PdII/AgI-Catalyzed Room-Temperature Reaction of γ-Hydroxy Lactams: Mechanism, Scope, and Antistaphylococcal Activity

Article abstract of DOI:10.1021/acs.joc.6b02378

The present work reports a Pd^II/Ag^I-promoted amidoalkylation reaction involving various γ-hydroxy lactams and C/O/S nucleophiles at room temperature. The dual mode of activation of both the electrophile and nucleophile by in situ generated catalytically active cationic Pd^II species facilitates the reaction at room temperature. Among the synthesized isoindoline derivatives, three compounds are found to be active against vancomycin and methicillin-resistant S. aureus strain with appreciable MIC values.

Full text of DOI:10.1021/acs.joc.6b02378

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Note
PdII/AgI Catalyzed room temperature Reaction of gamma-Hydroxy
Lactams: Mechanism, Scope, and antistaphylococcal activity
Manali Dutta, Santi M. Mandal, Rupa Pegu, and Sanjay Pratihar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02378 • Publication Date (Web): 17 Jan 2017
Downloaded from http://pubs.acs.org on January 18, 2017
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The Journal of Organic Chemistry
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PdII/AgI Catalyzed Room Temperature Reaction of γꢀHydroxy
Lactams: Mechanism, Scope, and Antistaphylococcal Activity
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Manali Dutta,a Santi M. Mandal,b Rupa Pegu,a and Sanjay Pratihar a,*
aDepartment of Chemical Sciences, Tezpur University, Napaam, Tezpur, Assamꢀ784028, India.
Email: spratihar@tezu.ernet.in or spratihar29@gmail.com
bCentral research Facility, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
Acyliminium ions and diaryl malonote,30 PdII for asymmetric addition of
ABSTRACT
The present work reports a PdII/AgI promoted amidoalꢀ
:
malonates to dihydroisoquinolines31 are noteworthy. Herein, we report the
utilization of in-situ generated cationic PdII catalyst in room temperature
amidoalkylation reaction with variety of C/N/O/S nucleophile via dual
mode of activation.
kylation reaction involving various γꢀhydroxy lactam and C/O/S nucleoꢀ
phile at room temperature. The dual mode of activation of both the elecꢀ
trophile and nucleophile by in-situ generated catalytically active cationic
PdII species facilitate the reaction at room temperature. Amongst the synꢀ
thesized isoindoline derivatives, three compounds are found to be active
against vancomycin and methicillin resistant S. aureus strain with appreꢀ
ciable MIC value.
Scheme 1. Catalytic αꢀamidoalkylation reaction
The development of a selective catalytic system for a particular type of
bond forming reaction between electrophiles (E) and nucleophile (N)
needs tunable accessibility of the catalyst active site, by which one can
activate either N or E or both in tandem.1 In this regard, various Lewis
acids or Brønstead acids were successfully utilized for both E or N activaꢀ
3
tion and successive bond formation between them.2 In case of biꢀ or
polyfunctional substrate, the choice of catalysts for the desired transforꢀ
mations relies on the relative ability of the metals to make a σꢀ or a πꢀ
complex with appropriate substrates.4 In this context, heterobimetallic or
multimetallic catalysis has received much attention since synergistic funcꢀ
tions of more than one active center in the catalyst could lead to superior
activity and selectivity via substrate activation using both σꢀ or πꢀ
complex.5 Towards this, development of cooperative homo or/and hetero
bimetallic,6 LAꢀNHC,7 tandem catalyst,8 dual metal reagents9 for various
types of bond forming methodologies are noteworthy. Similarly, develꢀ
opment of a single metal catalyst for the activation of both E and N in a
particular type of bond forming reaction is an important theme of research
in modern organic reactions.10 Thus, various catalysts based on gold,11
Initially, the reaction between 1a and indole was chosen as a model reacꢀ
tion in presence of different Brønsted acids, Lewis acids, palladium and
other transition metal catalysts. After the optimization of reaction condiꢀ
tion from the screening of solvent, temperature, and catalyst loading, our
study began with PdCl2(MeCN)2 as a catalyst.32 Although PdCl2(MeCN)2
was found to be active to produce desired 2a in 62% yield at 90 ˚C, but
model reaction failed at room temperature. Encouraged by the aforemenꢀ
tioned result, other reaction conditions and catalyst were investigated, and
the results are summarized in Table 1. To our delight, the model reaction
proceeds at room temperature with PdCl2(MeCN)2 after the introduction
of 2 eqv. of AgPF6 as a halide trapping agent. However, use of only
AgPF6 failed to produce any desired product, 2a at room temperature. On
the other hand, other PdII complexes (Table 1, entry 9ꢀ12) in combination
with AgPF6 were found to be inactive for desired transformation. The
inactivity of stronger ligand (BPy, DPPE, PPh3, COD) containing PdII
complexes suggest that vacant coordination site at PdII centre was required
for the reaction, which encouraged us to look for the active species of the
catalytic combination.33 For this, model reaction was performed with
synthesized [Pd(MeCN)4]2+ complex and found to be reactive to produce
desired 2a in 86% yield, which also confirmed the role of AgPF6 in the in-
silver,12 indium,13 ruthenium,14 rhodium,15 platinum16 have been reported
for the synthesis of various CꢀC and Cꢀheteroatom bond forming reacꢀ
tions. Simultaneously, utilization of Pd(OAc)2 both as a Lewis acid and as
a transition metal catalyst for the synthesis of cyclic alkenyl ethers from
acetylenic aldehyde17 or other types of bond formation methodologies are
noteworthy.18 19On the other hand, NꢀAcyliminium ions represent an
important electronꢀdeficient carbocations intermediates in organic syntheꢀ
sis because it provides various biologically important natural and unnatuꢀ
ral products via CꢀC and Cꢀheteoatom bond forming methodologies using
inter or intra molecular path. 20 21 The removal of good leaving group at
,
the αꢀposition of amides or lactams usually generates NꢀAcyliminium
ions, which acts as more electronꢀdeficient carbocations toward nucleoꢀ
23
philes. In this regard, chiral thiourea derivatives,22
superacidic reaꢀ
,
gents,24 various Lewis25 and Brønsted acidic26 systems have been utilized
for the generation of Nꢀacyliminium ions and subsequent catalytic intra or
inter molecular amidoalkylation reactions (Scheme 1). Along with that,
utilization of various interesting transition metal complexes, including
27
AuI/AgI,
Sn(NTf)4,28 and IrꢀSn29 for nucleophlic substitution of yꢀ
hydroxy lactams, CuII for enantioselective reaction between Nꢀ
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situ generation of active cationic species from inactive neutral
PdCl2(MeCN)2.34 Further, to check the effect of anions, two different
silver salts (Table 1, entry 7ꢀ8) were tested in the model reaction and
showed no further improvement in the product yield as compared to
AgPF6.
1
2
3
4
Table 1. Screening of Catalyst
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#
1
2
3
4
5
6
7
8
9
Cat.
AgY
X/Y
5
t, h
6
Yield,%
62a
0
T, ˚C
90
rt
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
ꢀ
ꢀ
ꢀ
5
6
AgPF6
2/2
10
2/4
2
rt
12
12
4
74
AgPF6
rt
<10
PdCl2(MeCN)2
[Pd(MeCN)4]2+
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd(COD)Cl2
AgPF6
rt
90
ꢀ
rt
4
86b
84
AgSbF6
2/4
2/4
5/10
5/10
5/10
5/10
5
rt
4
AgBF4
rt
4
85
AgPF6
rt
6
15
10 Pd(BPy)Cl2
11 Pd(DPPE)Cl2
12 Pd(PPh3)2Cl2
13 FeCl3
AgPF6
rt
6
8
AgPF6
rt
6
16
AgPF6
rt
6
12
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
rt
6
26
14 SnCl4
5
rt
6
21
Figure 1. Substrate scope for PdII/AgI catalyzed reaction of γꢀhydroxy
15 BF3.Et2O
16 pTSA
5
rt
6
15
lactam.
5
rt
6
20
Next, to check the role of the catalytic species, involvement of Lewis or
Brønsted acid, indole was chosen as a representative model and its reacꢀ
tion with 1aꢀ1c was studied under a variety of reaction conditions (Figure
2). The reaction between 1a and indole failed to produce any desired
product in presence of PdII complexes containing stronger ligand like BPy,
PPh3, and COD. On the other hand, PdII/AgI catalyzed reaction of indole
for both 1b and 1c was also found to be unsuccessful. All the above menꢀ
tioned observation suggested the need of available vacant site at the PdII
centre for binding of both the indole and γꢀhydroxy lactam, which bring
them close proximity to each other for facile interaction and successive
product formation.
17 TfOH
5
rt
6
52
18 HPF6
100
rt
6
<10
19 HCl
100
rt
6
<10
areaction done at 90˚C in 1,2 dichloro ethane, bBF4ꢀ used as an anion.
At the same time, all of the tested Lewis acids inclusive of BF3·Et2O,
FeCl3, SnCl4 and Brønsted acids like; HCl, HPF6, pTSA were less effective
on the reaction. However, catalytic amount of TfOH gave 52% yield of
2a. The substrate scope of PdII/AgI catalyzed alkylation reaction for γꢀ
Hydroxy Lactam derivatives was illustrated in Figure 1. Under optimized
reaction condition, good to excellent yields were achieved for the reaction
between 3ꢀhydroxyꢀ2ꢀphenylisoindolinꢀ1ꢀone (1a) and various electron
rich arenes (1,3,5ꢀtrimethoxybenzene and 2ꢀnapthol) and heteroarenes (2ꢀ
methylthiophene, 2ꢀmethylfuran and various indole derivatives). Similarꢀ
ly, the reaction of 2ꢀ(3,5ꢀdimethylphenyl)ꢀ3ꢀhydroxyisoindolinꢀ1ꢀone (1d)
was found to proceed smoothly with various arenes and heteroarenes
(Figure 1). On the other hand, relatively lower yield of product was
achieved in case of of 2ꢀ(4ꢀbromophenyl)ꢀ3ꢀhydroxyisoindolinꢀ1ꢀone (1e),
which suggest both the generation and stability of the Nꢀacyliminium ion
is important for the reaction. However, less electron rich arenes like; toluꢀ
ene, pꢀxylene, mesitylene remained inactive in all the three cases. Next,
the methodology was also found to be successful for the reaction between
2ꢀbenzylꢀ3ꢀhydroxyisoindolinꢀ1ꢀone (1f) with various aromatics and inꢀ
doles to produce the corresponding product almost quantitatively. Organꢀ
otin nucleophiles (allyltributyltin) and βꢀdicarbonyl nucleophiles (acetyl
acetone) also afforded the corresponding products 2j and 2o in 64 and
75% yield respectively. Apart from Cꢀnuclephiles, oxygen (isopropanol)
and sulphur (4ꢀmethoxy thiophenol) nucleophiles were also found to proꢀ
vide the corresponding 2p and 2q in 69% and 73% yield respectively.
However, Nꢀnucleophiles (aniline, pꢀtoluenesulfonamide, benzamide)
failed to produce any desired product.35
Figure 2. αꢀamidoalkylation reaction of indole under various reaction
conditions.
However, the same reaction in presence of 30 mol% HPF6 or even 30
mol% HCl afforded the desired product in 18% and 24% yield respectiveꢀ
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The Journal of Organic Chemistry
ly (Figure 2). To check the involvement of any in-situ generated Brønsted
Experimental
acid, 2,6ꢀdiꢀtertꢀbutylpyridine (2,6ꢀDTBP) was used as a proton scavenꢀ
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3
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All the reactions were performed under a dry oxygen free argon atmosꢀ
phere using standard vacuum lines and Schlenk techniques. All the solꢀ
vents used for the study have been dried and distilled by standard methods
and previously deoxygenated in the vacuum line. 1H (200, 400 MHz) and
13C NMR (54.6, 100 MHz) spectra (chemical shifts referenced to signals
for residual solvent) were recorded on 200 and 400 MHz spectrometers at
298 K. High resolution mass spectra (HRMS) were recorded on ESIꢀQꢀ
TOF mass spectrophotometer.
ger. The addition of 5 mol% of 2,6ꢀDTBP PdII/AgI catalyzed reaction still
resulted in the formation of the product 2a in 84% after 4h, which directly
ruled out the possible in-situ generated Brønsted acid catalysis.
The γꢀlactam derivatives were known to be good bioactive core36 because
it is similar to ßꢀlactam group containing antibiotics with one more numꢀ
ber of carbon in the core ring. However, bacteria often develop resistance
to ßꢀlactam antibiotics through the synthesis of ßꢀlactamases enzyme,
which could hydrolyze the ßꢀlactam ring.37 Till date, several approaches
have been tried to prevent this bacterial resistance. Amongst various apꢀ
proaches, γꢀlactams and their analogues may be an alternative and thus
various derivatives have been synthesized and tested previously against
broad spectrum antibacterial agents.38 Currently, methiciliin resistant
Staphylococcus aureus (MRSA) strains are also resistant to other group of
antibiotics like vancomycin, which is the second choice of antibiotics next
to methicillin for the treatment of complicated skin and skin structure
infection including surgical site infections.39 Towards the search for new
classes of antimicrobials to address the emergence of multidrugꢀresistant
MRSA and VRSA, synthesized analogues were tested against both
Gram(+)ve and Gram(ꢀ)ve bacteria. Activity against Gramꢀnegative bacteꢀ
ria was very weak compare to Gramꢀpositive bacteria. We have selected S.
aureus strain, a deadly infectious strain when it develops resistance to
both vancomycin and methicillin. Activities of all the synthesized comꢀ
pounds were checked against control type strain of S. aureus as well as
pathogenic vancomycin and methicillin resistant S. aureus strain.
Amongst all synthesized isoindoline derivatives, compound 2d, 2e and 2l
were found to be active against all type of strain with an appreciable MIC
value.40 Antibiotics resistant ability was also confirmed with standard
antibiotics like; methicillin, vancomycin, tetracycline, levofloxacin and
gentamicin. To our delight, comound 2w was found to be most active and
showed comparable activity with levofloxacin with MIC value of 0.48
against control as well as resistant strain (Table 2).
Synthesis of isoindolineꢀ1,3ꢀdione derivatives
In a 250 ml round bottom flask, Phthalic anhydride (7.4 g, 50 mmol) and
corresponding amine (50 mmol) was taken in 150 ml dry toluene. To this,
50 g molecular sieves (4 Å) and 300 mg Ambertlite IRꢀ120 resin was
added and stirred for 10 minutes at room temperature. After that, the reacꢀ
tion mixture was refluxed at 150 °C for 24 h using a Dean Stark apparatus.
During the course of the reaction appropriate amount of water, generated
from the reaction was collected. After the completion of the reaction,
remaining amount of toluene was evaporated in reduced pressure and as
obtained yellow condensed product was dried under reduced pressure and
collected for further use.
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Synthesis of γꢀHydroxy lactam derivatives
In a 100 ml round bottom flask, isoindolineꢀ1,3ꢀdione derivatives (5
mmol) was taken in 30 ml methanol and stirred for 5ꢀ10 minute to get a
solution. After that, reaction mixture was cooled down to 0ꢀ5 ˚C and gradꢀ
ually solid NaBH4 (50 mmol) added to it and continued for desired time.
After the completion of reaction (vide TLC), around 50 ml iceꢀwater was
added to it. Next, a dilute H2SO4 acid solution was drop wise added to
decompose the excess NaBH4. During the decomposition process, a solid
crystalline product was found to appeared in the round bottom flask,
which was collected by filtration and dried under reduced pressure for
further use.
General procedure for PdII/AgI promoted reaction γꢀHydroxy lactam
derivatives
Table 2. Effect of isoindolinone derivatives against MRSA
and VRSA positive strains
A 10 mL Schlenk flask equipped with a magnetic bar was charged with
PdCl2(MeCN)2 (0.01 mmol) and AgPF6 (0.02 mmol) in dichloroethane (3
mL) and stirred for 30 min. under argon atmosphere. After that, an approꢀ
priate arene or heteroarene (0.5 mmol) and hydroxylactam (0.5 mmol) was
added to the flask and allowed to continue at room temperature under
vigorous stirring. After completion of the reaction (vide TLC monitoring),
water was added to the reaction mixture to quench the reaction and prodꢀ
uct was extracted with ethylacetate (30 ml ×3) and washed with water (20
ml ×3), brine (10 mL) and dried over anhydrous Na2SO4. After removing
the solvent, the residue was subjected to silica gel column chromatography
(60–120 mesh, ethyl acetate–petroleum ether, and gradient elution) to
afford the pure isoindolinone derivative.
#
S. aureus U07
S.
aureus S.
aureus
ATCC25923
ATCC43300
(VRSA+MRSA+)
(Control strain) (MRSA+ Conꢀ
trol)
Vancomycin
31.2
125
500
16
1.95
1.95
3.9
3.9
Methicillin
31.2
500
Tetracycline
Gentamicin
0.975
0.24
7.8
0.975
0.24
15.6
3.9
Levofloxacin
0.48
15.6
3.9
Spectral and analytical data
2c
2d
2e
2k
2l
3ꢀ(1Hꢀindolꢀ2ꢀyl)ꢀ2ꢀphenylisoindolinꢀ1ꢀone (2a):41 Colorless solid (145
ο
1.95
0.975
7.8
mg, 90%). mp 253ꢀ255 C; δH (400MHz, DMSOꢀd6): 11.06 (1H, s), 7.90
1.95
15.6
1.95
0.487
0.975
15.6
0.975
0.487
(1H, d, J=8.0 Hz), 7.69 (2H, d, J=8.0 Hz), 7.63 (1H, s), 7.60ꢀ7.54 (2H, m),
7.34ꢀ7.25 (4H, m), 7.05 (1H, t, J=8.0 Hz), 6.95 (1H, d, J= 8 Hz), 6.76 (3H,
m). δC (100MHz, DMSOꢀd6): 166.9, 146.7, 138.1, 137.1, 133.0, 131.5,
129.0, 128.9, 126.7, 125.1, 125.0, 123.8, 123.6, 123.3, 121.7, 119.4,
118.5, 112.3, 110.2, 59.4. Anal: (C22H16N2O). Calcd, C: 81.46, H: 4.97,
N: 8.64, O: 4.93; found, C: 81.41, H: 4.76, N: 8.56.
0.975
0.487
2w
MIC values (µg. mLꢀ1) were determined in vitro against both clinical and
control strains
3ꢀ(5ꢀmethylthiophenꢀ2ꢀyl)ꢀ2ꢀphenylisoindolinꢀ1ꢀone (2b): white solid
(112 mg, 74%). mp 206ꢀ207 οC; δ H (400 MHz, DMSOꢀd6): 7.79 (1H, d, J
= 8 Hz), 7.65ꢀ7.61 (3H, t, J = 8 Hz), 7.56ꢀ7.53 (1H, m) 7.39ꢀ7.31 (3H, m),
7.13ꢀ7.07 (2H, m), 6.84 (1H, s), 6.55 (1H, d, J = 4 Hz), 2.21 (3H, s); δC
(100MHz, DMSOꢀd6): 166.4, 146.1, 140.5, 139.1, 133.4, 130.5, 129.4,
129.2, 128.3, 125.6, 125.5, 123.9, 123.9, 123.5, 60.7, 15.5.
Anal:(C19H15NOS) Calcd C: 74.72, H: 4.95, N: 4.59, O: 5.24, S: 10.50;
found, C: 74.61, H: 4.89, N: 4.51.
Conclusion. We have developed a synthetically attractive approach emꢀ
ploying in-situ generated cationic PdII catalyst using catalytic combination
of PdII/AgI for amidoalkylation reaction between various γꢀhydroxy lactam
and C/O/S nucleophile at room temperature. The origin of reactivity in
cationic PdII mainly lies on its coordination ability to both the nucleophile
and electrophile, which bring them in close proximity to each other for
facile interaction and successive product formation. The synthesized isoꢀ
indolinone darivatives were screened for the bioactivity against MRSA
and VRSA strain and some of them found to be effective with appreciable
MIC value.
3ꢀ(2ꢀhydroxynaphthalenꢀ1ꢀyl)ꢀ2ꢀphenylisoindolinꢀ1ꢀone (2c): Brown
solid (143 mg, 82%) mp 273ꢀ275 οC; δH (400MHz, DMSOꢀd6): 10.64 (1H,
s), 7.92 (1H, d, J = 8 Hz), 7.67 (1H, d, J = 12 Hz), 7.63ꢀ7.51 (5H, m),
7.33 (1H, s), 7.25 (1H, d, J = 8 Hz), 7.21ꢀ7.14 (3H, m), 7.08ꢀ7.02 (2H, m),
6.98ꢀ6.92 (2H, m). δC (100 MHz, DMSOꢀd6): 167.2, 155.5, 146.6, 138.0,
133.3, 132.5, 132.0, 131.3, 129.3, 129.1, 129.0, 128.9, 127.1, 124.9,
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124.1, 123.2, 122.9, 122.3, 121.7, 118.4, 112.1, 57.1 Anal. (C24H17NO2)
calcd, C: 82.03, H: 4.88, N: 3.99; found, C: 81.95, H: 4.58, N: 3.73.
2ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(2ꢀhydroxynaphthalenꢀ1ꢀyl)isoindolinꢀ1ꢀone (2l):
Brown solid, (141 mg, 66%). mp 261ꢀ263 C; δH (400 MHz, DMSOꢀd6):
ο
1
2
3
4
5
6
7
8
10.74 (1H, s), 7.92 (1H, t, J = 8.0 Hz), 7.78 (1H, m), 7.71 (1H, d, J = 8.0
Hz), 7.58ꢀ7.64 (2H, m), 7.52ꢀ7.56 (6H, m), 7.25ꢀ7.39 (6H, m), 7.15 (1H,
t, J= 8.0 Hz), 7.04 (2H, m), 6.92 (1H, m). δC (100 MHz, DMSOꢀd6):
187.3, 155.6, 154.4, 146.5, 145.7, 137.2, 134.3, 133.2, 131.8, 131.7,
129.1, 128, 127.2, 124.2, 124.2, 123.2, 123.0, 121.5, 118.4, 117.2, 111.7,
87.5, 57.8. Anal (C24H16BrNO2) Calcd C: 66.99, H: 3.75, N: 3.26; found,
C: 66.72, H: 3.53, N: 3.11.
2ꢀbenzylꢀ3ꢀ(thiophenꢀ2ꢀyl)isoindolinꢀ1ꢀone (2m):29 sticky liquid (120
mg, 79%). δH (400MHz, CDCl3): 7.92ꢀ7.96 (m, 1H), 7.46ꢀ7.51 (m, 2H),
7.23ꢀ7.33 (m, 7H), 7.00ꢀ7.04 (m, 2H), 5.57 (s, 1H), 5.40 (d, 1H, J = 14.8
Hz), 3.89 (d, 1H, J = 14.8 Hz). δC (100MHz, CDCl3): 167.9, 145.5, 139.9,
137.1, 131.7, 131.0, 128.6, 128.5, 128.3, 127.6, 127.5, 126.8, 126.6,
123.8, 123.1, 58.7, 43.5.
2ꢀphenylꢀ3ꢀ(2,4,6ꢀtrimethoxyphenyl)isoindolinꢀ1ꢀone (2d): White solid
(146mg, 78%). δH (400MHz, DMSOꢀd6): 7.74 (1H, d, J=8.0 Hz ), 7.54
(2H, d, J=8.0 Hz), 7.50ꢀ7.42 (2H, m), 7.25 (2H, t, J=8.0 Hz), 7.16 (1H, d,
J=8.0 Hz), 7.00 (1H, t, J=7.8 Hz), 6.71 (1H, s), 6.26 (1H, d, J=4.0 Hz),
5.91 (1H, d, J=4.0 Hz), 3.93 (3H, s), 3.65 (3H, s), 3.18 (3H, s). δC
(100MHz, DMSOꢀd6): 167.4, 161.5, 159.9, 159.8, 146.1, 138.4, 132.9,
132.4, 128.9, 128.3, 124.5, 123.2, 122.6, 122.1, 104.8, 100.0, 92.5, 91.5,
57.1, 56.2, 55.6. Anal. (C23H21NO4) Calcd, C: 73.58, H: 5.64, N: 3.73;
found, C: 73.41, H: 5.76, N: 3.56.
9
2ꢀ(3,5ꢀdimethylphenyl)ꢀ3ꢀ(5ꢀnitroꢀ1Hꢀindolꢀ2ꢀyl)isoindolinꢀ1ꢀone (2e):
Green Solid (150mg, 76%), mp 245ꢀ248 οC; δH (400 MHz, DMSOꢀd6):
10.90 (NH, s), 8.02 (1H, s), 7.65 (2H, t), 7.90 (1H, s), 7.60 (2H, t), 7.52
(1H, d), 7.42 (1H, t), 7.39 (2H, s), 6.85 (1H, s), 6.69 (1H, s), 2.16 (6H, s).
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17
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19
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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
δ
C (100 MHz, DMSOꢀd6): 166.7, 146.2, 141.0, 140.1, 138.0, 137.6, 133.2,
2ꢀbenzylꢀ3ꢀ(2,4,6ꢀtrimethoxyphenyl)isoindolinꢀ1ꢀone (2n):29 white solid
(169 mg, 87%). δH (400MHz, DMSOꢀd6): 7.68 (1H, d, J=8.0 Hz), 7.44ꢀ
7.37 (2H, m), 7.25ꢀ7.16 (3H, m), 7.08ꢀ7.02 (3H, m), 6.28 (1H, d, J=4.0
Hz), 6.03 (1H, d, J=4.0 Hz), 5.84 (1H, s), 4.89 (1H, d, J=16.0 Hz), 3.73
(3H, s), 3.67 (3H, s), 3.17 (3H, s). δC (100MHz, DMSOꢀd6): 168.0, 161.8,
160.3, 147.0, 138.2, 132.8, 131.7, 128.8, 128.2, 127.9, 127.5, 122.9,
122.4, 103.4, 92.2, 91.4, 56.6, 56.0, 55.7, 54.6, 43.8. Anal Calcd for
C24H23NO4: C, 74.02, H, 5.95; N, 3.60; found, C, 73.92, H, 5.75; N, 3.42.
3ꢀ(2ꢀbenzylꢀ3ꢀoxoisoindolinꢀ1ꢀyl) pentaneꢀ2,4ꢀdione (2o):25b sticky
liquid (120 mg, 75%). δH (400MHz, CDCl3): 7.95 (d, J= 7.0 Hz, 1H), 7.53
(quint, J=7.8 Hz, 2 H), 7.22–7.35 (m, 6 H), 5.43 (d, J=14.8 Hz, 1 H), 5.24
(s, 1 H), 3.94 (d, J=14.6 Hz, 1 H), 1.81 (s, 3H), 1.42 (s, 3 H). δC (100MHz,
DMSOꢀd6): 197.4, 190.2, 168.6, 145.0, 136.9, 132.5, 132.0, 129.2, 128.9,
128.2, 127.9, 124.2, 122.1, 104.9, 57.6, 43.6, 24.2, 22.1.
2ꢀbenzylꢀ3ꢀisopropoxyisoindolinꢀ1ꢀone (2p):29 liquid (96 mg, 69%). δH
(400MHz, CDCl3): 7.85 (1H, d, J = 7.4 Hz), 7.48ꢀ7.57 (3H, m), 7.26ꢀ7.31
(5H, m), 5.64 (1H, s), 5.27 (1H, d, J = 15.0 Hz), 4.25 (1H, d, J = 15.0 Hz),
3.64 (1H, septet, J = 6.0 Hz), 1.21 (3H, d, J = 6.0 Hz), 1.07 (3H, d, J = 6.2
Hz). δC (54.6MHz, CDCl3): 167.3. 142.2, 137.0, 132.3, 131.9, 129.7,
128.7, 128.4, 128.2, 127.5, 123.5, 85.2, 68.7, 43.1, 23.7, 23.4.
2ꢀbenzylꢀ3ꢀ((4ꢀmethoxyphenyl)thio)isoindolinꢀ1ꢀone (2q):29 liquid (131
mg, 73%). Yield: δH (400MHz, CDCl3): 7.58ꢀ7.59 (2H, m), 7.52 (1H, t, J
= 7.6 Hz), 7.26ꢀ7.36 (6H, m), 6.94 (2H, d, J = 8.4 Hz), 6.57 (2H, d, J = 8.4
Hz), 5.44 (1H, d, J = 14.8 Hz), 5.40 (1H, s), 4.55 (1H, d, J = 14.4 Hz),
3.68 (3H, s). δC(100MHz, CDCl3): 167.3, 160.4, 143.0, 137.2, 136.7,
131.5, 128.7, 128.5, 128.4, 127.6, 123.7, 123.3, 117.7, 114.1, 65.7, 55.1,
43.0.
131.4, 130.4, 129.3, 126.9, 124.7, 123.8, 121.3, 117.2, 115.5, 113.6,
113.0, 58.4, 21.4. HRMS (ESI) calcd for C24H19N3O3 [M+H]+ = 398.1499,
found 398.1503.
2ꢀ(3,5ꢀdimethylphenyl)ꢀ3ꢀ(5ꢀmethoxyꢀ1Hꢀindolꢀ3ꢀyl)isoindolinꢀ1ꢀone
(2f): White solid (156mg, 82%), mp 204ꢀ207 C; δH (400 MHz, DMSOꢀ
ο
d6): 10.60 (1H, d), 7.61 (1H, d, J=4.0 Hz), 7.27 (2H, m), 7.03 (3H, d,
J=8.0 Hz), 6.89 (1H, dd, J=8.0 Hz), 6.43 (2H, d, J=8.0 Hz), 6.35 (1H, d,
J=8.0 Hz), 5.95 (1H, s), 3.23 (3H, s, OMe, merge with DMSO water),
1.90 (6H, s). δC (100 MHz, DMSOꢀ d6): 166.6, 153.1, 146.3, 137.6, 132.8,
131.9, 131.3, 128.6, 126.8, 126.4, 125.4, 123.6, 123.1, 120.9, 112.6,
110.8, 109.7, 100.7, 59.09, 55.3, 21.2. Anal(C25H22N2O2) Calcd, C: 78.51,
H: 5.80, N: 7.32; found, C: 78.31, H: 5.71, N: 7.21.
3ꢀ(1ꢀbenzylꢀ1Hꢀindolꢀ2ꢀyl)ꢀ2ꢀ(3,5ꢀdimethylphenyl)isoindolinꢀ1ꢀone
(2g): White Solid (182mg, 82%). mp 188ꢀ192 C; δH (400 MHz, DMSOꢀ
ο
d6): 7.86ꢀ7.84 (1H, m), 7.78 (1H, s), 7.57ꢀ7.51 (2H, m), 7.33ꢀ7.26 (4H, m)
, 7.19ꢀ7.18 (3H, t, J = 4 Hz), 6.98ꢀ6.89 (3H, m), 6.82ꢀ6.68 (4H, m), 5.33
(2H, s), 2.13 (6H, s); δC (100MHz, DMSOꢀd6): 166.8, 146.4, 144.9, 138.5,
138.1, 137.9, 137.7, 136.9, 133.0, 131.7, 129.0, 128.9, 127.8, 127.2,
126.5, 125.8, 124.1, 123.8, 123.6, 121.9, 123.3, 120.9, 120.7, 119.8,
118.9, 111.1, 110.1, 59.2, 49.3, 21.5. HRMS (ESI) calcd for C31H26N2O
[M+H]+ = 443.2079, found 443.2043.
3ꢀ(1ꢀallylꢀ1Hꢀindolꢀ2ꢀyl)ꢀ2ꢀ(3,5ꢀdimethylphenyl)isoindolinꢀ1ꢀone (2h):
White Crystalline solid (160mg, 82%). δ H (400 MHz, CDCl3): 8.02 (1H,
dd, J=8.0 Hz), 7.51ꢀ7.45 (2H, m), 7.30 (1H, d, J=8.0 Hz), 7.25 (1H, s),
7.20 (1H, d, J=8.0 Hz), 7.13ꢀ7.04 (5H, m), 6.92 (1H, t, J=8.0 Hz), 6.71
(1H, s), 6.32 (1H, s), 5.93ꢀ5.86 (1H, m), 5.11 (1H, d, J=12 Hz), 4.82 (1H,
d, J=12 Hz), 4.62 (2H, d, J=4 Hz), 2.20 (6H, s), δC (100MHz, CDCl3):
167.7, 145.9, 138.2, 137.4, 136.9, 133.2, 132.3, 131.8, 128.5, 127.9,
127.3, 126.0, 124.0, 123.2, 122.1, 121.8, 119.8, 119.5, 117.2, 110.7,
109.8, 60.1, 48.6, 21.4. Anal. (C27H24N2O) calcd, C: 82.62, H: 6.16, N:
7.14; found, C: 82.75, H: 6.48, N: 7.34.
2ꢀbenzylꢀ3ꢀ(5ꢀmethylthiophenꢀ2ꢀyl)isoindolinꢀ1ꢀone (2r):29 White solid
ο
(121 mg, 76%). mp 103ꢀ108 C; δH (400MHz, DMSOꢀd6): 7.74 (1H, d,
J=8.0 Hz), 7.55ꢀ7.48 (2H, m), 7.30ꢀ7.22 (4H, m), 7.13 (2H, d, J=8.0 Hz),
7.01 (1H, s), 6.68 (1H, s,), 5.72 (1H, s), 5.03 (1H, d, J=16 Hz), 3.92 (1H,
d, J=16Hz), 2.32 (3H, s). δC (100MHz, DMSOꢀd6): 168.0, 146.5, 141.2,
138.1, 137.6, 132.7, 130.9, 129.1, 128.2, 125.8, 124.2, 123.5, 59.3, 43.7,
15.9.
2ꢀ(3,5ꢀdimethylphenyl)ꢀ3ꢀ(1Hꢀindolꢀ2ꢀyl)isoindolinꢀ1ꢀone (2i): White
crystalline solid (147mg, 84%). mp 236ꢀ238 C; δH (400MHz, CDCl3):
ο
8.01 (1H,m), 7.52ꢀ7.44 (2H, m), 7.32ꢀ7.25 (3H, m), 7.16ꢀ7.08 (5H, m),
6.96ꢀ6.92 (1H, t, J=4.0 Hz), 6.71 (1H, s), 5.84 (1H, s), 6.36 (1H, s), 2.19
(6H, s). δC (100MHz, CDCl3): 138.2, 137.3, 136.6, 132.3, 131.7, 128.5,
127.3, 124.0, 123.1, 121.7, 120.1, 120.1, 119.2, 111.4, 77.4, 77.1, 76.6,
76.6, 59.9, 43.5, 21.4.Anal (C24H20N2O) Calcd; C: 81.79, H: 5.72, N: 7.95;
found C: 81.62, H: 5.53, N: 7.68.
3ꢀallylꢀ2ꢀbenzylisoindolinꢀ1ꢀone (2j):25b White crystalline solid (75 mg,
64%). δH (200MHz, CDCl3): 7.87ꢀ7.91 (1H, m), 7.22ꢀ7.55 (8H, m), 5.42
(1H, d, J = 15.2 Hz), 5.24ꢀ5.41 (1H, m), 4.96ꢀ5.07 (2H, m), 4.42 (1H, t, J
= 5.2 Hz), 4.17 (1H, d, J = 15.2 Hz), 2.56ꢀ2.80 (2H, m). δC (54.6 MHz,
CDCl3): 168.5, 144.9, 137.1, 132.3, 131.4, 131.2, 128.8, 128.1, 127.6,
123.8, 122.4, 119.3, 58.0, 43.9, 35.2.
2ꢀbenzylꢀ3ꢀ(2ꢀhydroxynaphthalenꢀ1ꢀyl)isoindolinꢀ1ꢀone (2s): White
crystalline solid (116 mg, 64%). δH (400MHz, DMSOꢀd6): 10.31 (1H, s),
7.88 (1H, d, J = 8 Hz), 7.78 (1H, d, J=8 Hz), 7.72 (1H, d, J = 8 Hz), 7.52ꢀ
7.44(2H, m), 7.28 (1H, d, J=8 Hz), 7.21ꢀ7.15 (3H, m), 7.12ꢀ7.04 (6H, m),
6.74 (1H, d, J = 8 Hz), 6.56 (1H, s), 4.94 (1H, d, J = 16 Hz), 3.63 (1H, d,
J = 16 Hz ). δC (100MHz, DMSOꢀd6): 168.1, 156.1, 147.2, 137.8, 132.8,
132.7, 132.2, 129.4, 128.8, 128.2, 127.6, 127.0, 123.8, 123.3, 123.0,
121.7, 118.5, 111.0, 87.2, 56.3. HRMS (ESI) calcd for C25H19NO2
[M+H]+ = 366.1449, found 366.1437.
2ꢀbenzylꢀ3ꢀ(1Hꢀindolꢀ2ꢀyl)isoindolinꢀ1ꢀone (2t):25b White solid (153 mg,
91%). mp 199ꢀ203 οC; δH (400MHz, DMSOꢀd6): 11.22 (1H, s), 7.81 (1H,
d, J = 8 Hz), 7.53 (1H, s), 7.48 (2H, d, J = 8 Hz), 7.34ꢀ7.20 (5H, m), 7.12
(2H, d, J = 8 Hz), 7.02 (1H, t), 6.98 (1H, t, J = 8.2 Hz), 6.72 (1H, t, J =
8.2 Hz), 6.52 (1H, s), 5.72 (1H, d), 4.99 (1H, d, J = 16 Hz), 3.76 (1H, d, J
= 16Hz ). δC (100MHz, DMSOꢀd6): 167.6, 146.9, 138.1, 137.5, 132.4,
131.8, 129.1, 128.8, 128.0, 127.6, 124.1, 123.3, 121.9, 119.5, 118.4,
112.5, 109.1, 57.9, 44. Anal. (C23H18N2O) calcd, C: 81.63, H: 5.36, N:
8.28; found, C: 81.32, H: 5.62, N: 8.35.
3ꢀ(5ꢀbromoꢀ1Hꢀindolꢀ2ꢀyl)ꢀ2ꢀ(4ꢀbromophenyl)isoindolinꢀ1ꢀone (2k):
White Crystalline solid, ( 173 mg, 72%). mp 294ꢀ297 C; δH (400 MHz,
ο
DMSOꢀd6): 11.27 (1H, NH, s), 7.89 (1H, d, J = 8 Hz), 7.63ꢀ7.56 (5H, m),
7.44 (2H, d, J = 12 Hz), 7.26 (2H, dd, J = 8 Hz), 7.06 (1H, d, J = 8 Hz),
6.90 (1H, s), 6.77 (1H, s); δC (100 MHz, DMSOꢀd6): 166.9, 146.3, 137.3,
135.8, 133.4, 131.8, 131.1, 129.2, 128.3, 126.9, 125.0, 124.4, 123.9,
120.5, 117.4, 114.5, 112.1, 109.9, 58.9. Anal (C22H14Br2N2O) Calcd C:
54.80, H: 2.93, Br: 33.14, N: 5.81, O: 3.32. HRMS (ESI) calcd for
C22H14Br2N2O [M+H]+ = 482.9530, found 482.9541.
2ꢀbenzylꢀ3ꢀ(5ꢀmethoxyꢀ1Hꢀindolꢀ2ꢀyl)isoindolinꢀ1ꢀone (2u): White
ο
solid ( 169 mg, 92%). mp 118ꢀ120 C; δH (400MHz, DMSOꢀd6): 11.05
(1H, s), 7.82 (1H, q, J = 8 Hz ), 7.50 (3H, q, J = 8 Hz), 7.35ꢀ7.23 (6H, m),
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7.13 (2H, d, J = 8 Hz), 6.66 (1H, dd, J = 8 Hz), 5.71 (1H, s), 5.0 (1H, d, J
= 16 Hz), 3.79 (1H, d, J = 16 Hz), 3.35 (3H, s). δC (100MHz, DMSOꢀd6):
167.6, 153.5, 142.2, 138.3, 132.5, 132.4, 131.9, 129.0, 128.8, 128.0,
127.6, 124.2, 123.2, 113.1, 111.4, 100.8, 57.2, 55.4, 43.4. Anal Calcd for
C24H20N2O2 C, 78.24; H, 5.47; N, 7.60; found, C, 78.15; H, 5.35; N, 7.29.
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2ꢀbenzylꢀ3ꢀ(5ꢀnitroꢀ1Hꢀindolꢀ2ꢀyl)isoindolinꢀ1ꢀone (2v): White solid
(120 mg, 63%). mp 225ꢀ227 οC; δH (400MHz, Acetoneꢀd6): 11.08 (NH, s),
7.97ꢀ7.91 (2H, m), 7.80 (1H, s), 7.65 (1H, s), 7.58ꢀ7.49 (4H, m), 7.30ꢀ7.28
(1H, d, J = 8 Hz), 7.21ꢀ7.14 (4H, m), 5.85 (1H, s), 5.09 (1H, d, J = 16
Hz), 4.03 (1H, d, J = 16 Hz); δC (100MHz, Acetoneꢀd6): 167.3, 146.1,
140.5, 137.9, 132.0, 131.9, 128.6, 128.4, 128.1, 127.1, 123.5, 123.2,
117.2, 115.5, 113.1, 112.2, 87.2, 57.01, 43.6. Anal Calcd for C23H17N3O3
C, 72.05; H, 4.47; N, 10.96; found, C, 71.92; H, 4.35; N, 10.82.
Chem. Res. 2011, 45, 565ꢀ577. (c) Rueping M.; Nachtsꢀ
heim, B. J.; Beilstein, J. Org. Chem. 2010, 6, 6. DOI:
10.3762/bjoc.6.6 and references Therein
3
(a) Akiyama, T.; & Mori, K. Chem. Rev. 2015,
115, 9277ꢀ9306. (b) Parmar, D.; Sugiono, E.; Raja, S.; &
Rueping, M. Chem. Rev. 2014, 114, 9047ꢀ9153
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2ꢀbenzylꢀ3ꢀ(5ꢀbromoꢀ1Hꢀindolꢀ2ꢀyl)isoindolinꢀ1ꢀone (2w): White solid
(150 mg, 72%). mp 205ꢀ207 οC; δH (400MHz, Acetoneꢀd6): 10.62 (NH, s),
7.89 (1H, dd, J = 8 Hz), 7.59 (1H, s), 7.55ꢀ7.48 (2H, m), 7.39ꢀ7.37 (1H, d,
J = 8 Hz), 7.27ꢀ7.14 (7H, m), 6.81 (1H, s), 5.72 (1H, s), 5.15 (1H, d, J =
16 Hz), 3.88 (1H, d, J = 16 Hz); δC (100MHz, Acetoneꢀd6): 167.8, 146.4,
138.0, 136.2, 132.1, 131.9, 128.5, 128.0, 127.2, 124.6, 123.6, 123.1,
120.9, 113.8, 112.2, 109.9, 57.2, 48.9, 43.3.Anal Calcd for C23H17BrN2O
C, 66.20; H, 4.11; N, 6.71; found, C, 66.05; H, 4.22; N, 6.52.
4
(a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817ꢀ
7831. (b) Yamamoto, Y.; Patel N. T. Chem. Rev. 2008,
108, 3395ꢀ3442.
5
Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38,
2745–2755.
6
Matsunaga, S.; Shibasaki, M. Chem. Commun.,
ASSOCIATED CONTENT
Supporting Information
2014, 50, 1044ꢀ1057 and references therein.
7
Glorius, F. E. N-Heterocyclic Carbenes in Transi-
Procedural, spectral, biological data, optimized coordinates, geꢀ
ometries including frequency data in Supporting Information (SI).
Crystallographic cif files (CCDC Nos. 1501922 and 1506191) are
available at www.ccdc.cam.ac.uk/data_request/cif or as part of the
Supporting Information (SI). “This material is available free of
charge via the Internet at http://pubs.acs.org.”
tion Metal Catalysis (SpringerꢀVerlag, 2007), 1ꢀ229.
8
Denard, C. A.; Huang, H.; Bartlett, M. J.; Lu, L.;
Tan, Y.; Zhao, H.; Hartwig, J. F. Angew. Chem. Int. Ed.
2013, 52, 1–6
Corresponding Author
9
Chen, Z. S.; Huang, L. Z.; Jeon, H. J.; Xuan, Z.;
*Department of Chemical Sciences, Tezpur University, Napaam,
Tezpur, Assam, India, 784028
Email: spratihar@tezu.ernet.in or spratihar29@gmail.com.
Lee, S. ACS Catal. 2016, 6, 4914−4919.
10
Xiao, Y. P.; Liu, X. Y.; Che, C. M. Beilstein J.
Org. Chem. 2011, 7, 1100–1107.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
11
(a) Hashmi, A. S. K.; Toste, F. D., Eds.; Wileyꢀ
VCH: Weinheim, Germany, 2012. (b) Fürstner, A. Chem.
Soc. Rev. 2009, 38, 3208–3221.
ACKNOWLEDGMENT
12
Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.;
Financial support of this work by DSTꢀNew Delhi (to SP for
INSPIRE grant no. IFAꢀ12/CHꢀ39) is gratefully acknowledged.
We thank all the anonymous reviewers, who assisted us with
many useful suggestions and brought about a new look to the
original submission. SP is highly grateful to Professor M. K.
Chaudhuri for all the help, support and inspiration.
Gooßen, L. J. Chem. Rev. 2015 115, 2596ꢀ2697.
13
Shen, Z. L.; Wang, S. Y.; Chok, Y. K.; Xu, Y. H.;
Loh, T. P. Chem. Rev. 2013, 113, 271ꢀ401.
14
Zheng, Q. Z.; Liang, Y. F.; Qina, C.; Jiao, N.
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Please see Table S1 for details in SI.
33
In presence of added PPh3 or COD or BPy in 1:2
22
combination with PdCl2(MeCN)2 and AgPF6, model reacꢀ
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