Synthesis of Functionalized Isoindolinones via Calcium Catalyzed Generation and Trapping of N-Acyliminium Ions

Article abstract of DOI:10.1021/acs.joc.0c00482

Herein we report our full investigation into the calcium catalyzed generation and trapping of N-acyliminium ions from readily available 3-hydroxyisoindolinones. We have successfully employed a range of traditional nucleophiles including carbon, nitrogen, and sulfur containing reactive partners. The reaction is tolerant to a wide range of functionalities and provides high value scaffolds in good to excellent yields.

Full text of DOI:10.1021/acs.joc.0c00482

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Article
Synthesis of Functionalized Isoindolinones via Calcium
Catalyzed Generation and Trapping of N-Acyliminium Ions
Ashley Basson, and Mark Gerard McLaughlin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00482 • Publication Date (Web): 25 Mar 2020
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The Journal of Organic Chemistry
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Synthesis of Functionalized Isoindolinones via Calcium Catalyzed
Generation and Trapping of N-Acyliminium Ions
Ashley J. Basson and Mark G. McLaughlin*a
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Department of Natural Sciences, Manchester Metropolitan University, Chester Street, Manchester, United Kingdom,
M15GD.
m.mclaughlin@mmu.ac.uk
Ca(NTf2)2 (1-10 mol%)
R1
R1
Nuc
R2
OH
R2
nBu4NPF6 (1-10 mol%)
Nuc
N
H2O
N
1,2-DCE, 80 o
C
O
O
56 - 98%
48 examples
Nuc = C, S, N
ABSTRACT: Herein we report our full investigation into the calcium catalyzed generation and trapping of N-acyliminium ions from
readily available 3-hydroxyisoindolinones. We have successfully employed a range of traditional nucleophiles including carbon,
nitrogen and sulfur containing reactive partners. The reaction is tolerant to a wide range of functionalities and provides high value
scaffolds in good to excellent yields.
them using more functionally tolerant reagents remains high.
Success using stoichiometric Lewis acids such as BF3.OEt2,17
Sc(OTf)3,18 TiCl4,19 and AlCl320 have all recently been reported.
Furthermore, organic acids such as p-TsOH and TFA have also
been shown to generate N-acyliminium ions efficiently under
notably milder conditions.21 Although great successes have
been described employing stoichiometric reagents, there is a
clear need to develop catalytic processes by which these
important intermediates can be generated. This need is twofold;
firstly, catalytic generation inherently produces less waste, with
the byproducts using hydroxyl or akyloxy leaving groups being
water or innocuous alcohols. Secondly, from a reactivity point
of view, catalytic generation will result in a more controlled
reaction profile, with a much-reduced propensity for side
reactions. Unsurprisingly, there has been noted successes in this
endeavor (Scheme 1), with elegant examples using Brønsted
INTRODUCTION
N-acyliminium ions represent
a highly useful reactive
intermediate that has found use in a plethora of synthetic
methodologies and total synthesis alike.1-2 Over the course of
several decades, these reactive intermediates have been
employed to form new carbon-carbon and carbon-heteroatom
bonds with great success. In particular, N-acyliminium ions
have shown utility in the synthesis of fused ring systems
through intramolecular trapping of the generated reactive
intermediate.3-6 This strategy has been thoroughly explored over
the last two decades with noted examples such as in the total
syntheses of stemoamide,7 crispine A,8 and minfiensine (Fig
1).9
O
MeO
MeO
O
Activation of
Anodic
OH
H
N
H
N
Leaving Group
Oxidation
H
N
O
LG
O
O
H
N
H
H
-2e-. -H+
Lewis acid or
Brønsted acid
R
N
R2
R
O
N
R2
R
N
R2
O
Stemoamide
Crispine A
Minfiensine
"H+"
Figure 1. Synthesis of complex natural products employing N-
acyliminium ions
R
N
R2
Traditionally, N-acyliminium ions are generated via the
activation and release of a suitable leaving group under acidic
conditions. There is a wide range of these suitable leaving
groups including hydroxyl,10 alkyl- and aryloxy,11 acetoxy12-13
and carbamate,14-15 however sulfur containing and sulfoxide
based groups have also found use.16 As the synthetic utility of
these intermediates becomes more obvious, the need to generate
Protonation of
Enamide
acids,22-24 thiourea organocatalysts25-28 and Lewis acids.29-33
Scheme 1 .Strategies towards N-acyliminium Ions
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product was formed in high yield (83%). Reducing the catalyst
1
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5
6
7
8
loading to 1 mol% had little effect on the reaction, providing
the product in identical yield. Further optimization including
varying the solvent, temperature and concentration had a
deleterious effect on the yield of the reaction (Table 1). Finally,
lowering the catalyst loading to below 1 mol% resulted in a
noticeably more sluggish reaction, and we decided that in the
interest between balancing catalyst loading and reaction time, 1
mol% was optimum. Importantly, we also performed a series of
control experiments, most notable of which was using 2,6-
ditertbutylpyridine (entry 9), a known inhibitor of Brønsted
acid catalysis. The reaction proceeded unhindered, and proves
that the reaction is indeed calcium catalyzed.
Other methods including protonation of enamides34 and anodic
(Shono)oxidation35 have also been described with varying
success
Our group has a growing interest in developing methodology to
catalytically generate reactive intermediates,36 and in particular
using calcium complexes to mediate these processes.37-38
Calcium represents a relatively underexplored metal in
catalysis,39 however over the past decade there has been an
icrease in interest in exploring the reactivity of calcium, which
has resulted in a wealth of innovative uses for this abundant
element.40-60 We,37 and others,61 have recently reported the use
of Ca(NTf2)2 as an excellent catalyst to produce N-acyliminium
ions from readily available 3-hydroxyisoindolinones. Due to the
importance of these scaffolds in both total synthesis62-64 and
medicinal chemistry,65 we wanted to explore this reaction
further. In particular, we set out to probe the limits of the
reaction towards traditional carbon, amine and sulfur
nucleophiles. In particular, we wanted to focus our attention on
the synthesis of functionalized isoindolinones, due to their
importance in an ongoing medicinal chemistry campaign within
our group. Unsurprisingly, due to their range of interesting
biological activities,66-68 the synthesis of these scaffolds has
attracted much attention in the literature (Scheme 2). In
particular, the use of Brønsted and Lewis acids catalysts have
been shown to be well tolerated. Although these examples
provide the desired products in typically good yields, the use of
tertiary hydroxyisoindolinones remains underexplored. This
somewhat limits the use of the more complex catalytic systems,
as it results in less than optimum substrate availability. Thus we
wanted to explore these tertiary alcohols, and to probe the limits
of the reactions.
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NH
Ca(NTf2)2 (1 mol%)
Ph
OH
NH
Ph
Br
nBu4NPF6 (1 mol%)
NH
N
Solvent, 80 o
C
H
Br
O
1
2
3a
O
Entry
Calcium source
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
-
Additive
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
-
nBu4NPF6
nBu4NPF6
nBu4NPF6
Solvent
THF
MeCN
Toluene
CH2Cl2
1,2-DCE
1,2-DCE
DCE:DME
HFIP
Yielda
15%
66%
n.r.
79%
82%
39%
n.r.
1
2
3
4
5
6
7
8
9
Ca(NTf2)2
Ca(NTf2)2
decomp.
1,2-DCE
82%b
a Isolated Yield b 2,6-ditertbutylpyridine added
Table 1. Optimization study
With these conditions in hand we probed the substrate scope of
the reaction (Scheme 3). We observed excellent conversion to
the products in all cases, providing a wide variety of complex
scaffolds quickly. As shown, the reaction is tolerant to 5-bromo
and 5-pinacolboronate indoles, affording a range of highly
useful building blocks, including electron electron-withdrawing
(3b) and donating groups (3c, 3h) as well as further heterocyclic
substrates (3d, 3e, 3i).
Dunach (2010)
OH
Nuc
Sn(NTf2)4
Ar
N
Allyl
Ar
Ar
N
Allyl
Nuc
Nuc = C
O
NH
O
Ca(NTf2)2 (1 mol%)
R1
OH
NH
R1
R2
nBu4NPF6 (1 mol%)
Gredicak (2016)
NH
R1
OH
N
H
S-R2
NH
1,2-DCE, 80 oC, 15 mins
R1
R2
O
1
(R)-TRIP
Ni(ClO4)2 . H2O
Ca(NTf2)2
2
3
O
Ar
NH
R2-SH
CF3
MeO
O
O
NH
F3C
NH
NH
Zhao (2020)
Nuc
N
OH
NH
NH
NH
Br
R
Ar
N
O
R
Nuc
Nuc
O
Br
Br
O
O
Nuc = O, S, N, C
3a
, 82%
3b
, 91%
O
3c
, 93%
O
This work
S
NH
O
NH
R1
OH
R1
NH
Nuc
R2
Ar
Ar
NH
N
R2
N
NH
NH
Br
Nuc = C, S, N
Br
O
O
O
O
B(pin)
Scheme 2. Recent Successes in N-acyliminium chemistry
O
3d
, 96%
3e
, 94%
3f
, 90%
Cl
O
NH
NH
NH
MeO
HN
RESULTS AND DISCUSSION
NH
NH
O
We began our investigation employing indoles as nucleophiles.
We rationalized that due to its importance in medicinal
chemistry, paired with the availability of the motif, we could
provide high value scaffolds bearing pendant functional groups
in a controlled and high yielding manner. Furthermore, due to
the ubiquitous nature of functionalized indoles in natural
products, functionally tolerant catalytic methods to afford these
types of compounds are constantly required. Indeed, upon
O
B(pin)
B(pin)
B(pin)
O
3g
, 93%
3h
, 98%
3i
, 82%
CF3
F3C
NH
NH
B(pin)
O
3j
, 81%
treating 3-hydroxyisoindolinone with 10 mol% Ca(NTf2)2
-
Scheme 3. Indole Substituted Isoindolinones
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Page 3 of 15
The Journal of Organic Chemistry
As many catalytic processes are tolerant to carbon based As these examples all employed thiophenol as a nucleophile,
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7
8
functional groups, but show limited reactivity when
heterocyclic reaction partners are used, we wanted explore the
limits of the calcium system to these coupling partners. We
decided to therefore move onto sulfur containing fragments,
and in particular, aromatic and aliphatic thiols. N(acyl),S-
acetals are found in numerous pharmacologically relevant
natural products and APIs alike. The most well-known of these
being -lactam antibiotics69 and HIV-1 Reverse Transcriptase
inhibitors.67 Several methods have been developed for their
synthesis, including a range of Brønsted acid catalyzed
transformations,70 however they typically require long reaction
times and showed a limited scope towards certain functional
groups. We reasoned that the use of calcium to mediate these
reactions would have several advantages including much
shorter reaction times, a wider functional group tolerance and
overall easier reaction set up i.e. no requirement for anhydrous
or air free condition. Traditionally, it would be expected that
that the nucleophilic nature of these species would poison the
catalyst, or at the very least, drastically hinder the catalytic
turnover. However, to our delight, we found that the reaction
using thiophenol proceeded well, with the reaction complete in
under 15 minutes. Once again, we probed the substrate scope of
the reaction, and a range of substituted hydroxyisoindolinones
were subjected to our reaction conditions, resulting in a library
of 3,3-disubstituted lactams (Scheme 4). As shown, the reaction
was again tolerant of a range of functional groups with electron
donating (4a-b) and withdrawing groups (4c-e) providing the
desired products in high yields. Phenyl ring substituents was
also well tolerated, with ortho and meta substituents proceeding
smoothly (4f-g). Finally, heterocyclic substrates also worked
well, providing the lactam products in high yields (4h-j).
we wanted to explore the tolerance of other sulfur derivatives.
Once again, the reaction proceeded well, providing a wide range
of medicinally relevant scaffolds (Scheme 5). In addition to the
traditional electron donating (6a, 6d, 6e) and withdrawing (6b,
6c) groups, heteroaryl (6f, 6g), benzyl (6h) and alkyl (6i, 6j)
substituents all worked well. Furthermore, boronate esters (6k)
are also well tolerated, providing avenues for the modular
synthesis of bioactive small molecules.
R
1 OH
9
Ca(NTf2)2 (1 mol%)
R1
S
R3
nBu4NPF6 (1 mol%)
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R3
N
R2
N
R2
HS
1,2-DCE, 80 oC, 15 mins
O
5
O
1
6
Ph
S
Ph
Ph
S
S
Cl
NH
OMe
CF3
NH
NH
O
O
O
6a,
6b,
83%
78%
6c,
88%
S
MeO
N
Ph
Ph
S
Ph
S
N
NH
NH
NH
O
O
O
6f,
78%
6d,
6e,
98%
86%
O
Ph
S
Ph
Ph
S
S
NH
NH
NH
O
O
O
6i,
91%
6g,
6h,
92%
78%
Ph
Ph
S
S
O
B
NH
NH
O
O
O
Ca(NTf2)2 (1 mol%)
R
6j,
6k,
74%
R1
93%
S
1 OH
R2
Ph
R2
nBu4NPF6 (1 mol%)
N
N
Scheme 5. Scope of Sulfur Nucleophiles
HS
1,2-DCE, 80 oC, 15 mins
O
O
1
4
Cl
OMe
We next turned our attention to amine nucleophiles, as we
envisaged that they would be more problematic in the reaction,
mainly through direct Lewis acid-Lewis base interactions.
Additionally, in contrast to their sulfur counterparts, 3-
aminoisoindolinones are relatively underexplored in synthesis,
with very few reports focusing on the synthesis of carbamate
and sulfonamide derivatives. This is somewhat surprising,
given the fact that many isoindolinones have exhibited marked
activity against a range of bacterial infections71-72 as well as
interesting anticancer properties.68 Due to this, we initially
focused on delivering a robust method to produce these
potentially high value molecules from readily available starting
materials. We started our investigation employing our
optimized conditions and simple amine nucleophiles (Scheme
6). We observed a clear trend in reactivity, in which only
electron withdrawing anilines were tolerated, however we could
never manage to isolate the products in useful yields.
Additionally, the reaction was highly variable, and in our hands,
remained unreproducible. On the small amount of material we
did isolate, we observed a rapid degradation profile, with
complete degradation after 2 hours, regardless of storage
temperature. After some investigation, that the reaction
employing N-Bn substituted hydroxyisoindolinones were much
more user friendly, reproducibly providing the desired product
in good yield. As shown, the reaction proceeded well, with
substrates bearing contrasting electronics (8a-c) being
tolerated. Furthermore, unsaturated (8d) and benzyl amines (8e)
also worked well
Ph
Ph
Ph
S
S
S
NH
NH
NH
O
O
O
4b,
86%
4c,
86%
4a,
S
77%
CN
CF3
Ph
S
Ph
Ph
S
OMe
NH
NH
NH
O
O
O
4e,
96%
4f,
84%
4d,
79%
F3C
Ph
Ph
S
S
Ph
S
O
S
CF3
NH
NH
NH
O
O
O
4g,
4h,
S
4i,
98%
90%
86%
O
Ph
O
NH
O
4j,
91%
Scheme 4. Thiophenol substrate scope
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Page 4 of 15
therefore provides potentially new avenues of biological
1
2
3
4
5
6
7
8
activities to be uncovered. The reactivity pattern remained, with
only unsubstituted 11, providing reproducible reactivity and
good yields throughout. Probing the variability of the
sulfonamides produced a range of useful scaffolds using 5
mol% of the catalyst system. As shown above (Scheme9), the
reaction was once again tolerant to a range of synthetically
useful functional groups including electron donating (14a, 14b)
withdrawing (14c) halides (14d-f) thiophene (14g).
Furthermore, saturated groups (14h) also worked well,
providing access to 3-dimensional scaffolds.
H
OH
N
R2
N
Ca(NTf2)2 (10 mol%)
nBu4NPF6 (10 mol%)
N
R1
R2
H
7
N
R1
DCE, 80 °C, 12 hrs
O
8
O
1
MeO
F
Cl
HN
F
Me
HN
N
HN
CF3
Bn
N
Bn
N
Bn
9
O
O
O
10
11
12
13
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8a
8b
8c
, 81%
, 63%
, 68%
O
R2
Ca(NTf2)2 (5 mol%)
S
OH
N
HN
Bn
HN
O
S
O
HN
nBu4NPF6 (5 mol%)
H2N
R2
Bn
N
Bn
N
Bn
1,2-DCE, 80 oC, 12 hrs
O
13
N
Bn
14
11
O
O
O
O
Me
OMe
O
O
O
8d
8e
, 93%
, 67%
S
S
S
HN
HN
HN
O
O
O
OCF3
N
Bn
N
Bn
N
Bn
Scheme 6. 3-Amino substituted isoindolinones
O
O
O
14a,
14b,
14c,
85%
91%
68%
F
O
O
O
Once complete, we probed the applicability of using less
nucleophilic amine sources, such as the previously mentioned
amide and sulfonamide moieties. Once again employing our
optimized conditions, and using 1a as our model substrate, we
screened a range of carbamate nucleophiles. Unfortunately, all
of these proved unsuccessful, with the reactions plateauing at
25% conversion (Scheme 7).
S
S
S
HN
HN
HN
Cl
F
O
O
O
F
N
Bn
N
Bn
N Bn
O
O
O
14d,
14e,
14f,
60%
75%
75%
S
O
O
S
S
HN
HN
O
O
N
Bn
N
Bn
O
O
14g,
14h,
61%
77%
Ca(NTf2)2 (10 mol%)
O
H
N
O
Bn
nBu4NPF6 (10 mol%)
OH
NH
H2N
O
O
Scheme 9. Functionalized isoindolinones bearing
pendant sulfonamides
NH
CDCl3, 80 o
C
O
O
9a
1a
10,
25% conversion
Scheme 7. Reaction with Benzylcarbamate
As observed, the reaction is generally tolerant to a wide range
of functional groups and nucleophiles. However, during the
course of this work, we noted some limitations which we
believe the community will find useful when deciding to use
After extensive experimentation in which we screened a wide
range of conditions including solvent, temperature, time and
nucleophile, we were unsuccessful in delivering a reliable
reaction that produced these compounds in synthetically useful
yields. Although unsuccessful for compounds such as 1a, we
were successful in performing the reaction on 11 using a small
range of carbamate and amide nucleophiles, as shown (Scheme
8). This provides a range of differentially protected amines
(12a-12c), which has the potential to find use in target
synthesis.
this methodology. Firstly, when employing
amine
nucleophiles, the reactions were very sluggish with tertiary
alcohols such as 1a, with many reactions not going to
completion. This was consistent across all amine nucleophiles
used in this study. In a similar vein, we also observed that the
choice of amine was important, with secondary amines such as
piperidine and morpholine providing variable reactivity
patterns, with irreproducible results being obtained. Secondly,
carbon based nucleophiles (outside indole and allylsilane) were
unreactive towards the conditions described here. We are
currently working on this, and hope to report on it soon.
O
Ca(NTf2)2 (5 mol%)
OH
N
HN
O
R1
Bn
nBu4NPF6 (5 mol%)
H2N
Bn
11
N
R1
1,2-DCE, 80 oC, 15 mins
9
A proposed general mechanism is provided below (Fig. 2). The
postulated active catalyst, [CaPF6NTf2] A, is formed between
Ca(NTf2)2 and nBu4NPF6 which in turn produces N-
acyliminium ion B and complex C via loss of the non-
coordinating PF6 ligand. Following nucleophilic attack, the
aforementioned displaced PF6 re-enters the cycle, providing the
product, water byproduct and reforming the active catalyst.
12
O
O
Ph
O
Cbz
Boc
HN
HN
HN
N
O
O
N
Bn
N
Bn
N
Bn
N Bn
O
O
O
O
12a,
12b,
12c,
12d,
76%
90%
86%
95%
Scheme 8. Carbamate and amide substitution reactions
Due to the limited scope of these carbamates, we moved our
attention to the more useful sulfonamides. Once again these
have been seemingly ignored by the synthetic community, and
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The Journal of Organic Chemistry
denotes a broad resonance peak). Coupling constants recorded
Ca(NTf2)2 + nBu4nPF6
1
2
3
4
5
6
7
R1
NH
as Hz and round to the nearest 0.1 Hz. High Resolution Mass
Spectrometry (HRMS) was recorded using an Agilent
R1
OH
NH
H2O
+
-
PF6- Ca2+ NTf2
Technologies®
6540
Ultra-High-Definition
(UHD)
A
O
O
AccurateMass equipped with a time of flight (Q-TOF) analyzer
and the samples were ionized by ESI techniques and introduced
through a high pressure liquid chromatography (HPLC) model
Agilent Technologies® 1260 Infinity Quaternary LC system.
-
HO- Ca2+ NTf2
-
-
PF6
C
PF6
8
9
R
3-(5-bromo-1H-indol-3-yl)-3-phenyl-2,3-dihydro-1H-isoindol-
1-one (3a). To a 4 mL vial was added 3-hydroxy-3-
phenylisoindolin-1-one (50 mg, 0.22 mmol), Ca(NTf2)2 (1.3
mg, 0.0022 mmol) and nBu4NPF6 (1 mg, 0.0022 mmol) in DCE
(1 mL) at 80 ºC. The reaction was stirred for 1 minute and 5-
bromoindole (65 mg, 0.33 mmol) was added in a single portion
and stirred at 80 ºC for 15 minutes. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (3:1 EtOAc:Hex) to
afford a cream solid (73 mg, 82%). RF (3:1 EtOAc/Hex) = 0.37.
IR νmax (cm-1): 3209, 3058, 1978, 1671, 1491, 1314. HRMS
(ESI) m/z: [M+H]+ Calcd for C22H16BrN2O 403.0446; found
1Nuc-H
NH
R1
NH
10
11
12
13
14
15
16
17
D
B
O
O
Nuc-H
Figure 2. Proposed general catalytic cycle
18
19
20
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27
28
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50
51
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59
60
1
403.0441.. H NMR (400 MHz, DMSO-d6): δ 11.30 (s, 1H),
9.73 (s, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.64 – 7.57 (m, 2H), 7.53
(dq, J = 4.7, 4.1 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.40 – 7.25
(m, 4H), 7.16 (dd, J = 8.6, 1.6 Hz, 1H), 6.94 (dd, J = 15.7, 1.8
Hz, 2H). 13C {1H} (101 MHz, DMSO-d6): δ 168.6, 150.6, 142.5,
135.8, 132.1, 130.9, 128.5, 127.6, 126.9, 126.3, 125.9, 124.2,
123.9, 123.3, 122.1, 116.5, 113.8, 111.4, 65.9.
In conclusion, we have developed a robust and high yield
methodology to afford a range of substituted isoindolinones.
Using low loadings of catalyst, the reaction proceeded
smoothly, with reaction times ranging from 15 minutes to 12
hours. The reaction is tolerant towards a series of traditional
nucleophiles including carbon, nitrogen and sulfur containing
moieties. We envisage that this methodology will find use
within medicinal chemistry campaigns due to the range of
biological activities these scaffolds have shown.
Reaction also performed on a 2.2 mmol from 3-hydroxy-3-
phenylisoindolin-1-one (500 mg, 2.20 mmol), Ca(NTf2)2 (13
mg, 0.02 mmol) and nBu4NPF6 (9 mg, 0.02 mmol) with 5-
bromoindole (653 mg, 3.33 mmol) in DCE (10 mL) for 2.5 h.
Purification (3:1 EtOAc:Hex) afforded the product as a cream
solid (880 mg, 98%)
EXPERIMENTAL SECTION
Solvents and Reagents. All solvents were purchased from
commercial sources and used without purification (HPLC or
analytical grade). Anhydrous solvent was obtained from a The
Solv™ Solvent Purification System. Standard vacuum line
techniques were used and glassware was oven dried prior to use.
Organic solvents were dried during workup using anhydrous
Na2SO4. All calcium catalyzed reactions where done without
the need for anhydrous or air free conditions. All reaction were
performed using DrySyn™ heating mantles and pressure
regulated vials.
3-[3,5-bis(trifluoromethyl)phenyl]-3-(5-bromo-1H-indol-3-yl)-
2,3-dihydro-1H-isoindol-1-one (3b). To a 4 mL vial was added
3-hydroxy-3-(3,5-bis(trifluoromethyl))isoindolin-1-one
(50
mg, 0.14 mmol), Ca(NTf2)2 (4 mg, 0.0069 mmol) and
nBu4NPF6 (3 mg, 0.0069 mmol) in DCE (1 mL) at 80 ºC. The
reaction was stirred for 1 minute and 5-bromoindole (41 mg,
0.21 mmol) was added in a single portion and stirred at 80 ºC
for 30 minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAC:Hex) to afford a cream
solid (68 mg, 91%). RF (1:1 EtOAc/Hex) = 0.33 . IR νmax (cm-
1): 3333, 3185, 3052, 1978, 1669, 1368. HRMS (ESI) m/z:
[M+H]+ Calcd for C24H14BrF6N2O 539.0194; found 539.0188.
1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 9.91 (s, 1H),
8.16 (s,1H), 8.11 (s, 2H), 7.79 (dd, J = 15.3, 7.5 Hz, 2H), 7.67
(t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 8.6 Hz,
1H), 7.19 (dd, J = 8.7, 1.3 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H),
6.83 (s, 1H). 13C{1H} NMR (101 MHz, DMSO-d6):δ 168.4,
149.0, 145.9, 135.8, 132.8, 130.8, 130.5(q, JF = 32.3 Hz),
129.3, 127.0, 126.9, 126.3, 124.6, 124.3, 124.2, 123.6,
122.1, 121.8, 121.4, 115.1, 114.1, 111.7, 65.5.
Purification
and
chromatography.
Thin
Layer
Chromatography (TLC) was carried out using aluminum plates
coated with 60 F254 silica gel. Plates were visualized using UV
light (254 or 365 nm) or staining with 1% aq. KMnO4, vanillin
or ninhydrin. Normal-phase silica gel chromatography was
carried out using either a Biotage Isolera One flash column
chromatography system (LPLC) or traditional flash column
chromatography using Geduran® Silica gel 60, 40–63 microns
RE.
Characterization. Infrared spectroscopy was carried out with
a
Nicolet® 380 FT/IR – Fourier Transform Infrared
Spectrometer. Only the most significant frequencies have been
considered during the characterization and selected absorption
maxima (max) recorded in wavenumbers (cm-1). NMR spectra
were recorded using a JEOL® ECS-400 MHz spectrometer
using the deuterated solvent stated. Chemical shifts (δ) quoted
in parts per million (ppm) and referenced to the residual solvent
peak. Multiplicities are denoted as s- singlet, d- doublet, t-
triplet, q- quartet and quin- quintet and derivatives thereof (br
3-(5-bromo-1H-indol-3-yl)-3-(4-methoxyphenyl)-2,3-dihydro-
1H-isoindol-1-one (3c). To a 4 mL vial was added 3-(4-
methoxyphenyl)-3-hydroxyisoindolin-1-one (50 mg, 0.20
mmol mmol), Ca(NTf2)2 (1.1 mg, 0.002 mmol) and nBu4NPF6
(0.8 mg, 0.002 mmol) in DCE (1 mL) at 80 ºC. The reaction
was stirred for 1 minute and 5-bromoindole (58 mg, 0.29 mmol)
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The Journal of Organic Chemistry
Page 6 of 15
was added in a single portion and stirred at 80 ºC for 30 minutes. mmol) was added in a single portion and stirred at 80 ºC for 1h.
1
2
3
4
5
6
7
8
Once TLC analysis indicated conversion to the product, the
product was concentrated and purified by flash column
chromatography (1:1, EtOAc:Hex) to afford a cream solid (79
mg, 93%). RF (1:1 EtOAc/DCM) = 0.41. IR νmax (cm-1): 3169,
3040, 2838, 1668, 1608, 1255. HRMS (ESI) m/z: [M+H]+
Calcd for C23H18BrN2O2 433.0552; ; found 433.0549.. 1H NMR
(400 MHz, DMSO-d6): δ 11.28 (s, 1H), 9.67 (s, 1H), 7.73 (d, J
= 7.3 Hz, 1H), 7.65 – 7.46 (m, 3H), 7.34 (t, J = 8.6 Hz, 3H),
7.16 (d, J = 8.5 Hz, 1H), 7.01 (s, 1H), 6.99 – 6.79 (m, 3H), 3.72
(s, 3H). 13C{1H}NMR (101 MHz, DMSO-d6): δ 168.5, 158.6,
150.9, 135.8, 134.4, 132.0, 130.9, 128.4, 127.6, 126.9, 125.9,
124.1, 123.9, 123.2, 122.2, 116.7, 113.8, 113.7, 111.4, 65.50,
55.11.
Once TLC analysis indicated conversion to the product, the
product was concentrated and purified by flash column
chromatography (2:1, EtOAc:Hex) to afford a white solid (90
mg, 90%). RF (3:1 EtOAc/Hex) = 0.48. IR νmax (cm-1): 3257,
2976, 1683, 1613, 1352, 1142. HRMS (ESI) m/z: [M+H]+
1
Calcd for C28H28BN2O3 451.2193; found 451.2204. H NMR
(400 MHz, DMSO-d6): δ 11.20 (s, 1H), 9.73 (s, 1H), 7.74 (d, J
= 7.3 Hz, 1H), 7.65 – 7.44 (m, 4H), 7.44 – 7.22 (m, 7H), 6.88
(d, J = 2.2 Hz, 1H), 1.22 (s, 12H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 168.6, 151.1, 142.9, 139.2, 131.9, 131.0, 128.4,
128.3, 127.7, 127.5, 127.5, 126.5, 124.8, 124.3, 124.2, 123.2,
117.2, 111.2, 83.0, 66.2, 24.8, 24.6.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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48
49
50
51
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53
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56
57
58
59
60
3-(4-chlorophenyl)-3-[5-(4,4,5,5-tetramethyl-1,3,2-
3-(5-bromo-1H-indol-3-yl)-3-(thiophen-2-yl)-2,3-dihydro-1H-
isoindol-1-one (3d). To a 4 mL vial was added 3-hydroxy-3-
(thiophen-2-yl)isoindolin-1-one (50 mg, 0.22 mmol),
Ca(NTf2)2 (1.3 mg, 0.0022 mmol) and nBu4NPF6 (0.9 mg,
0.0022 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and 5-bromoindole (64 mg, 0.32 mmol) was added
in a single portion and stirred at 80 ºC for 30 minutes. Once
TLC analysis indicated conversion to the product, the product
was concentrated and purified by flash column chromatography
(1:1 EtOAc:DCM) to afford a light brown solid (85 mg, 96%).
RF (1:1 EtOAc/DCM) = 0.38. IR νmax (cm-1): 3172, 3041, 2851,
1667, 1466, 1356. HRMS (ESI) m/z: [M+H]+ Calcd for
C20H14BrN2OS 409.0010 ; found 409.0007. Cald. 1H NMR (400
MHz, DMSO-d6): δ 11.36 (m, 1H), 9.85 (s, 1H), 7.76 (d, J = 7.4
Hz, 1H), 7.68 – 7.51 (m, 3H), 7.45 (d, J = 5.0 Hz, 1H), 7.35 (d,
J = 8.6 Hz, 1H), 7.17 (dd, J = 8.6, 1.6 Hz, 1H), 7.08 (m, 2H),
7.05 – 6.92 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
168.3, 150.6, 147.3, 135.7, 132.3, 130.5, 128.8, 127.2, 126.7,
126.0, 125.7, 125.5, 124.0, 123.9, 123.2, 121.9, 115.4, 113.9,
111.6, 63.53.
dioxaborolan-2-yl)-3a,7a-dihydro-1H-indol-2-yl]-2,3-dihydro-
1H-isoindol-1-one (3g). To a 4 mL vial was added 3-(4-
chlorophenyl)-3-hydroxyisoindolin-1-one (50 mg, 0.19 mmol),
Ca(NTf2)2 (1mg, 0.0019 mmol) and nBu4NPF6 (0.8 mg, 0.0019
mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred for 1
minute and 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-indole (70 mg, 0.29 mmol) was added in a single portion
and stirred at 80 ºC for 30 mins. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (1:1, EtOAc:Hex) to
afford a white solid (87 mg, 93%). RF (1:1 EtOAc/Hex) = 0.19.
IR νmax (cm-1): 3237, 2977, 1673, 1613, 1469, 1352. HRMS
(ESI) m/z: [M+H]+ Calcd for C28H27BClN2O3 485.1803; found
485.1815. . 1H NMR (400 MHz, DMSO-d6): δ 11.24 (d, J = 1.9
Hz, 1H), 9.77 (s, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.64 – 7.49 (m,
3H), 7.46 – 7.29 (m, 7H), 6.89 (d, J = 2.1 Hz, 1H), 1.23 (s, 12H).
13C{1H}NMR (101 MHz, DMSO-d6): δ 168.6, 150.7, 142.0,
139.2, 132.2, 132.2, 131.0, 128.5, 128.4, 127.6, 127.6, 124.9,
124.7, 124.1, 123.3, 116.7, 111.3, 83.03, 65.8, 24.8, 24.7.
3-(2-methoxyphenyl)-3-[5-(4,4,5,5-tetramethyl-1,3,2-
3-(2H-1,3-benzodioxol-5-yl)-3-(5-bromo-3a,7a-dihydro-1H-
indol-2-yl)-2,3-dihydro-1H-isoindol-1-one (3e). To a 4 mL vial
was added 3-(benzo[d][1,3]dioxol-5-yl)isoindolin-1-one (50
mg, 0.19 mmol), Ca(NTf2)2 (1.1 mg, 0.0019 mmol) and
nBu4NPF6 (0.7 mg, 0.0019 mmol) in DCE (1 mL) at 80 ºC. The
reaction was stirred for 1 minute and 5-bromoindole (64 mg,
0.32 mmol) was added in a single portion and stirred at 80 ºC
for 30 minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (2:1, EtOAc:Hex) to afford a cream
solid (78 mg, 94%). RF (2:1 EtOAc/Hex) = 0.17. IR νmax (cm-
1): 3219, 2896, 1674, 1611, 1485, 1237. HRMS (ESI) m/z:
[M+H]+ Calcd for C23H16BrN2O3 447.0344 ; found 447.0350.
1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.89 (d, J = 7.4 Hz,
1H), 7.63 – 7.40 (m, 3H), 7.31 – 7.21 (m, 2H), 7.16 (s, 1H), 6.96
– 6.85 (m, 3H), 6.82 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 8.2 Hz,
1H), 5.95 (dd, J = 6.6, 1.1 Hz, 2H). 13C{1H} NMR (101 MHz,
CDCl3): δ 169.9, 150.9, 148.3, 147.7, 135.9, 135.3, 132.6,
128.8, 127.3, 125.9, 124.6, 124.3, 123.7, 122.7, 119.9, 117.7,
113.7, 113.3, 108.5, 107.2, 101.5, 66.5.
dioxaborolan-2-yl)-3a,7a-dihydro-1H-indol-2-yl]-2,3-dihydro-
1H-isoindol-1-one (3h). To a 4 mL vial was added 3-hydroxy-
3-(2-methoxyphenyl)isoindolin-1-one (50 mg, 0.20 mmol),
Ca(NTf2)2 (1.2 mg, 0.0020 mmol) and nBu4NPF6 (0.8 mg,
0.0020 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-indole (71 mg, 0.29 mmol) was added in a single portion
and stirred at 80 ºC for 30 mins. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (2:1, EtOAc:Hex) to
afford an off white solid (92 mg, 98%). RF (2:1 EtOAc/Hex) =
0.17. IR νmax (cm-1): 3414, 3264, 3008, 1680, 1612, 1351.
HRMS (ESI) m/z: [M+H]+ Calcd for C29H30BN2O4 481.2299;
found 481.2314. 1H NMR (400 MHz, DMSO-d6): δ 11.06 (d, J
= 1.9 Hz, 1H), 9.16 (s, 1H), 7.79 – 7.69 (m, 1H), 7.58 – 7.46
(m, 4H), 7.40 – 7.28 (m, 3H), 7.21 (dd, J = 7.7, 1.5 Hz, 1H),
7.04 (d, J = 7.7 Hz, 1H), 6.93 – 6.85 (m, 1H), 6.82 (d, J = 2.4
Hz, 1H), 3.51 (s, 3H), 1.23 (s, 12H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 168.6, 157.9, 150.7, 139.0, 131.6, 131.4, 129.7,
129.5, 128.1, 127.7, 127.4, 127.2, 124.7, 124.6, 123.5, 123.1,
119.9, 117.1, 112.6, 111.1, 83.0, 79.2, 65.4, 55.4, 24.1, 24.7.
3-phenyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
3a,7a-dihydro-1H-indol-2-yl]-2,3-dihydro-1H-isoindol-1-one
(3f). To a 4 mL vial was added 3-hydroxy-3-phenylisoindolin-
1-one (50 mg, 0.22 mmol), Ca(NTf2)2 (1.3 mg, 0.0022 mmol)
and nBu4NPF6 (0.9 mg, 0.0022 mmol) in DCE (1 mL) at 80 ºC.
The reaction was stirred for 1 minute and 5-(4,4,5,5-
Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (81 mg, 0.33
3-(furan-2-yl)-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-3a,7a-dihydro-1H-indol-2-yl]-2,3-dihydro-1H-isoindol-1-
one (3i). To a 4 mL vial was added 3-hydroxy-3-(furan-2-
yl)isoindolin-1-one (50 mg, 0.23 mmol), Ca(NTf2)2 (1.4 mg,
0.0023 mmol) and nBu4NPF6 (0.9 mg, 0.0023 mmol) in DCE
(1 mL) at 80 ºC. The reaction was stirred for 1 minute and 5-
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The Journal of Organic Chemistry
(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
(85 mg, 0.35 mmol) was added in a single portion and stirred at
1
2
3
4
5
6
7
8
9
80 ºC for 30 mins. Once TLC analysis indicated conversion to
the product, the product was concentrated and purified by flash
column chromatography (1:1 EtOAc:Hex) to afford a pale
orange solid (84 mg, 82%). RF (2:1 EtOAc/Hex) = 0.35. IR νmax
(cm-1): 3295, 3059, 2869, 1679, 1614, 1377. HRMS (ESI) m/z:
[M+H]+ Calcd for C26H26BN2O4 441.1989; found 441.1993.. 1H
NMR (400 MHz, DMSO-d6): δ 11.25 (d, J = 2.1 Hz, 1H), 9.70
(s, 1H), 7.80 – 7.73 (m, 1H), 7.70 – 7.65 (m, 1H), 7.63 – 7.50
(m, 3H), 7.41 – 7.30 (m, 3H), 6.97 (d, J = 2.5 Hz, 1H), 6.45 (dd,
J = 3.2, 1.8 Hz, 1H), 6.30 (dd, J = 3.2, 0.6 Hz, 1H), 1.25 (s,
12H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 169.0, 155.3,
149.5, 143.7, 139.4, 132.6, 131.6, 129.2, 127.9, 127.5, 125.0,
124.4, 123.6, 115.5, 111.8, 110.9, 107.5, 83.5, 62.6, 25.3, 25.2.
3-(4-methoxyphenyl)-3-(phenylthio)isoindolin-1-one (4b). To a
mL vial was added 3-(4-methoxyphenyl)-3-
4
hydroxyisoindolin-1-one (60 mg, 0.24 mmol), Ca(NTf2)2 (1.5
mg, 0.0024 mmol) and nBu4NPF6 (1 mg, 0.0024 mmol) in DCE
(1 mL) at 80 ºC. The reaction was stirred for 5 minutes and
thiophenol (39 mg, 0.353 mmol) was added in a single portion
and stirred at 80 ºC for 15 minutes. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (1:1 EtOAc:Hex) to
afford a white solid (70 mg, 86%). RF (1:1 EtOAc/CycHex) =
0.53. IR νmax (cm-1): 3057, 2930, 2849, 1700, 1606, 1509.
HRMS (ESI) m/z: [M+H]+ Calcd for C21H18NO2S 348.1058;
found 348.1053. 1H NMR (400 MHz, CDCl3): δ 7.74 – 7.64 (m,
3H), 7.61 – 7.51 (m, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.35 – 7.28
(m, 1H), 7.24 – 7.18 (m, 1H), 7.17 – 7.11 (m, 3H), 7.11 – 7.01
(m, 2H), 6.97 – 6.88 (m, 2H), 3.81 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): 169.1, 160.0, 148.9, 137.1, 132.5, 131.1, 131.04,
129.9, 129.8, 129.6, 128.6, 127.5, 123.8, 123.4, 114.4, 75.5,
55.5..
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-[3,5-bis(trifluoromethyl)phenyl]-3-[5-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-3a,7a-dihydro-1H-indol-2-yl]-2,3-
dihydro-1H-isoindol-1-one (3j). To a 4 mL vial was added 3-
hydroxy-3-(3,5-bis(trifluoromethyl))isoindolin-1-one (50 mg,
0.14 mmol), Ca(NTf2)2 (0.8 mg, 0.0014 mmol) and nBu4NPF6
(0.5 mg, 0.0014 mmol) in DCE (1 mL) at 80 ºC. The reaction
was stirred for 1 minute and 5-(4,4,5,5-Tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-indole (51 mg, 0.21 mmol) was added
in a single portion and stirred at 80 ºC for 30 mins. Once TLC
analysis indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(1:1, EtOAc:Hex) to afford an off white solid (66 mg, 81%). RF
(1:1 EtOAc/Hex) = 0.30. IR νmax (cm-1): 3273, 2980, 1695,
1355, 1275, 1131. HRMS (ESI) m/z: [M+H]+ Calcd for
C30H26BF6N2O3 587.1941; found 587.1947.. 1H NMR (400
MHz, CDCl3): δ 8.56 (s, 1H), 7.99 – 7.88 (m, 3H), 7.81 (s, 1H),
7.69 – 7.57 (m, 2H), 7.57 – 7.48 (m, 1H), 7.43 (d, J = 7.6 Hz,
1H), 7.41 – 7.29 (m, 2H), 7.18 (s, 1H), 1.28 (s, 12H). 13C{1H}
NMR (101 MHz, CDCl3): δ 170.2, 149.6, 145.3, 139.4, 133.2
(q, JF = 33.4 Hz), 132.0, 130.1, 129.3, 129.3, 126.8, 126.8,
125.0, 124.7, 124.6, 123.8, 123.6, 122.2, 121.9, 116.3, 111.6,
83.75, 66.24, 24.9, 24.8.
3-(4-chlorophenyl)-3-(phenylthio)isoindolin-1-one (4c). To a 4
mL vial was added 3-(4-chlorophenyl)-3-hydroxyisoindolin-1-
one (100 mg, 0.39 mmol), Ca(NTf2)2 (2 mg, 0.0039 mmol) and
nBu4NPF6 (1.5 mg, 0.0039 mmol) in DCE (2 mL) at 80 ºC. The
reaction was stirred for 5 minutes and thiophenol (64 mg, 0.578
mmol) was added in a single portion and stirred at 80 ºC for 15
minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAC:Hex) to afford a white
solid (116 mg, 86%). RF (1:1 EtOAc/CycHex) = 0.6. IR νmax
(cm-1): 3130, 3062, 2851, 1702, 1470, 1096. HRMS (ESI) m/z:
[M+H]+ Calcd for C20H15ClNOS 352.0563; found 352.0559. 1H
NMR (400 MHz, DMSO-d6): 9.84 (s, 1H), 7.98 – 7.72 (m, 3H),
7.72 – 7.59 (m, 1H),7.58-7.56 (m, 2H), 7.45 – 7.20 (m, 3H),
7.20 – 6.90 (m, 4H). 13C{1H} NMR (101 MHz, DMSO-d6):
δ167.7, 147.5, 138.5, 136.71, 133.4, 132.4, 130.3, 129.7, 129.1,
128.9, 128.8, 128.4, 128.0, 124.0, 122.4, 74.9.
3-phenyl-3-phenylsulfanyl-2,3-dihydro-isoindol-1-one (4a). To
a 4 mL vial was added 3-hydroxy-3-phenylisoindolin-1-one (50
mg, 0.22 mmol), Ca(NTf2)2 (3 mg, 0.0022 mmol) and
nBu4NPF6 (1.7 mg, 0.0022 mmol) in DCE (1 mL) at 80 ºC. The
reaction was stirred for 5 minutes and thiophenol (29 mg, 0.27
mmol) was added in a single portion and stirred at 80 ºC for 15
minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAc:Hex) to afford a white
solid (54 mg, 77%). RF (1:1 EtOAc/Hex) = 0.43. IR νmax (cm-
1): 3062, 2848, 1696, 1494, 1345, 742. HRMS (ESI) m/z:
4-(1-Hydroxy-3-oxoisoindolin-1-yl)benzonitrile (4d). To a 4
mL vial was added 4-(1-hydroxy-3-oxoisoindolin-1-
yl)benzonitrile (50 mg, 0.20 mmol), Ca(NTf2)2 (1.2 mg, 0.002
mmol) and nBu4NPF6 (0.8 mg, 0.002 mmol) in DCE (1 mL) at
80 ºC. The reaction was stirred for 5 minutes and thiophenol (33
mg, 0.3 mmol) was added in a single portion and stirred at 80
ºC for 15 minutes. Once TLC analysis indicated conversion to
the product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAc:Hex) to afford a cream
solid (54 mg, 79%). RF (1:1 EtOAc/CycHex) = 0.50. IR νmax
(cm-1): 3215, 3075, 2229, 1714, 1679, 1497. HRMS (ESI) m/z:
[M+H]+ Calcd for C21H15N2OS 343.0905; found 343.0907. 1H
NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.5 Hz, 2H), 7.71 (d, J
= 8.5 Hz, 2H), 7.68 – 7.57 (m, 2H), 7.54 – 7.46 (m, 2H), 7.38
(t, J = 7.3 Hz, 1H), 7.25 – 7.21 (m, 1H), 7.14 (d, J = 6.9 Hz,
2H), 7.11 – 7.04 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
169.3, 147.7, 144.5, 137.1, 133.0, 132.9, 130.2, 129.3, 128.9,
128.7, 127.2, 123.8, 123.7, 118.4, 112.9, 75.1.
1
[M+H]+ Calcd for C20H16NOS 318.0953; found 318.0947. H
NMR (400 MHz, CDCl3): δ 7.84 – 7.75 (m, 2H), 7.73 – 7.67
(m, 1H), 7.56 (td, J = 7.5, 1.1 Hz, 1H), 7.51 – 7.29 (m, 6H), 7.24
– 7.18 (m, 1H), 7.14 (dt, J = 8.2, 1.7 Hz, 1H), 7.08 – 7.02 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3): δ 169.2, 148.7, 139.1,
137.1, 132.6, 129.9, 129.8, 129.4, 129.2, 129.0, 128.7, 128.6,
126.1, 123.9, 123.4, 75.79.
Reaction also performed on a 2.0 mmol from 3-hydroxy-3-
phenylisoindolin-1-one (450 mg, 2.0 mmol), Ca(NTf2)2 (12 mg,
0.02 mmol) and nBu4NPF6 (8 mg, 0.02 mmol) with thiophenol
(265 mg, 2.40 mmol) in DCE (9 mL) for 30 min. Purification
(1:1 EtOAc:Hex) afforded the product as a white solid (608 mg,
96%)
3-(4-trifluoromethylphenyl)-3-(phenylthio)isoindolin-1-one
(4e). To
a
4
mL vial was added 3-hydroxy-3-(4-
(trifluoromethyl)phenyl)isoindolin-1-one (60 mg, 0.21 mmol),
Ca(NTf2)2 (1.2 mg, 0.0021 mmol) and nBu4NPF6 (0.8 mg,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
0.0021 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred product, the product was concentrated and purified by flash
1
2
3
4
5
6
7
8
for 5 minutes and thiophenol (34 mg, 0.307 mmol) was added
in a single portion and stirred at 80 ºC for 15 minutes. Once
TLC analysis indicated conversion to the product, the product
was concentrated and purified by flash column chromatography
(1:1, EtOAc:Hex) to afford a white solid (76 mg, 96%). RF (1:1
EtOAc/CycHex) = 0.60. IR νmax (cm-1): 3126, 3071, 1699, 1496,
1392. HRMS (ESI) m/z: [M+H]+ Calcd for C21H15F3NOS
386.0826; found 386.0823.. 1H NMR (400 MHz, CDCl3): δ 7.93
(d, J = 8.3 Hz, 1H), 7.73 – 7.62 (m, 2H), 7.59 (t, J = 7.0 Hz,
1H), 7.50 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.24 -
7.23 (m, 3.6 Hz, 1H), 7.15 – 7.07 (m, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 169.1, 148.1, 143.3, 137.1, 132.9, 130.1, 129.7,
129.2, 128.9, 128.8, 126.7, 126.2, 126.2, 123.7, 75.2.
column chromatography (1:1, EtOAc:Hex) to afford a light
brown solid (120 mg, 86%). RF (1:1 EtOAc/CycHex) = 0.60.
IR νmax (cm-1): 3155, 3060, 2836, 1691, 1470, 1354. HRMS
(ESI) m/z: [M+H]+ Calcd for C18H14NOS2 324.0517; found
324.0516. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.8 Hz,
1H), 7.59 (td, J = 7.5, 0.9 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H),
7.39 – 7.29 (m, 3H), 7.24 – 7.23 (m, 1H), 7.18 – 7.16 (m, 2H),
7.13 – 7.05 (m, 2H), 7.01 (dd, J = 5.0, 3.7 Hz, 1H), 6.92 – 6.91
(m, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 168.8, 148.2,
143.0, 136.9, 132.7, 130.0, 129.5, 129.5, 129.1, 128.7, 127.6,
126.4, 125.7, 123.8, 123.4, 72.8.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(furan-2-yl)-3-(phenylthio)isoindolin-1-one (4i). To a 4 mL
vial was added 3-hydroxy-3-(furan-2-yl)isoindolin-1-one (50
mg, 0.23 mmol), Ca(NTf2)2 (1.4 mg, 0.0023 mmol) and
nBu4NPF6 (1 mg, 0.0023 mmol) in DCE (1 mL) at 80 ºC. The
reaction was stirred for 5 minutes and thiophenol (38 mg, 0.35
mmol) was added in a single portion and stirred at 80 ºC for 15
minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAc:Hex) to afford a light
brown solid (70 mg, 98%). RF (1:1 EtOAc/CycHex) = 0.6. IR
3-(2-methoxyphenyl)-3-(phenylthio)isoindolin-1-one (4f). To a
4
mL
vial
was
added
3-(2-methoxyphenyl)-3-
hydroxyisoindolin-1-one (100 mg, 0.39 mmol), Ca(NTf2)2 (2.4
mg, 0.0039 mmol) and nBu4NPF6 (1.5 mg, 0.0039 mmol) in
DCE (2 mL) at 80 ºC. The reaction was stirred for 5 minutes
and thiophenol (65 mg, 0.353 mmol) was added in a single
portion and stirred at 80 ºC for 15 minutes. Once TLC analysis
indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(1:1, EtOAc:Hex) to afford a white solid (115 mg, 84%). RF
(1:1 EtOAc/CycHex) = 0.40. IR νmax (cm-1): 3283, 3051, 2932,
1692, 1489, 1249. HRMS (ESI) m/z: [M+H]+ Calcd for
ν
max (cm-1): 3153, 3060, 1689, 1500, 1307, 1154. HRMS (ESI)
m/z: [M+H]+ Calcd for C18H14NO2S 308.0745; found 308.0748.
1H NMR (400 MHz, CDCl3): δ 7.86 (t, J = 10.3 Hz, 1H), 7.65
– 7.57 (m, 2H), 7.51 (d, J = 0.9 Hz, 1H), 7.42 (t, J = 7.6 Hz,
1H), 7.31 – 7.20 (m, 2H), 7.18 – 7.10 (m, 4H), 6.94 (s, 1H), 6.37
– 6.28 (m, 2H). 13C{1H} NMR (101 MHz, DMSOd-6): δ 167.6,
150.7, 145.8, 144.0, 136.7, 132.4, 130.4, 129.7, 129.2, 128.6,
128.5, 124.1, 122.4, 110.9, 108.2, 70.6.
1
C21H18NO2S 348.1058; found 348.1050. H NMR (400 MHz,
CDCl3): δ 7.95 – 7.80 (m, 2H), 7.64 (td, J = 7.6, 1.1 Hz, 1H),
7.59 – 7.47 (m, 2H), 7.44 – 7.32 (m, 2H), 7.21 – 7.14 (m, 1H),
7.14 – 7.09 (m, 2H), 7.08 – 7.01 (m, 3H), 6.92 (td, J = 7.7, 1.1
Hz, 1H), 4.02 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
168.0, 157.8, 146.4, 136.8, 131.5, 131.4, 130.5, 129.4, 128.7,
128.4, 127.4, 126.5, 125.6, 123.5, 120.8, 112.8, 74.5, 56.2.
3-(benzo[d][1,3]dioxol-5-yl)-3-(phenylthio)isoindolin-1-one
(4j). To a 4 mL vial was added 3-(benzo[d][1,3]dioxol-5-
yl)isoindolin-1-one (80 mg, 0.30 mmol), Ca(NTf2)2 (1.8 mg,
0.003 mmol) and nBu4NPF6 (1.2 mg, 0.003 mmol) in DCE (1
mL) at 80 ºC. The reaction was stirred for 5 minutes and
thiophenol (33 mg, 0.3 mmol) was added in a single portion and
stirred at 80 ºC for 15 minutes. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (1:1, EtOAc:Hex) to
afford a peach solid (98 mg, 91%). RF (1:1 EtOAc/CycHex) =
0.56. IR νmax (cm-1): 3209, 2902, 1706, 1671, 1485, 1246.
HRMS (ESI) m/z: [M+H]+ Calcd for C21H16NO3S 362.0851;
3-(3,5-bis(trifluoromethyl))-3-(phenylthio)isoindolin-1-one
(4g). To
a 4 mL vial was added 3-hydroxy-3-(3,5-
bis(trifluoromethyl))isoindolin-1-one (100 mg, 0.28 mmol),
Ca(NTf2)2 (1.7 mg, 0.0028 mmol) and nBu4NPF6 (1 mg, 0.0028
mmol) in DCE (2 mL) at 80 ºC. The reaction was stirred for 5
minutes and thiophenol (46 mg, 0.42 mmol) was added in a
single portion and stirred at 80 ºC for 15 minutes. Once TLC
analysis indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(2:3, EtOAc:Hex) to afford a white solid (113 mg, 90%). RF
(2:3 EtOAc/CycHex) = 0.56. IR νmax (cm-1): 3208, 3094, 1715,
1469, 1312, 1280. HRMS (ESI) m/z: [M+H]+ Calcd for
C22H14F6NOS 454.0700; found 454.0699. 1H NMR (400 MHz,
CDCl3): δ 8.26 (s, 2H), 7.89 (s, 1H), 7.64 – 7.62 (m, 2H), 7.53
(d, J = 7.7 Hz, 1H), 7.47 – 7.36 (m, 1H), 7.28 – 7.24 (m, 2H),
7.20 – 7.05 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3): δ 167.6,
146.1, 142.6, 136.7, , 131.6 (d, J = 238 Hz), 131.1, 130.8, ,
130.1, 129.4, 128.6, 128.6, 126.8, , 124.2, 123.1 (d, J = 275 Hz),
123.0, 122.8, , 74.5.
1
found 362.0852. H NMR (400 MHz, CDCl3): δ 9.74 (s, 1H),
7.88 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.38 – 7.30
(m, 2H), 7.29 – 7.18 (m, 4H), 7.10 (d, J = 4.3 Hz, 5H), 6.96 (d,
J = 8.2 Hz, 1H), 6.06 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3):δ 167.6, 147.7, 147.4, 136.6, 133.2, 132.1, 130.4, 129.7,
129.5, 128.6, 128.3, 124.2, 122.3, 119.3, 108.2, 106.8, 101.6,
75.30.
3-((4-methoxyphenyl)thio)-3-phenylisoindolin-1-one (6a). To a
4 mL vial was added 3-hydroxy-3-phenylisoindolin-1-one (100
mg, 0.44 mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and
nBu4NPF6 (1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC. The
reaction was stirred for 5 minutes and 4-methoxythiophenol (75
mg, 0.533 mmol) was added in a single portion and stirred at 80
ºC for 15 minutes. Once TLC analysis indicated conversion to
the product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAc:Hex) to afford a cream
solid (121 mg, 78%). RF (1:1 EtOAc/Hex) = 0.26. IR νmax (cm-
3-(thiophen-2-yl)-3-(phenylthio)isoindolin-1-one (4h). To a 4
mL vial was added 3-hydroxy-3-(thiophen-2-yl)isoindolin-1-
one (100 mg, 0.43 mM), Ca(NTf2)2 (2.4 mg, 0.0043 mmol) and
nBu4NPF6 (1.5 mg, 0.0043 mmol) in DCE (2 mL) at 80 ºC. The
reaction was stirred for 5 minutes and thiophenol (72 mg, 0.65
mmol) was added in a single portion and stirred at 80 ºC for 15
minutes. Once TLC analysis indicated conversion to the
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Page 9 of 15
The Journal of Organic Chemistry
1): 3198, 3078, 2840, 1698, 1589, 1243. HRMS (ESI) m/z:
J = 7.4 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.42 – 7.27 (m, 2H),
[M+H]+ Calcd for C21H18NO2S 348.1058; found 348.1059. 1H
NMR (400 MHz, DMSO-d6): δ 9.73 (s, 1H), 7.86 (d, J = 7.8 Hz,
1H), 7.78 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.46 (t,
J = 7.5 Hz, 2H), 7.41 – 7.23 (m, 3H), 7.02 (d, J = 8.7 Hz, 2H),
6.67 (d, J = 8.7 Hz, 2H), 3.66 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 167.8, 160.4, 148.0, 139.5, 138.4, 132.1, 130.5,
128.8, 128.6, 128.5, 126.0, 124.0, 122.3, 120.1, 113.9, 75.4,
55.2.
6.87 (s, 1H), 6.68 (s, 2H), 2.04 (s, 6H). 13C{1H} NMR (101
MHz, DMSO-d6): δ 167.8, 148.0, 139.5, 137.2, 134.2, 132.0,
130.8, 130.6, 129.0, 128.9, 128.5, 126.0, 124.2, 122.2, 75.5,
20.6.
1
2
3
4
5
6
7
8
3-((2-methoxyphenyl)thio)-3-phenylisoindolin-1-one (6e). To a
4 mL vial was added 3-hydroxy-3-phenylisoindolin-1-one (100
mg, 0.44 mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and
nBu4NPF6 (1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC. The
reaction was stirred for 5 minutes and 2-methoxythiophenol (93
mg, 0.666 mmol) was added in a single portion and stirred at 80
ºC for 15 minutes. Once TLC analysis indicated conversion to
the product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAC:Hex) to afford a cream
solid (151 mg, 98%). RF (1:1 EtOAc/Hex) = 0.25. IR νmax (cm-
1): 3190, 3065, 2925, 2830, 1695, 1471. HRMS (ESI) m/z:
9
3-((4-(trifluoromethyl)phenyl)thio)-3-phenylisoindolin-1-one
(6b). To a 4 mL vial was added 3-hydroxy-3-phenylisoindolin-
1-one (100 mg, 0.44 mmol), Ca(NTf2)2 (2.7 mg, 0.0044 mmol)
and nBu4NPF6 (1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The reaction was stirred for
5
minutes and 4-
(trifluoromethyl)thiophenol (95 mg, 0.533 mmol) was added in
a single portion and stirred at 80 ºC for 15 minutes. Once TLC
analysis indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(1:1, EtOAc:Hex) to afford a cream solid (142 mg, 83%). RF
(1:1 EtOAc/Hex) = 0.54. IR νmax (cm-1): 3160, 3062, 2850,
1694, 1319, 1124. HRMS (ESI) m/z: [M+H]+ Calcd for
C21H15F3NOS 386.0826; found 386.0828. 1H NMR (400 MHz,
DMSO-d6): δ 9.96 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.80 (d, J
= 7.5 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.54 – 7.45 (m, 4H),
7.45 – 7.35 (m, 2H), 7.35 – 7.27 (m, 3H). 13C{1H} NMR (101
MHz, DMSO-d6): δ 167.7, 147.5, 139.1, 137.0, 134.9, 132.5,
130.2, 129.8, 129.4, 129.0, 128.8, 126.0, 125.1, 125.1, 124.1,
122.4, 75.8.
1
[M+H]+ Calcd for C21H18NO2S 348.1058; found 348.1060. H
NMR (400 MHz, CDCl3): δ 7.79 (d, J = 7.5 Hz, 2H), 7.69 (d, J
= 7.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H),
7.44 – 7.19 (m, 5H), 6.91 (d, J = 7.3 Hz, 1H), 6.81 – 6.73 (m,
2H), 6.59 (t, J = 7.4 Hz, 1H), 3.80 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): δ 160.9, 148.9, 139.5, 139.3, 132.3, 132.2, 129.0,
128.8, 128.6, 126.0, 124.0, 123.0, 120.7, 117.2, 111.3, 76.3,
55.9.
3-(2-pyrimidinethio)-3-phenylisoindolin-1-one (6f). To a 4 mL
vial was added 3-hydroxy-3-phenylisoindolin-1-one (100 mg,
0.44 mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and nBu4NPF6
(1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC. The reaction
was stirred for 5 minutes and 2-mercaptopyrimidine (75 mg,
0.666 mmol) was added in a single portion and stirred at 80 ºC
for 15 minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (3:1, EtOAC:Hex) to afford a white
solid (111 mg, 78%). RF (3:1 EtOAc/Hex) = 0.6. IR νmax (cm-
1): 3288, 3057, 2924, 1693, 1609, 1377. HRMS (ESI) m/z:
[M+Na]+ Calcd for C18H13N3OSNa 342.0672; found 342.0671.
1H NMR (400 MHz, CDCl3): δ.81 (s, 1H), 8.42 (d, J = 4.9 Hz,
2H), 7.90 (d, J = 7.1 Hz, 1H), 7.86 – 7.81 (m, 2H), 7.62 – 7.42
(m, 3H), 7.32 – 7.26 (m, 2H), 7.26 – 7.19 (m, 1H), 6.96 (t, J =
4.9 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.4, 169.4,
157.5, 147.7, 140.2, 133.1, 130.2, 129.7, 128.8, 128.3, 126.2,
124.6, 123.2, 117.7, 74.3.
3-((4-chlorophenyl)thio)-3-phenylisoindolin-1-one (6c). To a 4
mL vial was added 3-hydroxy-3-phenylisoindolin-1-one (100
mg, 0.44 mmol), Ca(NTf2)2 (2.67 mg, 0.0044 mmol) and
nBu4NPF6 (1.72 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC.
The reaction was stirred for 5 minutes and 4-chlorothiophenol
(77 mg, 0.533 mmol) was added in a single portion and stirred
at 80 ºC for 15 minutes. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (1:1, EtOAc:Hex) to
afford a cream solid (136 mg, 88%). RF (1:1 EtOAc/Hex) =
0.50. IR νmax (cm-1): 3162, 3060, 2828, 1694, 1469, 1312.
HRMS (ESI) m/z: [M+H]+ Calcd for C20H15ClNOS 352.0563;
1
found 352.0562. H NMR (400 MHz, DMSO-d6): δ 9.86 (s,
1H), 7.88 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.63 (dd,
J = 10.8, 4.2 Hz, 1H), 7.52 – 7.42 (m, J = 7.3 Hz, 2H), 7.42 –
7.29 (m, J = 15.2, 7.3Z Hz, 3H), 7.21 (d, J = 8.5 Hz, 2H), 7.11
(d, J = 8.5 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
167.8, 147.6, 139.2, 138.4, 134.9, 132.4, 130.3, 129.0, 128.9,
128.7, 128.5, 126.0, 124.0, 122.4, 75.6.
3-(2-furfurylthio)-3-phenylisoindolin-1-one (6g). To a 4 mL
vial was added 3-hydroxy-3-phenylisoindolin-1-one (100 mg,
0.44 mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and nBu4NPF6
(1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC. The reaction
was stirred for 5 minutes and 2-furfurylthiol (76 mg, 0.666
mmol) was added in a single portion and stirred at 80 ºC for 15
minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAc:Hex) to afford a cream
solid (143 mg, 78%). RF (1:1 EtOAc/Hex) = 0.39. IR νmax (cm-
1): 3170, 3061, 2926, 1692, 1467, 1148. HRMS (ESI) m/z:
3-((3,5-dimethylphenyl)thio)-3-phenylisoindolin-1-one (6d).
To a 4 mL vial was added 3-hydroxy-3-phenylisoindolin-1-one
(100 mg, 0.44 mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and
nBu4NPF6 (1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC. The
reaction was stirred for 5 minutes and 3,5-dimethylthiophenol
(74 mg, 0.533 mmol) was added in a single portion and stirred
at 80 ºC for 15 minutes. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (1:1, EtOAc:Hex) to
afford a cream solid (132 mg, 86%). RF (1:1 EtOAc/Hex) =
0.75. IR νmax (cm-1): 3173, 3062, 2920, 2855, 1699, 1312.
HRMS (ESI) m/z: [M+H]+ Calcd for C22H20NOS 346.1266;
1
Calcd for C19H16NO2S 322.0902; found 322.0901. H NMR
(400 MHz, DMSO-d6): δ 9.90 (s, 1H), 7.78 – 7.66 (m, J = 7.2
Hz, 4H), 7.61 (t, J = 7.3 Hz, 1H), 7.56 – 7.48 (m, J = 7.3 Hz,
1H), 7.46 (s, 1H), 7.43 – 7.36 (m, J = 7.1 Hz, 2H), 7.36 – 7.26
(m, 1H), 6.25 (s, 1H), 5.92 (s, 1H), 3.50 (d, J = 14.0 Hz, 1H),
3.42 (d, J = 14.0 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-
d6): δ 168.1, 149.7, 148.0, 142.5, 139.7, 132.8, 130.5, 129.2,
128.9, 128.5, 125.9, 123.8, 123.0, 110.7, 107.8, 72.9, 26.4.
1
found 346.1263. H NMR (400 MHz, DMSO-d6): δ 9.74 (s,
1H), 7.86 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 7.7 Hz, 2H), 7.64 (t,
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3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)benzenethiol)-3-phenylisoindolin-1-one (6k). To a 4 mL vial
was added 3-hydroxy-3-phenylisoindolin-1-one (50 mg, 0.22
mmol), Ca(NTf2)2 (3 mg, 0.0022 mmol) and nBu4NPF6 (1.7 mg,
0.0022 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 5 minutes and 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-
2-yl)benzenethiol (79 mg, 0.33 mmol) was added in a single
portion and stirred at 80 ºC for 15 minutes. Once TLC analysis
indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(1:1, EtOAc:Hex) to afford a peach solid (73 mg, 74%). RF (1:1
EtOAc/CycHex) = 0.60. IR νmax (cm-1): 3502, 3162, 3067, 2989,
1697, 1358. HRMS (ESI) m/z: [M+H]+ Calcd for C26H27BNO3S
444.1805; found 444.1813. 1H NMR (400 MHz, DMSO-d6): δ
9.88 (s, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.4 Hz, 2H),
7.68 – 7.61 (m, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (q, J = 8.1
Hz, 4H), 7.30 (d, J = 7.4 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 1.25
(s, 12H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 167.8, 147.8,
139.4, 135.9, 134.1, 133.1, 132.3, 130.3, 128.9, 128.8, 128.7,
126.0, 124.1, 122.4, 84.0, 75.5, 25.0, 24.7, 24.7.
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3-(benzylthio)-3-phenylisoindolin-1-one (6h). To a 4 mL vial
was added 3-hydroxy-3-phenylisoindolin-1-one (100 mg, 0.44
mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and nBu4NPF6 (1.7 mg,
0.0044 mmol) in DCE (2 mL) at 80 ºC. The reaction was stirred
for 5 minutes and benzylmercaptan (66 mg, 0.53 mmol) was
added in a single portion and stirred at 80 ºC for 15 minutes.
Once TLC analysis indicated conversion to the product, the
product was concentrated and purified by flash column
chromatography (1:1, EtOAC:Hex) to afford a cream solid (135
mg, 92%). RF (1:1 EtOAc/Hex) = 0.46. IR νmax (cm-1): 3127,
3056, 2843, 1694, 1609, 1491. HRMS (ESI) m/z: [M+H]+
Calcd for C21H18NOS 332.1109; found 332.1104. 1H NMR (400
MHz, DMSO-d6): δ 9.92 (s, 1H), 7.84 – 7.66 (m, 4H), 7.61 (t, J
= 7.1 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.46 – 7.38 (m, 2H),
7.38 – 7.27 (m, 1H), 7.26 – 7.12 (m, 3H), 7.11 – 7.03 (m, 2H),
3.45 (d, J = 12.2 Hz, 1H), 3.30 (d, J = 12.2 Hz, 1H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 168.1, 148.2, 139.9, 136.5,
132.8, 130.6, 129.1, 128.9, 128.8, 128.4, 127.0, 125.9, 123.8,
123.0, 73.1, 34.1.
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2-benzyl-3-(2-chloro-4-methylanilino)-2,3-dihydro-1H-
isoindol-1-one (8a). To a 4 mL vial was added 2-benzyl-3-
hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21 mmol),
Ca(NTf2)2 (13 mg, 0.021 mmol) and nBu4NPF6 (8 mg, 0.021
mmol) in DCE (1 mL) at room temperature. 2-chloro-4-
methylaniline (45 mg, 0.31 mmol) was added in a single portion
and the reaction was stirred at 80 ºC overnight. Once TLC
analysis indicated conversion to the product, the product was
concentrated and purified by flash column chromatography (0
to 2% EtOAc:DCM) to afford the desired product as a cream
solid (48 mg, 63%). RF (1:1 EtOAc/Hex) = 0.71. IR νmax (cm-
1): 3361, 3031, 2924, 1683, 1615, 1520. HRMS (ESI) m/z:
[M+H]+ Calcd for C22H20ClN2O 363.1264; found. 363.1265. 1H
NMR (400 MHz, DMSO-d6): δ 7.86 – 7.78 (m, 1H), 7.69 – 7.53
(m, 2H), 7.46 (d, J = 7.1 Hz, 1H), 7.33 – 7.22 (m, 2H), 7.22 –
7.17 (m, 2H), 7.09 (d, J = 1.5 Hz, 1H), 6.68 (dd, J = 8.4, 1.5 Hz,
1H), 6.25 (d, J = 8.2 Hz, 1H), 6.12 (d, J = 8.3 Hz, 1H), 6.04 (d,
J = 8.2 Hz, 1H), 4.87 (d, J = 15.4 Hz, 1H), 4.21 (d, J = 15.5 Hz,
1H), 2.10 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
166.6, 143.9, 139.1, 137.5, 132.3, 132.1, 129.7, 129.3, 128.4,
128.1, 128.0, 127.6, 127.1, 123.3, 122.9, 119.3, 113.8, 68.5,
42.4, 19.6.
3-(butanethio)-3-phenylisoindolin-1-one (6i). To a 4 mL vial
was added 3-hydroxy-3-phenylisoindolin-1-one (100 mg, 0.44
mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and nBu4NPF6 (1.7 mg,
0.0044 mmol) in DCE (2 mL) at 80 ºC. The reaction was stirred
for 5 minutes and butanethiol (48 mg, 0.53 mmol) was added in
a single portion and stirred at 80 ºC for 15 minutes. Once TLC
analysis indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(1:1, EtOAc:Hex) to afford a yellow oil which solidified upon
standing (120 mg, 91%). RF (1:1 EtOAc/Hex) = 0.70. IR νmax
(cm-1): 3185, 3066, 2956, 1698, 1310. HRMS (ESI) m/z:
1
[M+H]+ Calcd for C18H20NOS 298.1266; found 298.1259. H
NMR (400 MHz, CDCl3): δ 7.98 (s, 1H), 7.83 (d, J = 7.5 Hz,
1H), 7.77 – 7.67 (m, 2H), 7.67 – 7.53 (m, 2H), 7.45 (td, J = 7.4,
0.8 Hz, 1H), 7.40 – 7.27 (m, 3H), 2.35 – 2.25 (m, 1H), 2.11 –
1.98 (m, 1H), 1.45 – 1.12 (m, 4H), 0.74 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 169.7, 149.3, 140.0, 132.9,
130.3, 129.0, 128.9, 128.6, 125.8, 123.8, 123.7, 73.2, 30.7, 29.3,
22.1, 13.6.
3-(cyclohexanethio)-3-phenylisoindolin-1-one (6j). To a 4 mL
vial was added 3-hydroxy-3-phenylisoindolin-1-one (100 mg,
0.44 mmol), Ca(NTf2)2 (3 mg, 0.0044 mmol) and nBu4NPF6
(1.7 mg, 0.0044 mmol) in DCE (2 mL) at 80 ºC. The reaction
was stirred for 5 minutes and cyclohexanethiol (77 mg, 0.66
mmol) was added in a single portion and stirred at 80 ºC for 15
minutes. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:1, EtOAc:Hex) to afford a yellow
oil which solidified upon standing (134 mg, 93%). RF (1:1
EtOAc/Hex) = 0.52. IR νmax (cm-1): 3156, 3061, 2926, 1690,
1464, 1312. HRMS (ESI) m/z: [M+H]+ Calcd for C20H22NOS
324.1422; found 324.1418. 1H NMR (400 MHz, CDCl3): δ 7.83
(d, J = 7.5 Hz, 1H), 7.75 – 7.68 (m, 3H), 7.63 (d, J = 7.7 Hz,
1H), 7.56 (td, J = 7.6, 1.0 Hz, 1H), 7.45 (td, J = 7.5, 0.9 Hz,
1H), 7.39 – 7.24 (m, 3H), 2.35 – 2.20 (m, 1H), 1.91 – 1.75 (m,
1H), 1.68 – 1.55 (m, 1H), 1.55 – 1.44 (m, 1H), 1.44 – 1.28 (m,
3H), 1.28 – 0.97 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3): δ
169.5, 149.6, 140.3, 132.8, 130.1, 128.9, 128.6, 125.8, 124.0,
123.8, 77.5, 43.3, 35.1, 34.6, 26.0, 25.9, 25.5.
2-benzyl-3-(2,4-difluoroanilino)-2,3-dihydro-1H-isoindol-1-
one (8b). To a 4 mL vial was added 2-benzyl-3-hydroxy-2,3-
dihydro-isoindol-1-one (50 mg, 0.21 mmol), Ca(NTf2)2 (13 mg,
0.021 mmol) and nBu4NPF6 (8 mg, 0.021 mmol) in DCE (1 mL)
at room temperature. 2,4-difluoroaniline (41 mg, 0.31 mmol)
was added in a single portion and the reaction was stirred at 80
ºC overnight. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:10 EtOAc:Hex) to afford the
desired product as a colorless oil (48 mg, 68%). RF (1:1
EtOAc/Hex) = 0.58. IR νmax (cm-1): 3415, 2917, 1694, 1497,
1113. HRMS (ESI) m/z: [M+H]+ Calcd for C21H17F2N2O
351.1309; found 351.1315. . 1H NMR (400 MHz, DMSO-d6): δ
7.94 – 7.92 (m, 1H), 7.57 – 7.53 (m, 2H), 7.47 – 7.43 (m, 1H),
7.32 – 7.24 (m, 3H), 7.21 – 7.19 (m, 2H), 6.79 (ddd, J = 11.3,
8.4, 2.8 Hz, 1H), 6.56 (ddd, J = 4.3, 3.5, 1.6 Hz, 1H), 6.27 (td,
J = 9.3, 5.4 Hz, 1H), 5.71 (s, 1H), 5.26 (d, J = 15.1 Hz, 1H),
4.29 – 4.11 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
167.7, 143.2, 137.0, 132.4, 132.1, 129.8, 129.6 (dd, J = 11.4,
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2.9 Hz), 128.9, 128.2, 127.8, 124.00, 123.1, 115.3 (dd, J = 8.9,
3.4 Hz), 111.2 (d, J = 3.7 Hz), 111.0 (d, J = 3.7 Hz), 104.0 (dd,
J = 26.4, 23.5 Hz), 68.9, 43.2.
168.2, 143.6, 140.0, 137.8, 133.2, 132.3, 129.6, 129.3, 128.8,
128.7, 128.5, 128.1, 127.6, 124.0, 123.6, 72.7, 45.9, 43.6.
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Benzyl
(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-
2-benzyl-3-[2-methoxy-5-(trifluoromethyl)anilino]-2,3-
yl)carbamate (12a). To a 4 mL vial was added 2-benzyl-3-
hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21 mM),
Ca(NTf2)2 (1.3 mg, 0.0021 mmol) and nBu4NPF6 (0.8 mg,
0.0021 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and benzylcarbamate (35 mg, 0.23 mmol) was
added in a single portion and stirred at 80 ºC for 15 minutes.
Once TLC analysis indicated conversion to the product, the
product was concentrated and purified by flash column
chromatography (1:1, EtOAc:Hex) followed by trituration with
Et2O to afford the product as a white solid (70 mg, 90%). RF
(1:5 EtOAc/DCM) = 0.74. IR νmax (cm-1): 3306, 3034, 2925,
1687, 1528, 1425. . HRMS (ESI) m/z: [M+H]+ Calcd for
dihydro-1H-isoindol-1-one (8c). To a 4 mL vial was added 2-
benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21
mmol), Ca(NTf2)2 (13 mg, 0.021 mmol) and nBu4NPF6 (8 mg,
0.021 mmol) in DCE (1 mL) at room temperature. 2-methoxy-
5-(trifluoromethyl)aniline (60 mg, 0.31 mmol) was added in a
single portion and the reaction was stirred at 80 ºC overnight.
Once TLC analysis indicated conversion to the product, the
product was concentrated and purified by flash column
chromatography (0 to 5% EtOAc:DCM) to afford the desired
product as a light brown solid (70 mg, 81%). RF (1:20
EtOAc/DCM) = 0.33. IR νmax (cm-1): 3415, 2917, 1694, 1497,
1113. HRMS (ESI) m/z: [M+H]+ Calcd for C23H19F3N2O2
413.1477; found 413.1497. 1H NMR (400 MHz, DMSO-d6): δ
7.81 (d, J = 6.5 Hz, 1H), 7.70 – 7.52 (m, 2H), 7.48 (d, J = 6.8
Hz, 1H), 7.28 – 7.05 (m, 5H), 6.95 – 6.82 (m, 2H), 6.44 (d, J =
8.1 Hz, 1H), 6.21 (s, 1H), 6.12 (d, J = 8.3 Hz, 1H), 4.79 (d, J =
15.4 Hz, 1H), 4.28 (d, J = 15.5 Hz, 1H), 3.81 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 166.6, 149.6, 143.7, 137.4,
135.2, 132.3, 132.1, 129.4, 128.2, 127.4, 126.9, 123.4, 122.9,
114.6, 110.0, 107.5, 68.2, 55.8, 42.7.
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C23H21N2O3 373.1552 found 373.1552. H NMR (400 MHz,
DMSO-d6): δ 8.23 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H),
7.64 (t, J = 7.3 Hz, 1H), 7.55 (dd, J = 13.5, 7.3 Hz, 2H), 7.46 –
7.20 (m, 10H), 6.09 (d, J = 9.1 Hz, 1H), 5.20 – 4.98 (m, 2H),
4.80 (d, J = 15.4 Hz, 1H), 4.32 (d, J = 15.4 Hz, 1H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 166.5, 156.3, 143.0, 137.6,
136.7, 132.3, 131.7, 129.4, 128.4, 128.0, 127.8, 127.7, 127.2,
123.5, 122.7, 65.9, 65.8, 43.1
tert-butyl
(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-
2-benzyl-3-(cyclopropylamino)-2,3-dihydro-1H-isoindol-1-one
(8d). To a 4 mL vial was added 2-benzyl-3-hydroxy-2,3-
dihydro-isoindol-1-one (50 mg, 0.21 mmol), Ca(NTf2)2 (13 mg,
0.021 mmol) and nBu4NPF6 (8 mg, 0.021 mmol) in DCE (1 mL)
at room temperature. cyclopropylamine (18 mg, 0.31 mmol)
was added in a single portion and the reaction was stirred at 80
ºC overnight. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:5 EtOAc:Hex, 1% NEt3) to afford
the desired product as a colorless oil (39 mg, 67%). RF (1:5
EtOAc/Hex) = 0.48. IR νmax (cm-1): 3415, 2917, 1694, 1497,
1113. HRMS (ESI) m/z: [M+H]+ Calcd for C18H19N2O
279.1497; found 279.1492. 1H NMR (400 MHz, DMSO-d6): δ
7.88 – 7.86 (m, 1H), 7.55 – 7.46 (m, 3H), 7.33 – 7.24 (m, 5H),
5.30 (d, J = 15.0 Hz, 1H), 5.16 (s, 1H), 4.27 (d, J = 15.0 Hz,
1H), 2.05 – 2.00 (m, 1H), 0.39 – 0.30 (m, 2H), 0.22 – 0.08 (m,
2H). 13C{1H}NMR (101 MHz, DMSO-d6):δ 167.8, 144.6,
137.6, 132.5, 131.6, 129.0, 128.9, 128.3, 127.6, 123.6, 123.5,
72.4, 43.1, 24.7, 7.6, 6.0.
yl)carbamate (12b). To a 4 mL vial was added 2-benzyl-3-
hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21 mmol),
Ca(NTf2)2 (1.3 mg, 0.0021 mmol) and nBu4NPF6 (0.8 mg,
0.0021 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and tert-butylcarbamate (29 mg, 0.25 mmol) was
added in a single portion and stirred at 80 ºC for 15 minutes.
Once TLC analysis indicated conversion to the product, the
product was concentrated and purified by flash column
chromatography (1:1 EtOAC:Hex) followed by trituration with
Et2O to afford the product as a white solid (61 mg, 86%). RF
(1:1 EtOAc/Hex) = 0.50. IR νmax (cm-1): 3270, 2985, 2929,
1712, 1684, 1519. HRMS (ESI) m/z: [M+H]+ Calcd for
1
C20H23N2O2 339.1709; found 339.1696. H NMR (400 MHz,
DMSO-d6): δ 7.81 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H),
7.63 (t, J = 7.2 Hz, 1H), 7.58 – 7.46 (m, 1H), 7.39 – 7.18 (m,
1H), 6.03 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 15.3 Hz, 1H), 4.28
(d, J = 15.5 Hz, 1H), 1.39 (s, 1H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 166.6, 155.6, 143.3, 137.8, 132.2, 131.7, 129.3,
128.5, 127.6, 127.1, 123.5, 122.6, 79.0, 65.5, 43.1, 28.1.
2-benzyl-3-(benzylamino)-2,3-dihydro-1H-isoindol-1-one (8e).
To a 4 mL vial was added 2-benzyl-3-hydroxy-2,3-dihydro-
isoindol-1-one (50 mg, 0.21 mmol), Ca(NTf2)2 (12.5 mg, 0.021
mmol) and nBu4NPF6 (8.1 mg, 0.021 mmol) in DCE (1 mL) at
room temperature. benzylamine (34 mg, 0.31 mmol) was added
in a single portion and the reaction was stirred at 80 ºC
overnight. Once TLC analysis indicated conversion to the
product, the product was concentrated and purified by flash
column chromatography (1:5 EtOAc:Hex, 1% NEt3) to afford
the desired product as a colorless oil (64 mg, 93%). RF (1:1
EtOAc/Hex) = 0.61. IR νmax (cm-1): 3320, 3029, 2850, 1678,
1454, 1219. HRMS (ESI) m/z: [M+H]+ Calcd for C22H21N2O
329.1654; found 329.1652. 1H NMR (400 MHz, DMSO-d6): δ
7.89 (d, J = 7.3 Hz, 1H), 7.57 – 7.48 (m, 3H), 7.34 – 7.21 (m,
8H), 7.16 (d, J = 6.8 Hz, 2H), 5.34 (s, 1H), 5.19 (d, J = 15.0 Hz,
1H), 4.34 (d, J = 15.0 Hz, 1H), 3.36 (d, J = 13.0 Hz, 1H), 3.25
(d, J = 13.0 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)benzamide
(12c). To a 4 mL vial was added 2-benzyl-3-hydroxy-2,3-
dihydro-isoindol-1-one (50 mg, 0.21 mmol) Ca(NTf2)2 (6.3 mg,
0.0104 mmol) and nBu4NPF6 (4 mg, 0.0104 mmol) in DCE (1
mL) at 80 ºC. The reaction was stirred for 1 minute and
benzamide (38 mg, 0.3 mmol) was added in a single portion and
stirred at 80 ºC for 15 minutes. Once TLC analysis indicated
conversion to the product, the product was concentrated and
purified by flash column chromatography (1:1, EtOAc:Hex) to
afford a white solid (68 mg, 95%). RF (1:1 EtOAc/Hex) = 0.41.
IR νmax (cm-1): 3548, 3278, 3031, 2933, 1705, 1270. HRMS
(ESI) m/z: [M+H]+ Calcd for C22H19N2O2 343.1447; found
1
343.1441. H NMR (400 MHz, DMSO-d6): δ 9.20 (d, J = 8.9
Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.71
– 7.51 (m, 4H), 7.45 (t, J = 7.6 Hz, 2H), 7.38 – 7.14 (m, 5H),
6.61 (d, J = 8.9 Hz, 1H), 4.85 (d, J = 15.4 Hz, 1H), 4.37 (d, J =
15.4 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 167.3,
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166.9, 143, 137.7, 133.3, 132.3, 131.9, 131.9, 129.4, 128.5,
128.3, 127.7, 127.6, 127.2, 123.6, 122.8, 63.8, 43.2.
409.1222; found 409.1227. H NMR (400 MHz, DMSO-d6):δ
8.97 – 8.76 (m, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.70 (s, 1H), 7.57
– 7.47 (m, 2H), 7.35 – 7.09 (m, 7H), 6.77 (s, 1H), 5.86 – 5.65
(m, 1H), 4.82 (d, J = 15.6 Hz, 1H), 4.24 (d, J = 15.5 Hz, 1H),
3.87 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 166.3,
162.5, 142.8, 137.4, 133.5, 132.3, 131.2, 129.7, 128.6, 128.4,
127.5, 127.1, 123.2, 122.8, 114.6, 67.5, 55.8, 42.3.
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N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2-
2-benzyl-3-(2-oxo-1,3-oxazolidin-3-yl)-2,3-dihydro-1H-
(trifluoromethoxy)benzene-1-sulfonamide (14c). To a 4 mL vial
was added 2-benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (50
mg, 0.21 mmol), Ca(NTf2)2 (6.2 mg, 0.0104 mmol) and
nBu4NPF6 (4 mg, 0.0104 mmol) in DCE (1 mL) at 80 ºC. The
isoindol-1-one (12d). To a 4 mL vial was added 2-benzyl-3-
hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21 mmol),
Ca(NTf2)2 (1.3 mg, 0.0021 mmol) and nBu4NPF6 (1 mg, 0.0021
mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred for 1
minute and 2-oxazolidinone (27 mg, 0.31 mmol) was added in
a single portion and stirred at 80 ºC for 15 minutes. Once TLC
analysis indicated conversion to the product, the product was
concentrated and purified by flash column chromatography
(1:9, EtOAc:DCM) to afford a white semi-solid (49 mg, 76%).
RF (1:5 EtOAc/DCM) = 0.64. IR νmax (cm-1): 2972, 1755, 1701,
1404, 1215. HRMS (ESI) m/z: [M+H]+ Calcd for C18H17N2O3
9
10
11
12
13
14
15
16
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reaction
was
stirred
for
1
minute
and
2-
(trifluoromethoxy)benezenesulfonamide (55 mg, 0.23 mmol)
was added in a single portion and stirred at 80 ºC overnight.
Once TLC analysis indicated conversion to the product, hexane
(2 mL) was added and the product was collected by filtration as
a white solid (75 mg, 78%). RF (1:5 EtOAc/DCM) = 0.56. IR
ν
max (cm-1): 3106, 3063, 1687, 1592, 1444, 1163. HRMS (ESI)
m/z: [M+H]+ Calcd for C22H18F3N2O4S 463.0939; found
1
309.1239; found 309.1246. H NMR (400 MHz, CDCl3): δ 7.91
1
463.0930. H NMR (400 MHz, DMSO-d6): δ 9.28 (d, J = 8.8
(d, J = 6.9 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.46 (d, J = 6.9 Hz,
2H), 7.41 (d, J = 7.2 Hz, 1H), 7.38 – 7.27 (m, 3H), 6.42 (s, 1H),
4.96 (d, J = 14.7 Hz, 1H), 4.47 (d, J = 14.7 Hz, 1H), 4.06 (td, J
= 9.0, 6.5 Hz, 1H), 3.53 (td, J = 9.0, 7.2 Hz, 1H), 2.75 (dd, J =
15.9, 8.8 Hz, 1H), 2.54 (td, J = 9.0, 6.5 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3): δ 167.5, 158.2, 139.7, 137.4, 132.7, 132.4,
130.3, 128.9, 128.8, 128.0, 124.3, 123.0, 68.7, 62.2, 45.1, 38.8.
Hz, 1H), 8.03 – 7.81 (m, 2H), 7.80 – 7.61 (m, 2H), 7.61 – 7.46
(m, 3H), 7.42 – 7.19 (m, 3H), 7.12 (d, J = 6.8 Hz, 2H), 7.06 –
6.88 (m, 1H), 5.79 (d, J = 8.7 Hz, 1H), 4.90 (d, J = 15.6 Hz,
1H), 4.17 (d, J = 15.6 Hz, 1H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 166.4, 144.9, 142.5, 137.1, 135.5, 133.6, 132.4,
131.3, 130.1, 129.8, 128.5, 127.8, 127.3, 127.2, 123.0, 122.9,
121.1, 67.5, 42.2.
N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-3-
N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-4-
chlorobenzene-1-sulfonamide (14d). To a 4 mL vial was added
2-benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21
mmol), Ca(NTf2)2 (6.3 mg, 0.0104 mmol) and nBu4NPF6 (4 mg,
0.0104 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and 3-chloro-benezenesulfonamide (44 mg, 0.23
mmol) was added in a single portion and stirred at 80 ºC for 2h.
Once TLC analysis indicated conversion to the product, hexane
(2 mL) was added and the product was collected by filtration as
a white solid (65 mg, 75%). RF (1:5 EtOAc/DCM) = 0.60. IR
methylbenzene-1-sulfonamide (14a). To a 4 mL vial was added
2-benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21
mmol), Ca(NTf2)2 (6.3 mg, 0.0104 mmol) and nBu4NPF6 (4 mg,
0.0104 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and p-toluenesulfonamide (36 mg, 0.21 mmol) was
added in a single portion and stirred at 80 ºC overnight. Once
TLC analysis indicated conversion to the product, hexane (2
mL) was added and the product was collected by filtration as a
white solid (68 mg, 85%). RF (1:5 EtOAc/DCM) = 0.57. IR νmax
(cm-1): 3125, 2935, 2884, 1674, 1495, 1162. HRMS (ESI) m/z:
[M+H]+ Calcd for C22H21N2O3S 393.1273; found 393.1276. 1H
NMR (400 MHz, DMSO-d6): δ 8.94 (d, J = 8.8 Hz, 1H), 7.72
(dd, J = 25.2, 6.9 Hz, 3H), 7.58 – 7.46 (m, 2H), 7.43 (d, J = 7.9
Hz, 2H), 7.35 – 7.20 (m, 3H), 7.16 (d, J = 7.2 Hz, 2H), 6.73 (d,
J = 6.2 Hz, 1H), 5.78 (d, J = 8.7 Hz, 1H), 4.82 (d, J = 15.6 Hz,
1H), 4.22 (d, J = 15.5 Hz, 1H), 2.44 (s, 3H). 13C{1H} NMR (101
MHz, DMSO-d6): δ 166.3, 143.3, 142.7, 139.0, 137.3, 132.3,
131.2, 123.0, 129.7, 128.4, 127.50, 127.1, 126.4, 123.1, 122.8,
67.6, 42.3, 21.1.
ν
max (cm-1): 3181, 3056, 1687, 1494, 1468, 1157. HRMS (ESI)
m/z: [M+H]+ Calcd for C21H18ClN2O3S 413.0727; found
1
413.0727. H NMR (400 MHz, DMSO-d6): δ 9.19 (d, J = 8.7
Hz, 1H), 7.89 – 7.78 (m, 3H), 7.76 – 7.64 (m, 2H), 7.53 (p, J =
8.1 Hz, 2H), 7.36 – 7.22 (m, 3H), 7.18 (d, J = 7.3 Hz, 2H), 6.76
(d, J = 6.2 Hz, 1H), 5.90 (d, J = 8.7 Hz, 1H), 4.83 (d, J = 15.6
Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 166.3, 143.7, 142.4, 137.2, 134.1, 133.0, 132.3,
131.9, 131.2, 129.8, 128.5, 127.5, 127.2, 126.1, 125.0, 123.2,
122.9, 67.7, 42.7.
N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-3-
N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-4-
fluorobenzene-1-sulfonamide (14e). To a 4 mL vial was added
2-benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (50 mg, 0.21
mmol), Ca(NTf2)2 (6.3 mg, 0.0104 mmol) and nBu4NPF6 (4 mg,
0.0104 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and 3-fluorobenezenesulfonamide (40 mg, 0.23
mmol) was added in a single portion and stirred at 80 ºC
overnight. Once TLC analysis indicated conversion to the
product, hexane (2 mL) was added and the product was
collected by filtration as a white solid (65 mg, 68%). RF (1:5
EtOAc/DCM) = 0.60. IR νmax (cm-1): 3197, 3072, 2936, 1685,
1494, 1345. HRMS (ESI) m/z: [M+H]+ Calcd for
C21H FN2O3S 397.1022; found 397.1023. 1H NMR (400 MHz,
methoxybenzene-1-sulfonamide (14b). To a 4 mL vial was
added 2-benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (50 mg,
0.21 mmol), Ca(NTf2)2 (6.27 mg, 0.0104 mmol) and nBu4NPF6
(4.05 mg, 0.0104 mmol) in DCE (1 mL) at 80 ºC. The reaction
was stirred for 1 minute and 4-methoxybenezenesulfonamide
(39 mg, 0.21 mmol) was added in a single portion and stirred at
80 ºC overnight. Once TLC analysis indicated conversion to the
product, hexane (2 mL) was added and the product was
collected by filtration as a white solid (78 mg, 91%). RF (1:5
EtOAc/DCM) = 0.30. IR νmax (cm-1): 3130, 2929, 2843, 1677,
1594, 1495. HRMS (ESI) m/z: [M+H]+ Calcd for C22H21N2O4S
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Page 13 of 15
The Journal of Organic Chemistry
DMSO-d6): δ 9.17 (d, J = 8.8 Hz, 1H), 7.80 – 7.57 (m, 5H), 7.52
343.1118.. 1H NMR (400 MHz, DMSO-d6):δ 8.48 (s, 1H), 7.80
1
2
3
4
5
6
7
(p, J = 7.7 Hz, 2H), 7.35 – 7.14 (m, 5H), 6.73 (d, J = 6.0 Hz,
1H), 5.90 (d, J = 8.8 Hz, 1H), 4.83 (d, J = 15.6 Hz, 1H), 4.25
(d, J = 15.6 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
166.3, 163.1, 160.6, 143.9 (d, J = 6.6 Hz), 142.5, 137.3, 132.4,
132.1 (d, J = 7.9 Hz), 131.2, 129.8, 128.5, 127.5, 127.1, 123.1,
122.9, 122.6, 120.2 (d, J = 21.1 Hz), 113.6 (d, J = 24.5 Hz),
67.7, 42.5
– 7.65 (m, 3H), 7.65 – 7.54 (m, 1H), 7.42 – 7.28 (m, 4H), 7.28
– 7.17 (m, 1H), 5.88 (s, 1H), 4.92 (d, J = 15.5 Hz, 1H), 4.42 (d,
J = 15.6 Hz, 1H), 3.08 – 2.80 (m, 1H), 1.13 – 0.97 (m, 2H), 0.96
– 0.83 (m, 2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 166.3,
143.2, 137.7, 132.4, 131.3, 129.7, 128.5, 127.7, 127.1, 124.0,
122.7, 67.7, 42.2, 31.6, 5.6, 5.3.
8
9
Supporting Information
N-(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2,4-
The Supporting Information is available free of charge on the ACS
Publications website.
difluorobenzene-1-sulfonamide (14f). To a 4 mL vial was added
2-benzyl-3-hydroxy-2,3-dihydro-isoindol-1-one (43 mg, 0.18
mmol), Ca(NTf2)2 (6 mg, 0.00906 mmol) and nBu4NPF6 (4 mg,
0.0906 mmol) in DCE (1 mL) at 80 ºC. The reaction was stirred
for 1 minute and 2,4-difluorobenezenesulfonamide (35 mg,
0.18 mmol) was added in a single portion and stirred at 80 ºC
overnight. Once TLC analysis indicated conversion to the
product, hexane (2 mL) was added and the product was
collected by filtration as a white solid (45 mg, 60%). RF (1:5
EtOAc/DCM) = 0.69. IR νmax (cm-1): 3541, 3265, 3091, 1681,
1601, 1418. HRMS (ESI) m/z: [M+H]+ Calcd for C21H17F-
2N2O3S 415.0928; found 415.0924. 1H NMR (400 MHz,
DMSO-d6): δ 9.43 (d, J = 8.7 Hz, 1H), 7.80 (dd, J = 14.9, 8.5
Hz, 1H), 7.76 – 7.67 (m, 1H), 7.66 – 7.50 (m, 3H), 7.35 – 7.20
(m, 5H), 7.15 (d, J = 6.9 Hz, 2H), 7.06 (d, J = 6.9 Hz, 1H), 5.79
(d, J = 8.6 Hz, 1H), 4.89 (d, J = 15.8 Hz, 1H), 4.23 (d, J = 15.8
Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 166.5, 166.5,
164.0 (d, J = 11.6 Hz), 160.1 (d, J = 13.6 Hz), 157.5 (d, J = 13.5
Hz), 142.4, 137.1, 132.5, 131.4 (d, J = 10.8 Hz), 131.3, 129.8,
128.5, 127.2, 127.2, 126.2 (dd, J = 13.9, 3.4 Hz), 123.0 (d, J =
24.2 Hz), 112.4 (d, J = 22.7 Hz), 67.5, 42.3.
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PDF copies of 1H and 13
C
AUTHOR INFORMATION
Corresponding Author
* E-mail: m.mclaughlin@mmu.ac.uk
ACKNOWLEDGMENT
We thank Manchester Metropolitan University for startup funding
and infrastructural support
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max (cm-1): 3387, 3277, 3125, 1671, 1470, 1295. HRMS (ESI)
m/z: [M+H]+ Calcd for C18H19N2O3S 343.1116; found
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Page 14 of 15
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