Metal-Free Cross-Dehydrogenative C-O Coupling of Carbonyl Compounds with N-Hydroxyimides: Unexpected Selective Behavior of Highly Reactive Free Radicals at an Elevated Temperature

Article abstract of DOI:10.1021/acs.joc.9b02656

Cross-dehydrogenative C-O coupling of N-hydroxyimides with ketones, esters, and carboxylic acids was achieved employing the di-tert-butyl peroxide as a source of free radicals and a dehydrogenating agent. The proposed method is experimentally simple and demonstrates the outstanding efficiency for the challenging CH substrates, such as unactivated esters and carboxylic acids. It was shown that N-hydroxyphthalimide drastically affects the oxidative properties of t-BuOOt-Bu by intercepting the t-BuO radicals with the formation of phthalimide-N-oxyl radicals, a species responsible for both hydrogen atom abstraction from the CH reagent and the selective formation of the C-O coupling product by selective radical cross-recombination. The practical applicability of the developed method was exemplified by the single-stage synthesis of commercial reagent (known as Baran aminating reagent precursor) from isobutyric acid and N-hydroxysuccinimide, whereas in the standard synthetic approach, four stages are necessary.

Full text of DOI:10.1021/acs.joc.9b02656

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Article
Metal-Free Cross-Dehydrogenative C-O Coupling of Carbonyl
Compounds with N-Hydroxyimides: Unexpected Selective Behavior
of Highly Reactive Free Radicals at an Elevated Temperature
Igor B Krylov, Elena R. Lopat’eva, Alexander S. Budnikov,
Gennady Ivanovich Nikishin, and Alexander Olegovich Terent'ev
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02656 • Publication Date (Web): 30 Dec 2019
Downloaded from pubs.acs.org on December 30, 2019
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Metal-Free Cross-Dehydrogenative C-O Coupling of Carbonyl
Compounds with N-Hydroxyimides: Unexpected Selective Behavior
of Highly Reactive Free Radicals at an Elevated Temperature
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Igor B. Krylov,1 Elena R. Lopat’eva,1,2 Alexander S. Budnikov,1,2 Gennady I. Nikishin,1
Alexander O. Terent’ev1*
1
N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, 47
Leninsky prosp., 119991 Moscow, Russian Federation; e-mail: terentev@ioc.ac.ru
2
Mendeleev University of Chemical Technology of Russia, 9 Miusskaya sq., Moscow
125047, Russian Federation
O
O
N OH
N O
O
O
H
-BuOO -Bu
t
t
R3
O
O
R1
O
N
O
130-150 °C, 3-24 h
PhH, PhCl or
R2
O
O
R1
3-20 mmol
R3
R2
Solvent-free
R3
R1
R2
Abstract: Cross-dehydrogenative C-O coupling of N-hydroxyimides with ketones, esters, and
carboxylic acids was achieved employing the di-tert-butyl peroxide as a source of free radicals
and a dehydrogenating agent. The proposed method is experimentally simple and demonstrates
the outstanding efficiency for the challenging CH-substrates, such as unactivated esters and
carboxylic acids. It was shown that N-hydroxyphthalimide drastically affects the oxidative
properties of t-BuOOt-Bu by intercepting the t-BuO• radicals with the formation of phthalimide-
N-oxyl radicals - species responsible for both hydrogen atom abstraction from the CH-reagent
and the selective formation of the C-O coupling product by selective radical cross-
recombination. The practical applicability of the developed method was exemplified by the
single-stage synthesis of commercial reagent (known as Baran aminating reagent precursor) from
isobutyric acid and N-hydroxysuccinimide, whereas in the standard synthetic approach 4 stages
are necessary.
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Introduction
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Cross-dehydrogenative coupling (CDC) is a promising approach in modern organic synthesis
targeted towards the construction of complicated molecules from the widely available and simple
building blocks in atom-1 and step-economical1,2 fashion employing hydrogen atoms as leaving
groups.3-11 Between C-C CDC, C-Heteroatom CDC and Heteroatom-Heteroatom CDC, C-O
cross-dehydrogenative coupling is one of the most challenging due to a large number of possible
side oxidative processes, such as fragmentation, hydroxylation, and deeper oxidation.11
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Оne of the key problems in the development of the CDC methodology is the inertness of C-H
bonds. The free-radical chemistry demonstrates high potential in the CDC methodology,
especially for the substrates in which a sterically hindered C(sp3)-H bond has to be involved in a
coupling. Such substrates are unfavorable for the most of non-radical CH-activation methods12
but can undergo the C-H bond cleavage via H-atom abstraction by reactive free radicals. Imide-
N-oxyl radicals proved to be useful H-atom abstracting agents due to the high activity, mild
conditions of generation and slow self-decay13-16 compared to other O-centered radicals. Thus,
precursors of such radicals, N-hydroxyimides (NHI), were successfully used as OH-reagents in
cross-dehydrogenative C-O coupling with substrates containing benzyl,17-24 allyl,17,22 aldehyde,25-
34
ether35,36 moieties and even with cycloalkanes35,36 Nevertheless, the imide-N-oxyl radical
.
based approach found scant application in the oxidative C-O coupling employing the non-
aldehyde carbonyl compounds, presumably due to the inertness of C-H bonds in -position to
the carbonyl group. The scope of such reactions was limited to the highly CH-acidic -
dicarbonyl compounds (Scheme 1, A)37 and the aryl alkyl ketones having a primary alkyl
substituent (Scheme 1, B)23,38,39
.
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Previous works - limited scope of carbonyl compounds:
A) C-O CDC of NHI with strong CH-acids
O
O
O
Mn(OAc)3
EWG
O
or
O
N OH
Co(OAc)2(cat.)/KMnO4
+
N
EWG H
O
NHI
O
EWG = Ac, COOEt, CN
- EWG is necessary
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B) C-O CDC of NHI with arylketones
Ar
O
O
O
Bu4NI (cat.)
-BuOOH or K S O
O
t
2
2
8
H
O
NHI
+
Ar
N
- Applicable only
for arylketones
with primary substituent
Present work:
O
O
R
-BuOO -Bu
t
t
+
R
NHI
H
N O
O
R = Alkyl, Aryl,
OMe, OEt, OH
O
-BuO
t
via
selective
radical
O
R
N
cross-
O
O
recombination:
CH3
O
+ Useful method for challenging substrates: tertiary C(sp3)-H
carbonyl compounds, especially esters and carboxylic acids
+ Scope is not limited to carbonyl compounds
+ Metal-free
+ Solvent and solvent-free variants are applicable
+ The method affords direct access to practically important products
Scheme 1. Cross-dehydrogenative C-O coupling of N-hydroxyimides with different types of
substrates.
Carbonyl compounds without other activating groups, especially carboxylic acids and esters
are extremely challenging CH-substrates for the CDC. In the present work, a new metal-free
method for the C-O CDC of unactivated ketones, esters and carboxylic acids with N-
hydroxyimides was proposed (Scheme 1, present work). This method is based on widely
available organic peroxides as dehydrogenative reagents and opens direct access to compounds,
the preparation of which was laborious and time-consuming.
The C-O CDC of CH-reagents with N-hydroxyimides leads to O-substituted N-
hydroxyimides, which are widely used as precursors of O-substituted hydroxylamines40,
alcohols24 and as substrates for the generation of O-centered radicals and remote CH-
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functionalization41,42. In particular, α-oxyimido esters and carboxylic acids are used in the
synthesis of antimicrobial compounds,43-47 aminooxypeptides,48-51 anti-inflammatory agents,52
free-radical traps,53 and are known as plant growth-regulators,54 anticonvulsant compounds,55
etc. α-(Succinimidooxy)isobutyric acid is the commercially available precursor of Baran
aminating reagent.56
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Results and discussion
The present work was aimed at the development of the metal-free method for the cross-
dehydrogenative C-O coupling of N-hydroxyimides with inert CH-reagents, such as esters,
carboxylic acids, and ketones, for which the use of previously described techniques was
ineffective. The idea underlying the present work was to generate imide-N-oxyl radicals for the
CDC with inert substrates at high temperature, which is necessary for the H-atom abstraction
from the inert C-H bond. Thus, organic peroxides that generate free radicals at elevated
temperatures were chosen as oxidants.
At the first step, reaction conditions were optimized employing ethyl isobutyrate 1a and N-
hydroxyphthalimide (NHPI) 2a as the model coupling partners (Table 1). The nature of the
metal-free oxidant (PhI(OAc)2 or peroxides), the molar ratio of the reagents, the time (1-24 h)
and the reaction temperature (130-150 C) were varied. Reactions were carried out solvent-free
or in a solvent (MeCN, PhCN, MeNO2, AcOH, t-BuOH, C2H4Cl2, PhH, PhCl).
Table 1. Optimization of oxidant, solvent, and reagent ratio for the cross-dehydrogenative
coupling of ethyl isobutyrate 1a with NHPI 2a.
O
O
O
O
Metal-free oxidant
O
EtO
N
+
HO N
OEt
Solvent or solvent-free
130-150 °C, 1-24 h
O
3aa
O
1a
2a (NHPI)
Run
Metal-free oxidant
Molar ratio Solvent Time, 3a yield, % a
1a:2a:oxidant (mL)
h
3
3
3
3
3
1
2
3
4
5
t-BuOOt-Bu
10:1:1
neat
neat
neat
neat
neat
44 (40)
49 (42)
48
PhMe2COOCMe2Ph
BzOOt-Bu
10:1:1
10:1:1
MeEtC(OOt-Bu)2
1,1-(OOt-
10:1:0.5
10:1:0.5
38
20
Bu)cyclohexane
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BzOOBz
10:1:1
10:1:1
neat
3
3
3
22
23
30
t-BuOOH 70% aq
neat
neat
t-BuOOH 5-6M in 10:1:1
6
7
8
decane
9
9
MCPBA
10:1:1
10:1:1
10:1:1
10:1:1
10:1:1.5
10:1:1.5
10:1:2
10:1:2
10:1:3
5:1:2
neat
3
3
1
6
3
6
3
6
3
3
3
3
24
3
3
3
3
10
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10
11
12
13
14
15
16
17
18
19
20b
21c
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
PhI(OAc)2
neat
26
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
neat
17
neat
47 (41)
54
neat
neat
60
neat
64 (61)
57
neat
neat
61 (55)
54 (51)
62 (60)
64
neat
20:1:2
10:1:2
10:1:2
5:1:2
neat
neat
neat
56
MeCN
PhCN
MeNO2
AcOH
44
5:1:2
41
5:1:2
32
5:1:2
33
5:1:2
t-BuOH 3
45
5:1:2
C2H4Cl2
C2H4Cl2
PhH
3
6
3
6
3
3
3
3
3
3
3
50
5:1:2
54
5:1:2
59 (54)
59
5:1:2
PhH
1:1.5:2
1:1:2
PhH
45
PhH
35
2:1:2
PhH
41
3:1:2
PhH
48
10:1:2
5:1:1.5
5:1:3
PhH
67 (64)
54 (43)
65 (60)
PhH
PhH
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t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
t-BuOOt-Bu
5:1:2
10:1:2
5:1:2
5:1:2
PhH
2
55 (50)
58
39c
40
PhH
PhCl
PhCl
24
3
58
41d
24
59
9
General procedure: NHPI (1 mmol), ethyl isobutyrate (1-20 mmol), peroxide (1-3 mmol)
and solvent (2 mL, “neat” means no solvent was added) were placed into a hermetic glass tube
equipped with a magnetic stirring bar and a screw cap. The mixture was stirred in an oil bath
(150 C) for a given time.
10
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a The yields were determined by GC using ethyl benzoate as internal standard. Isolated yields
are given in parenthesis.
b The reaction mixture was bubbled with argon for 5 min before heating.
c The oil bath temperature was set to 130 C.
d The reaction was conducted under reflux conditions at atmospheric pressure in a flask with a
reflux condenser, the temperature was limited by PhCl boiling point (131 C)
In the runs 1-10 the nature of an oxidant was varied. The best results were obtained using di-
tert-alkyl peroxides (di-tert-butyl peroxide and dicumyl peroxide, runs 1-2) and tert-butyl
peroxybenzoate (run 3), yields of 3aa 44-49%. It should be noted that previously di-tert-butyl
peroxide was successfully used in decarbonylative alkylation-aminoxidation of styrene
derivatives with aliphatic aldehydes and N-hydroxyphthalimide.57 Geminal bis-tert-
butylperoxides (runs 4-5), dibenzoyl peroxide (run 6), and t-BuOOH (runs 7-8) afforded the
14,17,19
target C-O coupling product 3aa in 20-38% yield. Using MCPBA58 (run 9) and PhI(OAc)2
(run 10), known as effective oxidants for the generation of phthalimide-N-oxyl radicals from
NHPI even at room temperature, gave 3aa in low yields (10-26%). Thus, it is likely that the
gradual generation of phthalimide-N-oxyl radicals at high temperature is desirable. Based on
runs 1-10, t-BuOOt-Bu was chosen as the best oxidant for further optimization of reaction
conditions despite it was slightly less effective than dicumyl peroxide and tert-butyl
peroxybenzoate. The reason was the volatility of t-BuOOt-Bu and its decomposition products,
which was convenient for the isolation of the target products of the cross-dehydrogenative
coupling.
In the runs 11-12 the reaction time was varied compared to the run 1. The shortening reaction
time form 3 h to 1 h (run 11 compared to run 1) resulted in strong decrease of the 3aa yield (44
to 17%), whereas increase of the reaction time from 3 h to 6 h (run 12 compared to run 1)
resulted in insufficient improvement of the 3aa yield (44 to 47%).
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Optimization of reaction conditions was continued with the variation of the molar ratio of
reagents, 1a:2a and t-BuOOt-Bu (runs 13-19). Increase of t-BuOOt-Bu amount from 1 to 2
mmol (runs 13-16) allowed to reach 64% yield of 3aa (run 15). Further increase of t-BuOOt-Bu
amount to 3 mmol resulted in slightly lower 3aa yield 61% (run 17). The optimal amount of
ethyl isobutyrate 1a was about 10 mmol per 1 mmol of NHPI 2a (run 15). Both increase or
decrease of 1a amount resulted in lower 3aa yields (runs 18-19, 52-62%).
10
11
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60
The bubbling of the reaction mixture with argon before heating (run 20) did not change the
3aa yield compared the synthesis under air atmosphere (run 15). In the run 21 the temperature of
the reaction was decreased from 150 C to 130 C compared to run 15. In this case, the longer
reaction time was necessary (24 h instead of 3 h) and the lower yield of 3aa was obtained (56%).
The solvent-free procedure requires a large excess of CH-reagent to play the role of the liquid
reaction medium and is not applicable for solid substrates. To make the discovered method of the
C-O CDC more general, experiments with the use of solvents were performed (runs 22-41). In
runs 22-29 and 40 benzene was identified as the best solvent between the tested group (MeCN,
PhCN, MeNO2, AcOH, t-BuOH, C2H4Cl2, PhH, PhCl), the highest yield was obtained in the runs
28 and 30 (59%). Employing C2H4Cl2 (runs 27-28) somewhat lower yield was observed (50-
54%). Presumably, the main requirement for the solvent is its inertness with respect to reactive
free radicals generated in the reaction mixture. Experiments 40-41 show that chlorobenzene can
be used instead of benzene without significant loss in the yield of 3aa. Importantly, high boiling
point of chlorobenzene made it possible to conduct the synthesis at atmospheric pressure with a
good yield (59%) although in this case the reaction required 24 hours. (run 41). Chlorobenzene is
somewhat less convenient than benzene at evaporation step of the product isolation, but it was
used as more safe option for scaling up the synthesis (see below). Analogously to the solvent-
free procedure, reagent ratio, reaction time and temperature were optimized for the procedure
with benzene as the solvent (runs 30-39). The best yield of 3aa (67%) was achieved using 10:1:2
ratio of ethyl isobutyrate 1a, NHPI 2a, and t-BuOOt-Bu, reaction temperature 150 C and
reaction time 3 h (run 35).
The efficiency of the developed method was compared with that of the previously
documented procedures for the C-O CDC involving NHPI and other types of CH-reagents (Table
2). The cross-dehydrogenative coupling between ethyl isobutyrate 1a and NHPI 2a was
conducted in accordance with the published procedures, which had been developed for other
types of CH-reagents (Table 2, runs 3-8), the obtained yields of 3aa were compared to those
achieved in the present work (Table 2, runs 1-2).
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Table 2. Efficiency of the previously documented procedures and the developed t-BuOOt-Bu-
based method in the synthesis of 3aa from ethyl isobutyrate 1a and NHPI 2a
5
6
7
8
O
O
O
O
Conditions
O
+
OEt
HO N
EtO
N
9
O
O
3aa
1a (5 mmol)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
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38
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60
2a NHPI (1 mmol)
Run Conditions
3aa yield, %a The procedure adapted
from:
1
2
51
Table 1, run 18
Table 1, run 29
t-BuOOt-Bu (2 mmol), 150 C, 3 h
t-BuOOt-Bu (2 mmol), PhH (2 mL) 150 54
C, 3 h
3
4
CuCl (0.1 mmol), PhI(OAc)2 (1 mmol), 24
MeCN (2 mL), Ar atm, 70 °C, 6 h
(NH4)2Ce(NO3)6 (2 mmol), Acetone (5 10
mL) - H2O (3 mL)
See ref. 17
See ref. 18
20-25 °C, 30 min
5b
6
TBAI (0.1 mmol),
0
0
See ref. 38
See ref. 21
t-BuOOH in decane 5.5 M (1 mmol),
DMA, 100 °C, 2 h
TBAI (0.2 mmol),
t-BuOOH in decane 5.5 M (3 mmol),
MeCN (4 mL) 75 °C, 6 h
7
8
Co(OAc)2•4H2O (0.05 mmol), KMnO4 21
(0.4 mmol), AcOH (5 mL), 80 °C, 20 min
Mn(OAc)3•2H2O (2 mmol), AcOH (5 15
mL), 80 °C, 20 min
See ref. 37
See ref. 37
a Isolated yields are given.
b The quantities of reagents were changed according to the procedure described in Ref. 38: 1a (1
mmol), NHPI (3 mmol).
As can be seen, the literature procedures for the C-O CDC involving NHPI (runs 3-8, yield 0-
24%) were sufficiently less effective in the synthesis of 3aa compared to the developed method
(runs 1-2, yield 51-54%). TBAI/t-BuOOH combination, that was developed for the C-O CDC of
N-hydroxyimides with arylalkylketones21,38 gave no 3aa at all. This fact indicates that the
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TBAI/t-BuOOH system is very sensitive to the nature of carbonyl compound employed as the
CH-reagent.
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8
To test the scope of the proposed method, a number of products of the C-O CDC of N-
hydroxyimides (NHPI, N-hydroxysuccinimide, tetrachloro-N-hydroxyphthalimide, and 4,5-
dichloro-N-hydroxyphthalimide) with various CH-reagents (esters, ketones, -dicarbonyl
compounds, nitriles, alkylarenes, and ethers) was synthesized (Table 3).
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60
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Table 3. Cross-dehydrogenative C-O coupling of various CH-reagents (esters, ketones, -
dicarbonyl compounds, nitriles, alkylarenes, and ethers) with N-hydroxyimides (N-
hydroxyphthalimide, N-hydroxysuccinimide, tetrachloro-N-hydroxyphthalimide, and 4,5-
dichloro-N-hydroxyphthalimide).
O
O
t-BuOOt-Bu (2 mmol)
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13
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15
16
17
18
19
20
21
22
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24
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28
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30
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O
+
R
N
R
H
HO N
PhH ( 2 ml)
145 - 150 oC, 3 h
CH - reagent
(3-20 mmol)
O
O
N-hydroxyimide (1 mmol)
O
O
O
O
O
O
OEt
OMe
OEt
OMe
OEt
O
O
O
OEt
O
O
O
O
O
O
Cl
Cl
O
O
O
N
N
N
N
N
N
Cl
Cl
O
O
O
O
O
O
3aa
3ca
3da
3ba
Cl
Cl
3ad
3ac
64% (10, PhH)
61% (10, neat)
60% (20, neat)
65% (10, PhH)
74% (20, neat)
45% (10, PhH)
43% (10, PhH)
29% (10, PhH)
30% (10, PhH)
42% (10, neat)
47% (20, neat)
O
O
O
O
O
O
Ph
OH
O
O
O
OMe
OH
O
O
O
O
O
N
O
O
N
O
O
N
N
N
N
O
O
O
O
O
O
3fb
3ha
3ga
3fa
3ea
3ia
32%(10, PhH)
45% (10, PhH)
51% (10, PhH)
27% (10, neat)
51% (10, PhH)
83% (5, PhH)
58% (10, PhH)
56% (10, neat)
40% (10, neat)
68% (20, neat)
30% (10, neat)
O
O
O
O
O
O
Ph
Ph
n-C5H11
O
N
O
O
O
O
O
O
O
O
O
O
N
O
N
N
N
N
N
O
O
O
O
O
O
3la
3ka
3jb
3ja
65%(10, PhH)
57%(10, neat)
3na
57% (10, PhH)
56% (5, PhH)
3ma
65%(10, PhH)
61% (10, neat)
25%(5, PhH)
55%(10, PhH)
26% (10, PhH)
52% (10, neat)
O
O
O
O
O
O
O
Ph
CN
CN
CN
Ph
O
O
Ph
Ph
Ph
O
OEt
EtO
OEt
O
O
N
O
N
O
O
O
O
Ph
O
O
O
O
O
O
N
N
N
N
N
O
O
O
O
3ta
3ua
3sa
3qa
3oa
17% (5, PhH)
3ra
64% (3, PhH)
3pa
47% (5, PhH)
47% (20, neat)
41% (10, neat)
19% (5, PhH)
75% (3, PhH)
45% (3, PhH)
16% (10, neat)
Cl
O
Cl
O
CHCl2
O
O
N
O
O
O
O
N
O
O
O
N
O
EtO
N
O
N
O
O
O
N
O
O
O
O
O
O
5
3xa
3ya
34% (5, PhH)
3va
54% (5, PhH)
3wa
0% (20, neat)
0% (10, PhH)
4
20% (20, neat)
0% (10, PhH)
44% (5, PhH)
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General reaction conditions: NHPI (1 mmol), CH-reagent (3 – 20 mmol, values are given in
brackets for each product), t-BuOOt-Bu (2 mmol) and PhH (2 mL, “neat” means no solvent was
added) were placed into a hermetic glass tube equipped with a magnetic stirring bar and a screw
cap. The mixture was stirred in an oil bath at 150 °C for 3 h. Isolated yields are given.
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Both solvent (PhH) and solvent-free procedures were tested and showed similar results. The
excess of CH-reagent depended on the convenience of its separation from the target product. It
was minimized in case of the substrates with high boiling points and Rf values close to those of
the C-O coupling products. N-Hydroxysuccinimide, tetrachloro-N-hydroxyphthalimide and 4,5-
dichloro-N-hydroxyphthalimide gave somewhat lower yields of the C-O coupling products in
comparison with NHPI (products 3aa and 3ac-3ad, 3fa and 3fb, 3ja and 3jb). The developed
method was successfully applied to the C-O CDC of N-hydroxyimides with esters (products 3aa,
3ac, 3ad, 3ba, 3ca, 3da, 3ea), carboxylic acids (products 3fa, 3fb), ketones (products 3ga, 3ha,
3ia, 3ja, 3jb, 3ka, 3la, 3ma, 3na), β-dicarbonyl compounds (products 3oa, 3pa, 3qa) and
benzylmalononitrile (product 3ra), compounds containing benzyl fragment (products 3ea, 3na,
3qa, 3sa, 3ta, 3ua, 3va, 3wa), THF (product 3xa), and 1,1,2,2-tetrachloroethane (product 3ya).
In case of non-symmetric dialkyl ketones more substituted side was functionalizaed selectively
(products 3ga, 3ha, 3ia) In contrast to propiophenone (product 3la, yield 57-65%), acetophenone
gave no target coupling product with NHPI (structure 4), presumably due to higher C-H bond-
dissociation energy. Similarly, the target product was not obtained from the reaction of NHPI
with cyclohexane. Thus, the general method was developed for functionalization of diverse
classes of CH-reagents and its scope is not limited to carbonyl compounds. The most important
result was the successful C-O CDC of N-hydroxyimides with not activated esters, carboxylic
acids and ketones (products 3aa, 3ac, 3ad, 3ba, 3ca, 3da, 3fa, 3fb, 3ga, 3ha, 3ia, 3ja, 3jb, 3ka,
3la, and 3ma) with functionalization of a secondary or tertiary C(sp3) atom. Despite the yields
are moderate (26-65%), such compounds are hardly achievable by other CDC methods and
traditional synthetic approaches.
Scheme 2 demonstrates the practical applicability of the developed method for the synthesis
on 10 mmol scale. Compound 3fb is known as a commercial product - the precursor of Baran
aminating reagent.56 It was previously synthesized in 2 stages starting from tert-butyl 2-bromo-2-
methylpropionate,56 that can be prepared from isobutyric acid in another 2 stages59,60. The
synthetic sequence starting from isobutyric acid consists of 4 stages, the overall yield can be
estimated as 29-32%. Using the newly developed method, compound 3fb can be obtained from
isobutyric acid in a single stage in a superior yield of 51% (Scheme 2). This synthesis was scaled
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up to 10 mmol of N-hydroxysuccinimide employing the PhCl-based atmospheric pressure
procedure for safety reasons. Although lower isolated yield 30% was obtained in this case, the
scaled up procedure is still less time consuming and more atom-economical compared to the
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four-step synthetic sequence.
O
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N
OH
O
K2CO3
t-BuOH
Pyridine
O
Br2 (excess)
Red phosporus (10 mol%)
Br
Br
N
COBr
CH2Cl2
ice bath 4 h ® 15 h RT
69%
CO2t-Bu
DMF
95 °C, 12 h
56%
O
CO2t-Bu
CO2H
100 °C, 6 h
75-83%
O
Ref. 57
Ref. 58
Ref. 55
CF3COOH
CH2Cl2
10 min RT
ca. 100%
- Single stage
- Simple procedure
O
- Toxic reagents avoided
- High step and time economy
- High atom economy
N
OH t-BuOOt-Bu (2 equiv.)
This work:
O
NHSI
O
N
O
CO2H
 1 mmol scale of NHSI, PhH, 150 °C, 3 h: 51% (103 mg, isolated yield)
 10 mmol scale of NHSI, PhCl,
refulx, 24 h: 30% (0.604 g, isolated yield), 37% by NMR
O
3fb
Baran aminating reagent precursor
O
O
O
O
t-BuOOt-Bu (20 mmol)
O
+
OEt
HO N
EtO
N
a)
PhCl 20 mL,
reflux, 24h
O
O
1a (100 mmol) 2a (10 mmol)
3aa
41% (1.147g, isolated yield), 50% by NMR
O
O
O
O
t-BuOOt-Bu (10 mmol)
O
b)
+
OEt
HO N
EtO
N
PhH 5 mL,
150 ºC, 24h
(in autoclave)
O
O
1a (50 mmol) 2a (5 mmol)
3aa
45% (0.624 g, isolated yield), 52% by NMR
Scheme 2. Practical applicability of the developed method: the synthesis of the Baran aminating
reagent precursor and scale up experiments.
The synthesis of model product 3aa was also scaled up using two procedures: PhCl-based
atmospheric pressure procedure (Scheme 2, a) and standard PhH-based procedure (Scheme 2, b).
For procedure b a 25 mL stainless-steel autoclave with PTFE liner and pressure gauge was used
as reaction vessel. Similar yields were observed for both procedures (41% for procedure a and
45% for procedure b).
To study the role of t-BuOOt-Bu in the discovered reaction, the ratio of products of its
thermal decay depending on the composition of the reaction mixture was studied by gas
chromatography (Scheme 3).
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Additives
O
O
O
PhH (2 mL)
or
solvent-free
150 ºC, 2 h
2 mmol
RH
- R
- CH3
(A) (B)
8
9
O
Unreacted
Run
Additives
OH
-BuOO -Bu
t
t
Experiments in PhH (2 mL)
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1
2
3
4
-
6%
21%
36%
4%
67%
49%
51%
42%
-PrCOOEt (2 mmol)
i
12%
37%
47%
NHPI (1 mmol)
NHPI (1 mmol), -PrCOOEt (2 mmol)
i
6%
Solvent-free experiments
5
6
-PrCOOEt (10 mmol)
i
34%
49%
30%
12%
34%
35%
NHPI (1 mmol), -PrCOOEt (10 mmol)
i
Scheme 3. Influence of NHPI and i-PrCOOEt on the ratio of the thermal decomposition
products of t-BuOOt-Bu
It is known that t-BuOOt-Bu thermally decomposes to tert-butoxyl radicals, which can
abstract hydrogen from the medium to give t-BuOH (Scheme 3, pathway A) or undergo β-
scission to give methyl radical and acetone (Scheme 3, pathway B). The ratio between pathways
A and B was studied by monitoring the yields of t-BuOH and acetone by GC. The runs 1-4 were
performed in benzene to model the solvent-based general procedure, and runs 5-6 were
performed in i-PrCOOEt to model the solvent-free general procedure. The conversion of t-
BuOOt-Bu was not dramatically influenced by the composition of reaction mixture but was
higher in i-PrCOOEt (35-39% of unreacted t-BuOOt-Bu was observed) then in PhH (42-67% of
unreacted t-BuOOt-Bu was observed). In pure PhH (run 1) t-BuOOt-Bu was decomposed mainly
by pathway B: acetone yield (21%) was more than 3 times higher than the yield of t-BuOH (6%).
Addition of i-PrCOOEt (run 2) did not change A / B ratio significantly, indicating the low ability
of i-PrCOOEt to intercept tert-butoxyl radicals by playing the role of a H-atom donor. A
strikingly different result was observed when NHPI was added to the reaction mixture (run 3). In
this case, pathway A became major (A / B ratio = t-BuOH / acetone ratio = 37 / 4), indicating
that NHPI effectively intercepts tert-butoxyl radicals. The addition of i-PrCOOEt (run 4) had a
negligible effect on A / B ratio.
In the case of the t-BuOOt-Bu decomposition in pure i-PrCOOEt A / B ratio was close to 1:1
(Scheme 3, run 5). The addition of NHPI made pathway A major (run 6, A / B ratio = t-BuOH /
acetone ratio = 54 / 13) analogously to the previously discussed case of the reaction in benzene
(runs 1-4). To sum up, NHPI acts as an effective scavenger of tert-butoxyl radicals preventing
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their fragmentation to acetone and methyl radicals. This reactive radical scavenging ability of
NHPI may be responsible for the good selectivity of the discovered process. It is known that
thermolysis of di-tert-butylperoxide in i-PrCOOMe (analog of i-PrCOOEt) leads to its C-C
dehydrogenative dimerization61-63 and telomerization63 of i-PrCOOMe.
The plausible reaction pathway is depicted in Scheme 4. Based on the experimental results
presented in Scheme 3 and discussed above, the plausible major reaction route is highlighted by
plain reaction arrows in Scheme 4. The possible minor routes are represented by dashed reaction
arrows.
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O
O
N
O
PINO
- -BuOH
t
- CH4
O
OH
A
N
F
O
O
NHPI
E
O
O O
N
D
O
H3C
- Me2C=O
CO2Et
O
H
CO2Et
C
G
-NHPI
PINO
B
- CH4
- -BuOH
t
CO2Et
Scheme 4. Plausible mechanism of the cross-dehydrogenative coupling of NHPI with CH-
reagents employing t-BuOOt-Bu as the dehydrogenation reagent.
First, the thermal decomposition of di-tert-butylperoxide produces tert-butoxyl radicals (t-
BuO•). The plausible major reaction route consists of three stages: H-atom abstraction by t-BuO•
from NHPI to give PINO radical (stage A),64 H-atom abstraction by PINO or t-BuO• from the
CH-reagent to give a C-centered radical (stages B and C, respectively), and coupling of PINO
radical with the C-centered radical to form the C-O CDC product (stage D). Minor competing
routes include -scission of t-BuO• producing methyl radical (stage E), H-atom abstraction from
NHPI by methyl radical (stage F), and H-atom abstraction form CH-reagent by methyl radicals
(stage G).
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Conclusion
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Di-tert-butyl peroxide mediated metal-free cross-dehydrogenative C-O coupling of N-
hydroxyimides with various CH-reagents was discovered. The developed procedure is
experimentally simple, compatible with solvent-based or solvent-free mode of synthesis, and
uses inexpensive di-tert-butylperoxide as the dehydrogenation agent. The method is effective for
the CH-functionalization of esters, carboxylic acids and ketones that are challenging substrates
CH-functionalization and affords 2-5 fold higher yields than previously reported protocols
developed for other types of CH-reagents. Based on the control experiments, the plausible major
reaction route was proposed. Tert-butoxyl radical (t-BuO•) abstract hydrogen atom from N-
hydroxyimide with the formation of imide-N-oxyl radical. The hydrogen atom of carbonyl
compound is abstracted by imide-N-oxyl radical and new C-O bond is formed by recombination
of resultant C-centered radical with imide-N-oxyl radical. The uncommon feature of the
discovered process is the highly selective sequence of hydrogen atom abstraction stages followed
by the cross-recombination of free radicals at high temperature. Moreover, generation of imide-
N-oxyl radicals at lower temperatures by previously known procedures does not allow to reach
such efficiency of the C-O coupling.
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Experimental
Caution! Experimental procedures involving heating of reaction mixtures in sealed glass tubes
impose a potential risk of explosion due to the increased internal pressure. Although no incidents
occurred during the course of the present work, the use of protective shields and personal
protective equipment is strongly recommended. The given values of the temperatures for
carrying out the synthesis (in most cases 150 ° C) relate to the temperature of the oil bath. It must
be kept in mind, that the temperature and pressure inside the reaction tube depend on
composition of the reaction mixture and heat loss in the upper part of the tube (above the oil
level), where the vapor of the boiling mixture is condensed on the inner surface of the walls
(photos of the used reaction setup are given in Supporting information). In case of the scaling the
synthesis to more than 1 mmol of N-hydroxyimide it is strongly recommended to avoid the use
of hermetic reaction vessels made of glass. An autoclave with internal pressure control or an
open reaction flask equipped reflux condenser can be used instead (see examples below). In case
of usage of peroxides other than di-tert-butylperoxide, especially hydroperoxides, quench of
peroxide before work up is recommended. The risk of peroxide explosion during or after the
concentration of the reaction mixture can be higher in the presence of metal compounds and
other initiating impurities.
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General
C-O CDC reactions were performed in hermetic borosilicate glass tubes (OD = 18 mm, ID =
15.4 mm, wall thickness = 1.3 mm, height = 18 cm, volume = 30 mL) equipped with screw caps
(18 DIN Thread, PTFE coating of the cap seal). The given reaction temperatures (Tables 1,2,3
and Scheme 3) refer to the temperature of an oil bath at which the reaction mixtures were
thermostated (1 °С). See SI for the photos of the reaction heating procedure.
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Unless otherwise noted, removal of solvents on rotary evaporator was performed under a
vacuum of a water jet pump at 30-50 °C.
GC analysis was performed using a capillary low polarity column (5% Phenyl / 95%
Dimethyl Polysiloxane, length 30 m, inner diameter 0.25 mm, film thickness 0.25 μm). The
helium flow rate was 3.16 mL/min.
Benzene was distilled over CaH2. MeCN and PhCN were distilled over P2O5. THF was
distilled over sodium. t-BuOH (99.5%), MeNO2 (99%), glacial acetic acid, C2H4Cl2 (99.5%),
chlorobenzene (>99%), N-Hydroxyphthalimide (98%), N-Hydroxysuccinimide (98+%), t-
BuOOt-Bu (99%), dicumyl peroxide (PhMe2COOCMe2Ph, 99%), tert-butyl peroxybenzoate
(BzOOt-Bu, 98%), 2,2-Di(tert-butylperoxy)butane (MeEtC(OOt-Bu)2, 50% solution in aromatic
free mineral spirit), 1,1-Di(tert-butylperoxy)cyclohexane (1,1-(OOt-Bu)cyclohexane, 50%
solution in mineral oil), dibenzoyl peroxide (BzOOBz, 75%, remainder water), t-BuOOH (70%
solution in water), t-BuOOH (5-6M in decane), 3-Chloroperoxybenzoic acid (MCPBA, 70-75%,
balance 3-Chlorobenzoic acid and water), (Diacetoxyiodo)benzene (PhI(OAc)2, 98%), ethyl
isobutyrate (99%), ethyl propionate (99+%), ethyl benzoate (99+%), methyl isobutyrate (99%),
methyl 2-methylbutyrate (98%), methyl phenylacetate (99+%), isobutyric acid (99+%), 3-
methyl-2-butanone (98%), 4-Methyl-2-pentanone (99%), 2,4-Dimethyl-3-pentanone (98%), 6-
undecanone (97%), propiophenone (99%), 1-phenylbutan-2-one (95%), Ethyl 2-
methylacetoacetate (95%), diethyl phenylmalonate (98%), diphenylacetonitrile (99+%), toluene
(99.5%), cumene (99%), 4'-Methylacetophenone (95%), ethyl 4-methylbenzoate (99%), 2-
hexanone (98%), acetophenone (98%), cyclohexane (>99%), and 1,1,2,2-Tetrachloroethane
(98.5%) were used as is.
Tetrachloro-N-hydroxyphthalimide,65 4,5-dichloro-N-hydroxyphthalimide14 2-methyl-1-
(pyridin-3-yl)propan-1-one,66 3-methyl-2,4-pentanedione,67 and benzylmalononitrile68 were
prepared as described in the literature.
Experimental details for Table 1
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NHPI (163-245 mg, 1-1.5 mmol), ethyl isobutyrate (1-20 mmol, 0.116-2.32 g), peroxide (0.5-
3 mmol) and a solvent (2 mL, “neat” means no solvent was added) were placed into a glass tube
equipped with a magnetic stirring bar and a hermetic screw cap. The mixture was stirred at 130
or 150 °C for 1-24 h, and then cooled to room temperature. The yields were determined by GC
analysis of the reaction mixture using ethyl benzoate as an internal standard. The following GC
analysis settings were used: evaporating chamber temperature — 300 °C, column chamber
temperature was gradually increased from 70 °C to 300 °C at a rate of 10 °C/min.
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To determine the isolated yield of 3aa (given in parenthesis in Table 1) the reaction mixture
was transferred to a round bottom flask using acetone (10 mL), then rotary evaporated under
reduced pressure (water jet pump). Product 3aa was isolated by column chromatography on
silica gel using eluent EtOAc/petroleum ether = 2/5.
Experimental details for Table 2
Runs 1-2 are described above in Experimental details for Table 1.
Run 3 (employing CuCl (cat.) / PhI(OAc)2 system) was performed analogously to the
procedure described in ref.17. N-hydroxyphthalimide (163 mg, 1 mmol), PhI(OAc)2 (322 mg, 1
mmol) and CuCl (9.9 mg, 0.1 mmol) were loaded into a hermetic tube equipped with a magnetic
stirring bar and a screw cap, then the tube was flushed with argon. MeCN (2 mL) was added
followed by ethyl isobutyrate (581 mg, 5 mmol). The reaction mixture was stirred at 70 C for 6
h.
The reaction mixture was diluted by CH2Cl2 (10 mL) and then by water (30 mL); after
shaking the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×10
mL). All organic extracts were combined, washed with water (2×20 mL), dried over MgSO4 and
the solvent was removed using a water-jet vacuum pump. The residue was purified by flash
column chromatography on silica gel (EtOAc/petroleum ether = 2/5) to give ethyl 2-
(phthalimide-N-oxy)-2-methylpropanoate 3aa (67 mg, 0.241 mmol, 24%).
Run 4 (employing (NH4)2Ce(NO3)6) was performed analogously to the procedure described
in ref.18. A mixture of N-hydroxyphthalimide (163 mg, 1 mmol), ethyl isobutyrate (581 mg, 5
mmol) and acetone (5 mL) was placed in a round-bottomed flask and then flushed with argon. A
solution of (NH4)2Ce(NO3)6 (1096 mg, 2 mmol) in water (3 ml) was added dropwise with
vigorous stirring under argon for 10 minutes, and the reaction mixture was stirred at RT for 30
min.
Then it was diluted with H2O (20 mL). The aqueous layer was and extracted with CH2Cl2
(3×10 mL) and the combined organic layers were washed with a saturated aqueous NaHCO3
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solution (15 mL), and H2O (2×20 mL). The mixture was dried over MgSO4 and the solvent was
rotary evaporated. The residue was purified by column chromatography on silica gel (eluent
EtOAc /petroleum ether = 2/5) to give ethyl 2-(phthalimide-N-oxy)-2-methylpropanoate 3aa (29
mg, 0.101 mmol, 10%).
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Run 5 (employing TBAI/t-BuOOH system in DMA) was performed analogously to the
procedure described in ref.38. N-hydroxyphthalimide (489 mg, 3 mmol), ethyl isobutyrate (116
mg, 1 mmol), t-BuOOH in decane 5-6 M (1 mmol, 0.182 mL), Bu4NI (36.9 mg, 0.1 mmol) and
dimethylacetamide (DMA, 2 mL) were placed into a round-bottomed flask. The reaction mixture
was stirred at 100 °C for 2 h, then cooled to room temperature, diluted with H2O (20 mL) and
extracted with CH2Cl2 (3×20 mL). Combined organic extracts were washed with a saturated
aqueous NaHCO3 solution (15 mL), H2O (2×20 ml). The mixture was dried over MgSO4 and the
solvent was rotary evaporated. No product 3aa was obtained by column chromatography
separation of the residue (silica gel, eluent EtOAc/petroleum ether = 2/5).
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Run 6 (employing TBAI/t-BuOOH system in MeCN) was performed analogously to the
procedure described in ref.21. N-hydroxyphthalimide (163 mg, 1 mmol), ethyl isobutyrate (581
mg, 5 mmol), t-BuOOH in decane 5.5 M (3 mmol, 0.546 mL), TBAI (36.9 mg, 0.1 mmol) and
MeCN (2 mL) were placed in a round-bottomed flask. The reaction mixture was stirred at 75 °C
for 6 h, then cooled to room temperature, diluted with H2O (20 mL) and extracted with CH2Cl2
(3×20 mL). Combined organic extracts were washed with a saturated aqueous NaHCO3 solution
(15 mL), and H2O (2×20 mL). The mixture was dried over MgSO4 and the solvent was rotary
evaporated. No product 3aa was obtained by column chromatography separation of the residue
(silica gel, eluent EtOAc/petroleum ether = 2/5).
Run 7 (employing Co(OAc)2•4H2O and KMnO4 in AcOH) was performed analogously to the
procedure described in ref.37. N-hydroxyphthalimide (163 mg, 1 mmol), ethyl isobutyrate (581
mg, 5 mmol), Co(OAc)2•4H2O (12 mg, 0.05 mmol), KMnO4 (63 mg, 0.4 mmol) and AcOH (5
mL) were placed in a round-bottomed flask. The reaction mixture was stirred at 80 °C for 20
min, then cooled to room temperature. The reaction mixture was diluted with H2O (20 mL) and
extracted with CH2Cl2 (3×20 mL). Combined organic extracts were washed with a saturated
aqueous NaHCO3 solution (15 mL), H2O (2×20 mL). The mixture was dried over MgSO4 and
the solvent was rotary evaporated. The residue was purified by column chromatography on silica
gel (eluent EtOAc / Petroleum ether = 2/5) to give 3aa (58 mg, 0.209 mmol, 21%).
Run 8 (employing Mn(OAc)3•2H2O in AcOH) was performed analogously to the procedure
described in ref.37. N-hydroxyphthalimide (163 mg, 1 mmol), ethyl isobutyrate (581 mg, 5
mmol), Mn(OAc)3•2H2O (536 mg, 2 mmol) and AcOH (5 mL) were placed in a round-bottomed
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flask. The reaction mixture was stirred at 80 °C for 20 min, then cooled to room temperature.
The reaction mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (3×20 mL).
Combined organic extracts were washed with a saturated aqueous NaHCO3 solution (15 mL),
H2O (2×20 mL). The mixture was dried over MgSO4 and the solvent was rotary evaporated. The
residue was purified by column chromatography on silica gel (eluent EtOAc / Petroleum ether =
2/5) to give 3aa (42 mg, 0.151 mmol, 15%).
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Experiments for Table 3
General reaction conditions: NHPI (163 mg, 1 mmol), CH-reagent (3-20 mmol), t-BuOOt-
Bu (293 mg, 2 mmol) and PhH as a solvent (2 mL, “neat” means no solvent was added) were
placed into a hermetic tube equipped with a magnetic stirring bar and a screw cap. The mixture
was stirred in an oil bath (150 C) for 3 h, then the mixture was cooled to room temperature,
transferred to a round-bottomed flask using acetone (10 mL), and rotary evaporated under
reduced pressure (water jet pump, 20 mm Hg, 30-50 °C). Additional evaporation step using
rotary vane pump (0.5 mm Hg) at 80 °C was made for the isolation of products 3fa, 3fb derived
from isobutyric acid. The residue was purified by column chromatography on silica gel (eluent is
given for each product, see below).
Ethyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate 3aa: isolated by column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (60-64%, 0.602-0.642 mmol,
167-178 mg); mp = 74-76 C (lit.47 mp = 74-77 C); 1H NMR (300.13 MHz, CDCl3) δ 7.86-7.79
(m, 2H), 7.79-7.70 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.63 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H);
13C{1H}NMR (75.48 MHz, CDCl3) δ 171.0, 164.6, 134.7, 129.2, 123.7, 86.6, 62.1, 23.1, 14.1;
FTIR (KBr): max = 1796, 1743, 1727, 1469, 1352, 1296, 1186, 1157, 1138, 1111, 970, 878, 706
cm-1. Anal. Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.58; H, 5.42; N, 5.04.
Ethyl 2-methyl-2-((4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)oxy)propanoate 3ac:
isolated by column chromatography (EtOAc/petroleum ether from 1/5 to 2/5) as a white solid
1
(30%, 0.301 mmol, 125 mg); mp = 157-158 C; H NMR (300.13 MHz, CDCl3) δ 4.25 (q, J =
7.1 Hz, 2H), 1.62 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 170.5,
160.2, 140.9, 130.2, 124.9, 87.3, 62.2, 23.1, 14.1; FTIR (KBr): max = 1794, 1741, 1369, 1338,
1304, 1288, 1178, 1162, 1133, 1037, 734, 702 cm-1. Anal. Calcd for C14H11Cl4NO5: C, 40.51; H,
2.67; N, 3.37. Found: C, 40.58; H, 2.68; N, 3.35.
Ethyl 2-((5,6-dichloro-1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate 3ad: isolated by
column chromatography (EtOAc/petroleum ether 1/8) as a white solid (29%, 0.29 mmol, 100
1
mg); mp = 39-40 °C; H NMR (300.13 MHz, CDCl3) δ 7.91 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H),
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1.61 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 170.7, 162.8, 139.8,
128.2, 125.9, 87.1, 62.2, 23.1, 14.1; FTIR (KBr): max = 1794, 1735, 1384, 1344, 1297, 1187,
1139, 1110, 1025, 987, 765, 723 cm-1; HR-MS (ESI-TOF) m/z: [M + Na]+ calcd for
C14H13Cl2NO5Na: 368.0063, 370.0034; found: 368.0059, 370.0030.
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Ethyl
2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate
3ba:
isolated
by
column
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chromatography (EtOAc/petroleum ether = 2/5) as a white solid (43-47%, 0.429—0.471 mmol,
113-124 mg); mp = 73-75 C (lit.55 mp = 79-80 C); 1H NMR (300.13 MHz, CDCl3) δ 7.89-7.79
(m, 2H), 7.79-7.70 (m, 2H), 4.86 (q, J = 6.9 Hz, 1H), 4.33 – 4.13 (m, 2H), 1.64 (d, J = 6.9 Hz,
13
3H), 1.27 (t, J = 7.1 Hz, 3H); C{1H}NMR (75.48 MHz, CDCl3) δ 169.8, 163.4, 134.7, 129.0,
123.8, 81.5, 61.8, 16.5, 14.1.
Methyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylpropanoate 3ca: isolated by column
chromatography (EtOAc/petroleum ether from 2/5 to 1/2) as a white solid (65-74%, 0.650-0.741
1
mmol, 171-195 mg); mp = 101-102 C; H NMR (300.13 MHz, CDCl3) δ 7.87-7.79 (m, 2H),
7.79-7.72 (m, 2H), 3.84 (s, 3H), 1.64 (s, 6H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 171.4, 164.6,
134.8, 129.1, 123.8, 86.6, 53.0, 23.1; FTIR (KBr): max = 1794, 1742, 1465, 1374, 1354, 1297,
1187, 1170, 1135, 973, 881, 709 cm-1. Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32.
Found: C, 59.33; H, 4.94; N, 5.13.
Methyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methylbutanoate 3da: isolated by column
chromatography (EtOAc/petroleum ether from 1/4 to 1/3) as a white solid (42-45%, 0.418-0.451
mmol, 116-125 mg); mp = 63-65 C; 1H NMR (300.13 MHz, CDCl3) δ 7.86-7.78 (m, 2H), 7.78-
7.70 (m, 2H), 3.84 (s, 3H), 2.21-1.88 (m, 2H), 1.54 (s, 3H), 1.00 (t, J = 7.5 Hz, 3H);
13C{1H}NMR (75.48 MHz, CDCl3) δ 171.1, 164.6, 134.7, 129.1, 123.7, 90.0, 52.9, 29.8, 19.0,
8.6; FTIR (KBr): max = 1790, 1740, 1464, 1355, 1186, 1166, 1117, 966, 879, 706 cm-1. Anal.
Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.58; H, 5.51; N, 5.03.
Methyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phenylacetate 3ea: isolated by column
chromatography (EtOAc/ CHCl3 from 0/1 to 1/4) as a white solid (83%, 0.829 mmol, 258 mg);
mp = 129-130 C (lit.21 mp = 128-131 C); 1H NMR (300.13 MHz, CDCl3) δ 7.82-7.74 (m, 2H),
7.74-7.68 (m, 2H), 7.65-7.56 (m, 2H), 7.44-7.35 (m, 3H), 5.87 (s, 1H), 3.78 (s, 3H);
13C{1H}NMR (75.48 MHz, CDCl3) δ 168.4, 163.2, 134.7, 132.6, 130.2, 128.8, 128.8, 123.7,
85.7, 52.8; FTIR (KBr): max = 1793, 1753, 1732, 1225, 1210, 1187, 1036, 701 cm-1. Anal. Calcd
for C17H13NO5: C, 65.59; H, 4.21; N, 4.50. Found: C, 65.25; H, 3.96; N, 4.49.
2-((1,3-Dioxoisoindolin-2-yl)oxy)-2-methylpropanoic acid 3fa: isolated by column
chromatography (EtOAc/petroleum ether/AcOH = 50/50/1) as a white solid (30-51%, 0.301-
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0.510 mmol, 75-127 mg); mp = 127-129 C (lit.46 mp = 133-135 °C); H NMR (300.13 MHz,
CDCl3) δ 9.03 (bs, 1H), 8.00-7.67 (m, 4H), 1.68 (s, 6H); C{1H}NMR (75.48 MHz, CDCl3) δ
13
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174.2, 165.5, 135.3, 128.8, 124.3, 88.3, 23.7; FTIR (KBr): max = 1794, 1752, 1745, 1714, 1468,
1374, 1352, 1311, 1188, 1145, 1114, 1081, 1067, 975, 879, 790, 704, 521 cm-1. Anal. Calcd for
C12H11NO5: C, 57.83; H, 4.45; N, 5.62. Found: C, 58.07; H, 4.65; N, 5.45.
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2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-methylpropanoic acid 3fb: isolated by column
chromatography (EtOAc/СH2Cl2/AcOH = 10/100/1) as a white solid (27-51%, 0.268-0.512
mmol, 54-103 mg); mp = 129-130 C (Recrystallized from diethyl ether, lit.56 mp = 130–131
C); 1H NMR (300.13 MHz, DMSO-d6) δ 2.64 (s, 4H), 1.39 (s, 6H); 13C{1H}NMR (75.48 MHz,
DMSO-d6) δ 173.1, 171.9, 85.8, 25.4, 23.0.
2-((2-Methyl-3-oxobutan-2-yl)oxy)isoindoline-1,3-dione 3ga: isolated by column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (45-68%, 0.449-0.679 mmol,
1
111-168 mg); mp = 56-58 C; H NMR (300.13 MHz, CDCl3) δ 7.86-7.79 (m, 2H), 7.79-7.73
13
(m, 2H), 2.50 (s, 3H), 1.48 (s, 6H); C{1H}NMR (75.48 MHz, CDCl3) δ 207.9, 164.9, 134.8,
129.1, 123.8, 91.8, 25.2, 22.5; FTIR (film): max = 1794, 1738, 1721, 1467, 1357, 1189, 1150,
1130, 1081, 976, 878, 706 cm-1. Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found:
C, 63.14; H, 5.38; N 5.40.
2-((2-Methyl-4-oxopentan-3-yl)oxy)isoindoline-1,3-dione 3ha: isolated by column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (32-40%, 0.321-0.398 mmol,
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84-104 mg); mp = 75-78 C; H NMR (300.13 MHz, CDCl3) δ 7.84-7.70 (m, 4H), 4.05 (d, J =
8.1 Hz, 1H), 2.45 (s, 3H), 2.30-2.08 (m, 1H), 1.27 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H);
13C{1H}NMR (75.48 MHz, CDCl3) δ 207.6, 163.5, 134.8, 128.9, 123.8, 98.3, 30.2, 26.0, 18.9,
18.1; FTIR (KBr): max = 1792, 1741, 1715, 1467, 1377, 1352, 1233, 1188, 1124, 1081, 1015,
982, 878, 703, 518 cm-1. Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C,
64.31; H, 5.80; N, 5.39.
2-((2-oxohexan-3-yl)oxy)isoindoline-1,3-dione 3ia: isolated by column chromatography
(EtOAc/petroleum ether = form 1/10 to 1/4) as a white solid (56-58%, 0.56-0.58 mmol, 146-152
mg); mp = 110-111°C; 1H NMR (300.13 MHz, CDCl3) δ 7.85-7.78 (m, 2H), 7.78-7.68 (m, 2H),
4.43 (t, J = 6.4 Hz, 1H), 2.45 (s, 3H), 2.04-1.86 (m, 1H), 1.83-1.67 (m, 1H), 1.66-1.49 (m, 2H),
0.99 (t, J = 7.3 Hz, 3H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 207.3, 163.5, 134.8, 128.9, 123.8,
92.9, 32.9, 25.7, 18.2, 14.0. FTIR (KBr): max = 1792, 1732, 1463, 1361, 1187, 1113, 1074, 982,
874, 702, 517 cm-1; HR-MS (ESI-TOF) m/z: [M + Na]+ calcd for C14H15NO5+Na+: 284.0893;
found: 284.0895.
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2-((2,4-Dimethyl-3-oxopentan-2-yl)oxy)isoindoline-1,3-dione 3ja: isolated by column
chromatography (EtOAc/petroleum ether form 1/2 to 2/3) as a white solid (61-65%, 0.610-0.650
mmol, 168-179 mg); mp = 82-83 C; 1H NMR (300.13 MHz, CDCl3) δ 7.93-7.82 (m, 2H), 7.82-
7.72 (m, 2H), 3.61 (heptet, J = 6.8 Hz, 1H), 1.49 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H); 13C{1H}NMR
(75.48 MHz, CDCl3) δ 214.1, 165.3, 134.8, 129.3, 123.8, 93.2, 35.3, 23.8, 19.3; FTIR (KBr):
max = 1794, 1737, 1708, 1467, 1380, 1364, 1349, 1190, 1149, 1110, 1042, 974, 877, 712, 699
cm-1. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.48; H, 6.33; N, 4.83.
1-((2,4-Dimethyl-3-oxopentan-2-yl)oxy)pyrrolidine-2,5-dione 3jb: isolated by column
chromatography (EtOAc/petroleum ether from 1/2 to 2/3) as a white solid (56%, 0.559 mmol,
127 mg); mp = 57-59 C; 1H NMR (300.13 MHz, CDCl3) δ 3.65-3.45 (m, 1H), 2.75 (s, 4H), 1.41
(s, 6H), 1.15 (d, J = 6.8 Hz, 6H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 213.8, 172.5, 93.2, 35.1,
25.6, 23.6, 19.4; FTIR (KBr): max = 1784, 1728, 1466, 1378, 1366, 1187, 1154, 1078, 1043, 998,
942, 816, 656 cm-1; HR-MS (ESI-TOF) m/z: [M + Na]+ calcd for C11H17NO4Na 250.1050; found
250.1053.
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2-((6-Oxoundecan-5-yl)oxy)isoindoline-1,3-dione 3ka: isolated by column chromatography
(EtOAc/petroleum ether = 1/3) as a viscous gum (52-57%, 0.519-0.570 mmol, 172-189 mg); 1H
NMR (300.13 MHz, CDCl3) δ 7.86-7.78 (m, 2H), 7.78-7.70 (m, 2H), 4.52-4.43 (m, 1H), 3.05
(dt, J1 = 18.3, J2 = 7.4 Hz, 1H), 2.64 (dt, J1 = 18.3, J2 = 7.4 Hz, 1H), 2.05-1.87 (m, 1H), 1.86-
1.70 (m, 1H), 1.69-1.20 (m, 10H), 0.98-0.81 (m, 6H); 13C{1H}NMR (75.48 MHz, CDCl3) δ
209.1, 163.6, 134.8, 129.0, 123.8, 92.7, 38.0, 31.5, 30.7, 26.9, 22.7, 22.6, 14.1, 13.9; FTIR
(film): max =2958, 2932, 2872, 1792, 1738, 1467, 1374, 1314, 1292, 1242, 1220, 1189, 1172,
1159, 1125, 1082, 984, 877, 702 cm-1. Anal. Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23.
Found: C, 68.68; H, 7.62; N, 4.17.
2-((1-Oxo-1-phenylpropan-2-yl)oxy)isoindoline-1,3-dione 3la: isolated by column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (57-65%, 0.569-0.650 mmol,
168-192 mg); mp = 91-92 °C (lit.23 mp = 87-88 °C); 1H NMR (300.13 MHz, CDCl3) δ 8.18-8.12
(m, 2H), 7.85-7.77 (m, 2H), 7.77-7.68 (m, 2H), 7.62-7.54 (m, 1H), 7.52-7.44 (m, 2H), 5.73 (q, J
= 6.7 Hz, 1H), 1.67 (d, J = 6.7 Hz, 3H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 195.4, 163.7,
134.8, 134.7, 133.8, 129.3, 128.9, 128.8, 123.7, 83.7, 16.3.
2-((2-Methyl-1-oxo-1-(pyridin-3-yl)propan-2-yl)oxy)isoindoline-1,3-dione 3ma: isolated
by column chromatography (EtOAc/petroleum ether = 1/2) as a slightly yellow solid (26%,
1
0.264 mmol, 82 mg); mp = 134-136 C; H NMR (300.13 MHz, CDCl3) δ 9.49 (s, 1H), 8.81-
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8.62 (m, 2H), 7.88 – 7.70 (m, 4H), 7.48-7.37 (m, 1H), 1.71 (s, 6H); C{1H}NMR (75.48 MHz,
CDCl3) δ 197.6, 164.8, 152.7, 151.4, 138.1, 135.0, 130.9, 129.0, 123.9, 123.2, 92.6, 24.1; FTIR
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(KBr): max = 1792, 1736, 1690, 1584, 1569, 1469, 1459, 1418, 1388, 1372, 1351, 1320, 1289,
1202, 1189, 1144, 1107, 1078, 970, 921, 877, 741, 705, 652, 519 cm-1; HR-MS (ESI-TOF) m/z:
[M + H]+ calcd for C17H15N2O4: 311.1026; found 311.1017.
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2-(2-Oxo-1-phenylbutoxy)isoindoline-1,3-dione 3na: isolated by column chromatography
(EtOAc/petroleum ether = 2/5) as a white solid (25-55%, 0.246-546 mmol, 76-169 mg); mp =
108-110 C (lit.18 mp = 113-114 C); 1H NMR (300.13 MHz, CDCl3) δ 7.81-7.65 (m, 4H), 7.56-
7.45 (m, 2H), 7.42-7.32 (m, 3H), 5.79 (s, 1H), 2.94-2.74 (m, 1H), 2.72-2.53 (m, 1H), 1.06 (t, J =
7.2 Hz, 3H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 205.4, 163.3, 134.7, 133.2, 129.8, 128.93,
128.87, 128.3, 123.7, 92.0, 32.1, 7.4; FTIR (KBr) : max = 1792, 1730, 1465, 1457, 1371, 1355,
1187, 1127, 1114, 983, 973, 876, 757, 701 cm-1. Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89;
N, 4.53. Found: C, 69.58; H, 4.81; N, 4.54.
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2-((3-Methyl-2,4-dioxopentan-3-yl)oxy)isoindoline-1,3-dione 3oa: isolated by column
chromatography (EtOAc/petroleum ether = 1/3) as a white solid (17%, 0.167 mmol, 46 mg); mp
=105-107 C; 1H NMR (300.13 MHz, CDCl3) δ 7.90 – 7.72 (m, 4H), 2.53 (s, 6H), 1.49 (s, 3H);
13C{1H}NMR (75.48 MHz, CDCl3) δ 203.0, 164.1, 135.1, 128.8, 124.1, 96.8, 26.3, 16.0; FTIR
(KBr) : max = 1792, 1736, 1713, 1357, 1188, 1117, 978, 878, 710 cm-1. Anal. Calcd for
C14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C, 60.83; H, 4.62; N, 5.05.
Ethyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-2-methyl-3-oxobutanoate 3pa: isolated by column
chromatography (CH2Cl2/EtOAc from 0/1 to 1/5) as a white solid (47%, 0.472 mmol, 144 mg);
mp = 90-91 C (lit.37 mp =90-91 C); 1H NMR (300.13 MHz, CDCl3) δ 7.94-7.69 (m, 4H), 4.32
13
(q, J = 7.1 Hz, 2H), 2.55 (s, 3H), 1.63 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); C{1H}NMR (75.48
MHz, CDCl3) δ 202.6, 167.5, 164.0, 135.0, 128.9, 124.0, 92.3, 62.8, 26.1, 17.2, 14.0.
Diethyl 2-((1,3-dioxoisoindolin-2-yl)oxy)-2-phenylmalonate 3qa: isolated by column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (45%, 0.448 mmol, 178 mg);
1
mp = 87-88 C (lit.37 mp = 81.5-83 C); H NMR (300.13 MHz, CDCl3) δ 7.83-7.63 (m, 6H),
7.39-7.27 (m, 3H), 4.49-4.26 (m, 4H), 1.31 (t, J = 7.1 Hz, 6H); 13C{1H}NMR (75.48 MHz,
CDCl3) δ 165.9, 163.4, 134.6, 132.1, 130.1, 129.5, 128.9, 128.1, 123.7, 90.0, 62.9, 14.0.
2-Benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)malononitrile 3ra: isolated by column
chromatography (EtOAc/petroleum ether from 1/5 to 2/5) as a white solid (64%, 0.643 mmol,
204 mg); mp = 144-145 C; Lit. mp = 158 – 159 C [37]; 1H NMR (300.13 MHz, CDCl3) δ 8.05-
13
7.74 (m, 4H), 7.58 – 7.34 (m, 5H), 3.72 (s, 2H); C{1H}NMR (75.48 MHz, CDCl3) δ 162.9,
135.7, 130.8, 129.5, 129.3, 129.0, 128.8, 124.8, 111.7, 76.5, 43.5.
2-((1,3-Dioxoisoindolin-2-yl)oxy)-2,2-diphenylacetonitrile 3sa: isolated by column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (75%, 0.748 mmol, 265 mg);
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mp = 141-142 C; H NMR (300.13 MHz, CDCl3) δ 7.81-7.67 (m, 8H), 7.48-7.39 (m, 6H);
13C{1H}NMR (75.48 MHz, CDCl3) δ 163.5, 135.6, 134.9, 130.4, 128.9, 128.7, 128.4, 124.0,
117.6, 88.5; FTIR (KBr): max = 1798, 1745, 1452, 1349, 1300, 1186, 1073, 977, 950, 874, 773,
765, 755, 712, 696, 521 cm-1. Anal. Calcd for C22H14N2O3: C, 74.57; H, 3.98; N, 7.91. Found: C,
74.59; H, 3.99; N, 7.98.
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2-(Benzyloxy)isoindoline-1,3-dione
3ta:
isolated
by
column
chromatography
(EtOAc/petroleum ether = 2/5 as a white solid (41-47%, 0.407-0.466 mmol, 103-118 mg); mp
1
=142-143 C (lit.18 mp = 144-146 C); H NMR (300.13 MHz, CDCl3) δ 7.85-7.75 (m, 2H),
7.75-7.65 (m, 2H), 7.57-7.49 (m, 2H), 7.42-7.31 (m, 3H), 5.21 (s, 2H); 13C{1H}NMR (75.48
MHz, CDCl3) δ 163.6, 134.5, 133.8, 130.0, 129.4, 129.0, 128.6, 123.6, 80.0.
2-((2-Phenylpropan-2-yl)oxy)isoindoline-1,3-dione
3ua:
isolated
by
column
chromatography (EtOAc/petroleum ether = 2/5) as a white solid (16-19%, 0.156-0.192 mmol,
1
44-54 mg); mp = 125-127 C; H NMR (300.13 MHz, CDCl3) δ 7.90-7.80 (m, 2H), 7.80-7.67
13
(m, 4H), 7.47 – 7.29 (m, 3H), 1.81 (s, 6H); C{1H}NMR (75.48 MHz, CDCl3) δ 165.6, 143.0,
134.5, 129.4, 128.1, 126.3, 123.5, 88.7, 27.2; FTIR (KBr): max = 1790, 1733, 1368, 1352, 1190,
1153, 1118, 1107, 1078, 975, 877, 766, 701, 552, 519 cm-1. Anal. Calcd for C17H15NO3: C,
72.58; H, 5.37; N, 4.98. Found: C, 72.65; H, 5.31; N, 4.91.
2-((4-Acetylbenzyl)oxy)isoindoline-1,3-dione 3va: isolated by column chromatography
(EtOAc/petroleum ether = 2/3) as a white solid (54%, 0.542 mmol, 160 mg); mp = 144 – 145 C
1
(lit.18 mp = 148-149 C); H NMR (300.13 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 2H), 7.85-7.70
13
(m, 4H), 7.64 (d, J = 7.7 Hz), 5.26 (s, 2H), 2.60 (s, 3H); C{1H}NMR (75.48 MHz, CDCl3) δ
197.8, 163.5, 138.9, 137.8, 134.7, 129.8, 128.9, 128.7, 123.7, 79.1, 26.8.
Ethyl 4-(((1,3-dioxoisoindolin-2-yl)oxy)methyl)benzoate 3wa: isolated by column
chromatography (EtOAc/CHCl3 from 0/1 to 1/4) as a white solid (44%, 0.437 mmol, 142 mg);
mp = 153-154 °C (lit.18 mp = 151-152 °C); 1H NMR (300.13 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz,
2H), 7.84-7.76 (m, 2H), 7.76-7.69 (m, 2H), 7.60 (d, J = 8.1 Hz, 2H), 5.26 (s, 2H), 4.37 (q, J =
7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 166.3, 163.5, 138.6,
134.7, 131.4, 129.9, 129.6, 128.9, 123.7, 79.2, 61.2, 14.4.
2-((Tetrahydrofuran-2-yl)oxy)isoindoline-1,3-dione
3xa:
isolated
by
column
chromatography (EtOAc/petroleum ether = form 1/5 to 2/5) as a white solid (20%, 0.197 mmol,
46 mg); mp =120-132 °C (lit.17 mp = 121-123 C); 1H NMR (300.13 MHz, CDCl3) δ 7.84-7.75
(m, 2H), 7.75 – 7.60 (m, 2H), 5.76 (d, J = 4.6 Hz, 1H), 4.39-4.25 (m, 1H), 4.05-3.91 (m, 1H),
2.34-1.83 (m, 4H); 13C{1H}NMR (75.48 MHz, CDCl3) δ 164.0, 134.4, 129.2, 123.5, 108.9, 69.2,
30.9, 22.6.
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2-(1,1,2,2-tetrachloroethoxy)isoindoline-1,3-dione
3ya:
isolated
by
column
chromatography (DCM) as a white solid (34%, 0.34 mmol, 112 mg); mp = 146-147 °C; 1H NMR
(300.13 MHz, DMSO-d6) δ 8.10-7.84 (m, 4H), 7.48 (s, 1H); 13C{1H}NMR (75.48 MHz, DMSO-
d6) δ 162.6, 135.6, 128.7, 124.0, 117.6, 75.1; FTIR (KBr): max = 1802, 1755, 1290, 1091, 994,
776, 709 cm-1; HR-MS (ESI-TOF) m/z: [M + Na]+ calcd for C10H5Cl4NO3Na: 349.8916,
351.8887, 353.8857; found: 349.8916, 351.8887, 353.8857.
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Experimental for Scheme 2
1 mmol scale synthesis of 3fb was performed as described in experimental for Table 3.
Scaled-up PhCl-based atmospheric pressure procedure for the synthesis of 3fb and 3aa.
N-hydroxyimide (1.15-1.63 g, 10 mmol), isobutyric acid or ethyl isobutyrate (8.81-11.6 g, 100
mmol), di-tert-butylperoxide (2.92 g, 20 mmol) and solvent PhCl (20 mL) were placed into a
round bottomed flask with a magnetic stirring bar. The mixture was stirred for 24 hours under
reflux. Then reaction mixture was cooled to the room temperature.
In the case of 3fb synthesis the mixture was rotary evaporated under reduced pressure (water
jet pump). Additional evaporation step using rotary vane pump (0.5 mm Hg) at 80 °C was
conducted to get rid of residual isobutyric acid. The product 3fb was isolated as slightly yellow
powder (0.604 g, 30%) by recrystallization from diethyl ether.
In the case of 3aa synthesis saturated aqueous NaHCO3 solution (25 mL) was added to the
reaction mixture. Product 3aa was extracted by CH2Cl2 (3×20 mL), extracts were combined,
washed with H2O (2×20 mL), dried over MgSO4 and rotary evaporated. Column
chromatography on silica gel (EtOAc/petroleum ether = 2/5) gave ethyl 2-((1,3-dioxoisoindolin-
2-yl)oxy)-2-methylpropanoate 3aa as a white solid (41%, 4.14 mmol, 1.147 g).
Scaled-up PhH-based procedure for the synthesis of 3aa. N-hydroxyphthalimide (816 mg,
5 mmol), di-tert-butylperoxide (1.46 g, 10 mmol), ethyl isobutyrate (5.81 g, 50 mmol) and
benzene (5 mL) were loaded into PTFE liner of a 25 mL stainless-steel autoclave equipped by
pressure gauge. The mixture was stirred for 3 h on an oil bath (150 C). The pressure inside the
autoclave gradually raised from 0 to approximately 0.45 MPa during all reaction time. After 3 h,
the reaction mixture was cooled to the room temperature. Saturated aqueous NaHCO3 solution
(25 mL) was added to the reaction mixture. Product 3aa was extracted by CH2Cl2 (3×20 mL),
extracts were combined, washed with H2O (2×20 mL), dried over MgSO4 and rotary evaporated.
Column chromatography on silica gel (EtOAc/petroleum ether = 2/5) gave ethyl 2-((1,3-
dioxoisoindolin-2-yl)oxy)-2-methylpropanoate 3aa as a white solid (45%, 2.25 mmol, 0.624 g).
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Experimental details for Scheme 3.
t-BuOOt-Bu (292 mg, 2 mmol), i-PrCOOEt (0, 232, or 1162 mg; 0, 2, or 10 mmol,
respectively), NHPI (0 or 163 mg, 0 or 1 mmol, respectively) and PhH (2 mL or not added) were
placed into a glass tube equipped with a magnetic stirring bar and a hermetic screw cap. The
mixture was stirred at 150 °C for 2 h, then cooled to room temperature. The yields of t-BuOH,
acetone and the quantity of unreacted t-BuOOt-Bu were determined by GC analysis of the
reaction mixture using flame ionization detector and ethyl propionate as an internal standard.
Evaporating chamber temperature for GC analysis was 150 °C, column chamber temperature
was gradually increased from 40 °C to 300 °C at a rate of 10 °C/min.
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Supporting Information
Copies of 1H and 13C spectra for all products, photos of the reaction heating procedure (PDF)
Acknowledgments
This work was supported by the Russian Science Foundation to T.A. (Grant no. 18-13-00027)
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