic peaks) δ Medium-pressure chromatography on Florisil® (5% EtOAc, 2% 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 NEt3, pentane) afforded 26e as white solid (0.0942 g, 92%). 1H NMR (500 MHz; CDCl3): δ 7.94-7.92 (m, 1H), 7.76-7.73 (m, peaks) δ 122.9, 107.4, 101.4, 56.4; IR (thin film) 3077, 3009, 1H), 7.70-7.67 (m, 1H), 7.62-7.60 (m, 1H), 6.98-6.96 (m, 2H), 2845, 1779, 1755, 1711, 1492. 1465, 1346, 1315; HRMS (ESI) 6.83-6.81 (m, 1H), 2.64 (s, 3H), 1.33 (s, 9H); 13C NMR (125 m/z calcd. for C17H13NO5Na (M+Na+) 334.0691, found MHz, CDCl3): δ 169.8, 165.3, 147.0, 145.6, 144.7, 140.9, 140.7, 334.0690; m.p. 98-100 ºC. 135.4, 132.2, 128.0, 124.4, 122.8, 118.3, 106.8, 105.5, 34.8, 31.7, 4.9.11 Imidate 26l. Prepared by general procedure C using N26.1; IR (thin film) 2905, 2874, 1773, 1749, 1713, 1506, 1490, aryloxyphthalimide 23l (0.085g, 0.31 mmol) and Ac2O (3.0 mL, 1429, 1370, 1312; HRMS (ESI) m/z calcd. for C20H19NO4Na 0.1 M). The reaction mixture was heated to 140 °C for 18 h. + (M+Na ) 360.1212, found 360.1203; m.p. 70-72 ºC. Medium-pressure chromatography on Florisil® (5% EtOAc, 2% 4.9.7 Imidate 26f. Prepared by general procedure C using NNEt3, pentane) afforded 26l as white solid (0.0.077 g, 76%). 1H aryloxyphthalimide 23f (0.0948 g, 0.301 mmol) and Ac2O (3.0 NMR (500 MHz; CDCl3): δ 7.98-7.97 (m, 1H), 7.87-7.85 (m, mL, 0.1 M). The reaction mixture was heated to 140 °C for 18 h. 1H), 7.79-7.69 (m, 3H), 7.63-7.61 (m, 1H), 7.57-7.55 (m, 1H), Medium-pressure chromatography on Florisil® (5% EtOAc, 2% 7.46-7.43 (m, 1H), 7.37-7.34 (m, 1H), 7.29-7.27 (m, 1H); 13C 1 NEt3, pentane) afforded 26f as white solid (0.0731 g, 69%). H NMR (125 MHz, CDCl3): δ 169.6, 165.3, 142.7, 140.7, 140.6, NMR (500 MHz; CDCl3): δ 7.96-7.95 (m, 1H), 7.78-7.75 (m, 135.5, 132.3, 130.1, 128.5, 128.0, 126.3, 124.4, 124.0, 122.9, 1H), 7.72-7.69 (m, 1H), 7.65-7.63 (m, 1H), 7.57-7.56 (m, 2H), 122.1, 119.5, 119.0, 109.6, 109.5, 26.2; IR (thin film); HRMS 7.44-7.41 (m, 2H), 7.34-7.32 (m, 1H), 7.21-7.19 (m, 1H), 7.16(ESI) m/z calcd. for C18H15NO4Na (M+Na+) 354.0742, found 13 7.14 (m, 1H), 6.99-6.98 (m, 1H), 2.66 (s, 3H); C NMR (125 354.0739; m.p. 198-201 ºC. MHz, CDCl3): δ 169.8, 165.2, 147.7, 146.6, 140.9, 140.7, 140.4, 4.10. General procedure for catechol synthesis via imidate 136.0, 135.5, 132.4, 128.8, 128.7, 128.0, 127.0, 124.5, 122.8, hydrolysis and characterization data 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 4.10.1 General procedure D. A scintillation vial was charged with a 0.3 M solution of imidate (1 equiv) in EtOH, treated with

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4.10.7 Catechol 25g.27 Prepared by general procedure D using hydrazine hydrate (2 equiv), and sealed with a Teflon-lined MANUSCRIPT ACCEPTED cap. The solution was then allowed to stir for 12 h at 25 °C. The imidate 26g (0.109 g, 0.302 mmol), EtOH (3.0 mL, 0.10 M), and reaction mixture was then concentrated under vacuum, dissolved N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure chromatography afforded 25g as an amorphous solid (0.0438 g, in EtOAc (10.0 mL), and filtered through glass fiber filter paper. The filtrate was diluted with H2O (6.0 mL). The aqueous layer 77%). 1H NMR (500 MHz; CDCl3): δ 7.02 (s, 1H), 6.93 (d, J = 5, was extracted with EtOAc (6.0 mL x 3). The organic layers were 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) 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 3331, 2923, 2851, 1597, 1651, 1445, 1427, 1327, 882, 851; product mixture was then concentrated under vacuum and 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 12c, 27 4.10.2 Catechol 25a. Prepared by general procedure D using imidate 26j (0.0921 g, 0.298 mmol), EtOH (3.0 mL, 0.10 M), and imidate 26a (0.0891 g, 0.302 mmol), EtOH (3.00 mL, 0.10 M), N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure and N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure chromatography affored 25j as an amorphous solid (0.0316 g, chromatography afforded 25a as an amorphous solid (0.0334 g, 76%). 1H NMR (500 MHz; CDCl3): δ 6.54 (s, 1H), 6.53 (s, 1H), 1 5.19 (br, 2H), 2.22 (s, 3H), 2.21 (s, 3H); 13C NMR (125 MHz, 90%). H NMR (500 MHz; CDCl3): δ 6.76 (d, J = 10 Hz, 1H), 6.70 (s, 1H), 6.61 (d, J = 10 Hz, 1H), 5.29 (br, 2H), 2.24 (s, 3H); CDCl3): δ 143.0, 139.6, 130.8, 124.3, 123.4, 113.7, 20.7, 15.5; IR 13 C NMR (125 MHz, CDCl3): δ 143.3, 141.0, 131.1, 121.5, (thin film) 3357, 2919, 2858, 1603, 1518, 1461, 1302, 1184, 116.3, 115.4, 20.7; IR (thin film) 3339, 2920, 2865, 1603, 1518, 1140, 1034; HRMS (ESI) m/z calcd. for C8H10O2 (M+H)+ 1433, 1352, 1281, 1108, 941; HRMS (ESI) m/z calcd. for 138.0681, found 138.0679. C7H8O2 (M+H)+ 124.0524, found 124.0525. 4.10.9 Catechol 25k.12c, 27 Prepared by general procedure D using 12c, 28 4.10.3 Catechol 25b. imidate 26k (0.0945g, 0.303 mmol), EtOH (3.0 mL, 0.10 M), and 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 25k as an amorphous solid (0.0368g, N2H4•H2On (0.037 mL, 0.60 mmol). Medium pressure chromatography afforded 25b as an amorphous solid (0.026g, 85%). 1H NMR (500 MHz; CDCl3): (major isomer) δ 6.75 (d, J = 1 70%). H NMR (500 MHz; CDCl3): δ 6.80-6.77 (m, 1H), 6.6610.0, 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, 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, 116.0, 105.5, 102.6, 55.8; 1H NMR (500 MHz; CDCl3): (minor JCF = 9.7 Hz), 106.8 (d, JCF = 22.9), 103.4 (d, JCF = 26.6 Hz); IR 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, (thin film) 3297, 2923, 2828, 1627, 1518, 1480, 1450, 794, 731, 598; HRMS (ESI) m/z calcd. for C6H5O2F (M+H)+ 128.0274, 1305, 833; HRMS (ESI) m/z calcd. for C7H8O3 (M+H)+ found 128.0272. 140.0473, found 140.0471.

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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%). 1 H 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.

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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, 83%). 1H NMR (500 MHz; CDCl3): δ 6.95-6.92 (m, 1H), 6.816.79 (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. 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%). 1 H 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), 6.956.93 (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.

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, 75%). 1H NMR (500 MHz; CDCl3): δ 8.04-8.02 (m, 1H), 7.767.74 (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. Acknowledgments 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. Author information Corresponding Author *E-mail: [email protected]. Notes The authors declare no competing financial interest. Supplementary Material Supplementary data associated with this article can be found in the online version.

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