Diastereoselective Synthesis of Oxazoloisoindolinones via Cascade Pd-Catalyzed ortho-Acylation of N-Benzoyl α-Amino Acid Derivatives and Subsequent Double Intramolecular Cyclizations

Article abstract of DOI:10.1021/acs.joc.8b02509

The first cascade diastereoselective synthesis of oxazoloisoindolinones via the palladium-catalyzed decarboxylative ortho-acylation of N-benzoyl α-amino acid derivatives followed by double intramolecular cyclizations has been demonstrated. This reaction, using α-amino acids as directing groups and α-oxocarboxylic acids as the acylation source, features a broad substrate scope, good functional group tolerance, high regioselectivity, and excellent diastereoselectivity.

Full text of DOI:10.1021/acs.joc.8b02509

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Article
Diastereoselective Synthesis of Oxazoloisoindolinones via
Cascade Pd-Catalyzed ortho-Acylation of N-Benzoyl #-Amino Acid
Derivatives and Subsequent Double Intramolecular Cyclizations
Kun Jing, Xiang-Nan Wang, and Guan-Wu Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02509 • Publication Date (Web): 04 Dec 2018
Downloaded from http://pubs.acs.org on December 4, 2018
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Diastereoselective Synthesis of Oxazoloisoindolinones via
Cascade Pd-Catalyzed ortho-Acylation of N-Benzoyl α-Amino
Acid Derivatives and Subsequent Double Intramolecular
Cyclizations
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†
†
,†,‡
Kun Jing, Xiang-Nan Wang, and Guan-Wu Wang*
†CAS Key Laboratory of Soft Matter Chemistry, Collaborative Innovation Center of
Chemistry for Energy Materials (iChEM), Hefei National Laboratory for Physical
Sciences at Microscale, and Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, P. R. China
E-mail: gwang@ustc.edu.cn;
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, P. R. China
ABSTRACT
O
R2
R2
O
H
O
Pd(OAc)2
OH
N
K S O , PTSA
N
COOH
2
2
8
R1
+ R3
R1
H
O
o
O
DCE, 70 C, 12 h
O
R3
large-scale synthesis
broad substrate scope
high regioselectivity
(rac)
36 examples
excellent diastereoselectivity
cis isomer, dr > 99:1
up to 91% yield
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The first cascade diastereoselective synthesis of oxazoloisoindolinones via the
palladium-catalyzed decarboxylative ortho-acylation of N-benzoyl α-amino acid
derivatives followed by double intramolecular cyclizations has been demonstrated. This
reaction, using α-amino acids as directing groups and α-oxocarboxylic acids as the
acylation source, features broad substrate scope, good functional group tolerance, high
regioselectivity, and excellent diastereoselectivity.
0
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INTRODUCTION
Isoindolinones are an important subclass of nitrogen-containing heterocycles found in
natural products and biologically active compounds such as lennoxamine,1
2
3
pestalachloride, and pagoclone. Additionally, isoindolinone derivatives display
4
5
6
versatile biological activities including antihypertensive, antipsychotic, antitumoral,
7
and so on. Among them, oxazoloisoindolinones represent the core unit of a wide range
of promising bioactive compounds like antidiabetic agents, antitumor agents, and
8
cancer drug candidates SLMP53-1/DIMP53-1 (Figure 1). Oxazoloisoindolinones
bearing the bicyclic lactam and N,O-acetal moiety have proven to be exceptional
building blocks for the asymmetric construction of various natural and unnatural
carbocyclic and heterocyclic compounds containing one or more stereogenic centers.9
Given the widespread utility of oxazoloisoindolinones, it is not surprising that a variety
of methods have been developed for their synthesis. The early employed methods for
the synthesis of oxazoloisoindolinones were the cyclodehydration process between
1
0
amino alcohols and ketoacids under azeotropic removal of water and the reaction of
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N-(2-bromoethyl)phthalimide with organolithiums or Grignard reagents. In 1997, the
Shim group developed the palladium-catalyzed stereoselective synthesis of
oxazoloisoindolinones via carbonylative cyclization between 2-bromobenzaldehyde
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and amino alcohols. Another approach is the intramolecular cationic cyclization with
1
3
N-acyliminium species. However, from a synthetic point of view, these methods
suffer from some intrinsic drawbacks including poor functional group tolerance, harsh
reaction conditions, bad stereoselectivity, and the requirement of prefunctionalization
of the coupling partners. Therefore, it is highly desirable to develop novel and efficient
protocols with fewer synthetic steps and better stereoselectivity for the synthesis of
oxazoloisoindolinones.
O
O
N
NH
O
N
O
O
N
N
H
NH
O
R
N
O
N
O
N
SLMP53-1 (R = H)
DIMP53-1 (R = Bn)
antidiabetic agent
antitumor agent
Figure 1. Representative bioactive oxazoloisoindolinones
The transition-metal-catalyzed C−H bond activation/cyclization reactions have
been recognized as one of the most powerful methods for the construction of
heterocycles in modern synthetic organic chemistry due to their practical and
14
environment-friendly properties. In 2012, Kim and co-workers reported the tandem
Rh(III)-catalyzed ortho-acylation and intramolecular cyclization of secondary
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benzamides and aryl aldehydes to synthesize 3-hydroxylisoindolinones. Soon after, a
more efficient approach to 3-hydroxylisoindolinones was realized by Zhao and co-
workers via the Pd-catalyzed C−H activation/annulation reaction of secondary
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benzamides and aldehydes. In our previous work of the Pd-catalyzed decarboxylative
ortho-acylation of benzamides with α-oxocarboxylic acids,17 when secondary
benzamides were employed as the substrates, the formed ortho-acylated benzamides
underwent further intramolecular cyclization to provide similar hydroxylisoindolinone
derivatives. However, to the best of our knowledge, further cyclization utilizing the
reactive hydroxyl to construct tricyclic isoindolinone derivatives has not been reported
yet now.
Amino acid derivatives are widespread and structurally diverse in natural products,
and functionalized molecules bearing amino acid moieties are of interest as potential
bioactive substrates.18 More recently, pioneering work utilizing environmentally
friendly and inexpensive amino acid moieties as novel directing groups in C
−H
activation for the modification of amino acid derivatives has been realized by the
1
9
Chatani, Yu, and Hong groups, respectively. The special structure of amino acid made
itself a feasible directing group without the necessity of being removed, and the
products were very useful building blocks for assembling bioactive molecules. In 2016,
Liu and co-workers disclosed the Pd-catalyzed alkoxylation of N-benzoyl α-amino acid
derivatives at room temperature.20 With our continuing interest in developing more
C−H bond activation protocols,14a,14c,17,21 herein we present the first one-step
diastereoselective synthesis of oxazoloisoindolinones via cascade Pd-catalyzed
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decarboxylative ortho-acylation of N-benzoyl α-amino acid derivatives and subsequent
double intramolecular cyclizations.
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RESULTS AND DISCUSSION
In our initial investigation, when racemic N-benzoyl-DL-valine (1a) and
phenylglyoxylic acid (2a) were conducted under our previous conditions (10 mol
%
Pd(OAc) as the catalyst, 2.0 equiv of K S O as the oxidant, 0.5 equiv of p-
2 2 2 8
toluenesulfonic acid (PTSA) as the additive, and 1,2-dichloroethane (DCE) as
1
7
the solvent), the desired product 3aa was successfully isolated in 67% yield
o
after 12 h at 70 C (Table 1, entry 1). Solvent screening showed that DCE was
the optimal solvent compared to other solvents such as CH CN, toluene, 1,4-
3
dioxane, hexafluoroisopropanol (HFIP), and N,N-dimethylformamide (DMF)
(Table 1, entries 2−6). When PTSA was replaced with other acids including
trifluoacetic acid (TFA), acetic acid (AcOH), methanesulfonic acid (CH SO H),
3
3
D-camphorsulfonic acid (D-CSA), or trifluoromethanesulfonic acid (TfOH), the
yield of 3aa was reduced (Table 1, entries 7−11). Other persulfate oxidants
including Na S O , (NH ) S O , and Oxone were inferior to K S O and other
2
2
8
4 2
2
8
2
2
8
types of oxidants such as Ag CO , Cu(OAc) , and 1,4-benzoquinone (BQ) failed
2
3
2
to provide the desired product, which indicated the superiority of K S O for
2
2
8
decarboxylation in our catalyst system (Table 1, entries 12−17). Other palladium
catalysts were also examined, and the results showed that Pd(TFA) could afford
2
the desired product 3aa albeit in a slightly lower yield, whereas using
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Pd(CH CN) Cl or Pd(PhCN) Cl as the catalysts gave only trace amount of 3aa
3
2
2
2
2
(
Table 1, entries 18−20). Increasing the amount of K S O from 2.0 to 2.5 equiv.
2 2 8
resulted in a better yield of 73%, but further increase to 3.0 equiv. gave a worse
result (Table 1, entries 21 and 22). Similarly, when the amount of PTSA was
increased from 0.5 equiv. to 1.0 equiv. and 1.5 equiv., 3aa was obtained in 80%
and 84% yields, respectively, while further increasing to 2.0 equiv. gave a lower
yield (Table 1, entries 23−25). Then the reaction temperature was examined,
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o
decreasing the temperature from 70 C to 60 C or increasing the temperature to
o
80 C both reduced the yield slightly (Table 1, entries 26 and 27). When the
reaction time was shortened to 10 h, the desired product 3aa was obtained in only
75% yield, and prolonging the reaction time to 14 h had no further improvement
of the yield (Table 1, entries 28 and 29). Control experiment revealed that PTSA
was essential for this reaction (Table 1, entry 30). PTSA may tune the
electrophilicity of the Pd(II) center and promote the insertion of Pd(II) into the
aromatic C−H bonds.22 On the other hand, PTSA may favor the second
2
3
intramolecular cyclization process to generate the desired lactone. Therefore,
the optimized reaction conditions were as follows: 10 mol % Pd(OAc) as the
2
catalyst, 2.5 equiv. of K S O as the oxidant, 1.5 equiv. of PTSA as the additive,
2
2
8
o
and 2.0 equiv. of 2a as the partner of 1a. The reaction performed best at 70 C
for 12 h with DCE as the solvent.
Table 1. Optimization of the Reaction Conditionsa
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O
O
O
catalyst
oxidant, additive
solvent, 70 oC, 12 h
N
OH
+
N
COOH
O
O
H
O
(rac)
1a
2a
3aa
1
1
1
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1
1
1
1
2
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2
2
2
2
2
2
2
2
3
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3
3
3
3
3
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0
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0
entry catalyst (10 mol %) oxidant (equiv)
additive (equiv)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
TFA (0.5)
solvent
DCE
yield (%)b
1
2
3
4
5
6
7
8
9
Pd(OAc)2
K S O (2.0)
67
0
2
2
8
Pd(OAc)2
K S O (2.0)
2
2
8
CH CN
3
Pd(OAc)2
K S O (2.0)
Toluene
1,4-dioxane
HFIP
DMF
DCE
31
56
45
0
2
2
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
K S O (2.0)
2 2 8
K S O (2.0)
2
2
8
K S O (2.0)
2
2
8
K S O (2.0)
8
2
2
8
K S O (2.0)
AcOH (0.5)
CH SO H (0.5)
DCE
trace
44
trace
47
7
2
2
8
K S O (2.0)
DCE
2
2
8
3
3
1
0
1
2
3
K S O (2.0)
D-CSA (0.5)
TfOH (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
DCE
2
2
8
1
1
1
K S O (2.0)
DCE
2
2
8
Na S O (2.0)
DCE
2
2
8
(NH ) S O (2.0)
DCE
63
27
0
4 2
2
8
14
Oxone (2.0)
DCE
1
1
1
1
5
6
7
8
Ag CO (2.0)
DCE
2
3
Cu(OAc) (2.0)
DCE
0
2
BQ (2.0)
DCE
0
K S O (2.0)
DCE
54
2
2
8
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Pd(CH CN) Cl
K S O (2.0)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (0.5)
PTSA (1.0)
PTSA (1.5)
PTSA (2.0)
PTSA (1.5)
PTSA (1.5)
PTSA (1.5)
PTSA (1.5)
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
trace
trace
73
3
2
2
2
2
8
2
2
0
1
Pd(PhCN) Cl
K S O (2.0)
2 2 8
2
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K S O (2.5)
2 2 8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
K S O (3.0)
66
2
2
8
2
3
K S O (2.5)
80
2
2
8
24
K S O (2.5)
84
2
2
8
2
5
K S O (2.5)
78
2
2
8
2
6c
27d
8e
29f
K S O (2.5)
71
2
2
8
K S O (2.5)
79
2
2
8
2
K S O (2.5)
75
2
2
8
K S O (2.5)
83
2
2
8
3
0
K S O (2.5)
trace
2
2
8
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst (0.03 mmol),
b
c
oxidant, additive, solvent (3 mL), 70 °C, 12 h. Isolated yields based on 1a. 60
d
e
f
°
C. 80 °C. 10 h. 14 h.
Having established the optimal reaction conditions, the substrate scope of
N-benzoyl α-amino acid derivatives was investigated, and the results are shown
in Table 2. Generally, various substituents on either the α-amino acid moiety or
the aromatic ring were well tolerated to afford the corresponding products in
moderate to excellent yields. α-Mono-substituted amino acid derivatives 1b−e
proceeded smoothly to give products 3ba−ea in 51−73% yields, and the desired
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product 3fa was obtained in 56% yield when R was the phenyl group. α-Di-
substituted amino acid derivative 1g gave the corresponding product 3ga in 55%
yield. To our satisfaction, cyclic amino acid derivatives 1h and 1i also worked
well under our optimal conditions, providing products 3ha and 3ia in 67% and
1
1
1
1
1
1
1
1
1
1
2
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
6% yields, respectively. The functional group tolerance of the aromatic ring was
also explored. To our delight, either electron-rich or electron-deficient group-
substituted amino acid derivatives were well tolerated with our optimized
conditions. Substrates 1j−l with para-substituted electron-donating groups gave
the corresponding oxazoloisoindolinones 3ja−la in good to high yields of
7
4−91%. This reaction was also compatible with α-amino acids bearing halogen
substituents on the phenyl ring and furnished products 3ma−oa in high yields of
9−90%. Particularly noteworthy was the tolerance of the reaction conditions to
7
chloro and bromo atoms, which provide a versatile synthetic handle for further
functionalization of the products. Substrates 1p and 1q with strong electron-
withdrawing groups (CF and NO ) proceeded well and delivered the desired
3
2
products 3pa and 3qa in 69% and 54% yields, respectively. In addition, the
cleavage of C−H bonds in meta-substituted substrates (1r−t) occurred
predominantly at the less hindered sites to give 3ra−ta in 61−82% yields with
excellent regioselectivities. What is more, this reaction could also be expanded
to ortho-substituted substrates and provided the desired products 3ua−xa in good
yields (62−78%). Finally, the α-amino acid derivatives bearing a disubstituted
benzoyl moiety proved to be feasible for this procedure and afforded the
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
corresponding products 3ya and 3za in 64% and 78% yields, respectively.
However, to our disappointment, N-benzoyl-DL-glycine was not compatible for
2
this reaction. When R was replaced with other functional groups such as OMe,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br, and CN, the corresponding substrates also failed to give the desired products,
probably due to their instability under our conditions. To demonstrate the
synthetic utility of this method, a large-scale reaction was conducted, and a
satisfactory yield of 73% for product 3ja was obtained under our optimized
reaction conditions.
Table 2. Scope of N-Benzoyl α-Amino Acid Derivativesa,b
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O
R2
O
R2
O
N
Pd(OAc)2
K2S2O8, PTSA
DCE, 70 oC, 12 h
OH
+
R1
N
H
COOH
O
R1
O
O
(rac)
1
a-z
2a
3aa-za
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
O
O
Ph
N
N
N
N
N
R
O
O
O
O
O
O
O
O
O
O
O
O
O
O
(
rac)
(rac)
(rac)
(rac)
(rac)
3
da, R = H, 63%
ea, R = Me, 51%c
O
3fa, 56%c
3
aa, 84%
3ba, 60%
3ca, 73%
3
O
N
O
O
N
O
O
N
O
O
N
O
N
O
O
O
O
O
(
rac)
(rac)
3ha, 67%d
3ia, 66%
3ja, 91% (73%)e
3ka, 74%
3ga, 55%
O
N
O
O
N
O
O
N
O
O
N
O
N
O
O
O
O
O
O
O
O
MeO
F
Cl
Br
F3C
(
rac)
(rac)
(rac)
(rac)
(rac)
3
la, 76%
3ma, 84%
3na, 90%
3oa, 79%
3pa, 69%
O
N
O
N
O
O
N
O
O
N
O
N
O
Cl
F3C
O
O
O
O
O
O N
2
(
rac)
(rac)
(rac)
(rac)
(rac)
3qa, 54%c
3ra, 74%
3sa, 82%
3ta, 61%
3ua, 77%
O
O
N
O
O
N
O
O
N
O
N
O
MeO
F
Cl
N
Cl
O
O
O
O
O
Cl
(
rac)
va, 62%c,d
(rac)
(rac)
(rac)
(rac)
3
3wa, 78%
3xa, 78%
3ya, 64%
3za, 78%
a
Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), Pd(OAc) (0.03 mmol),
2
o
b
K S O (0.75 mmol), PTSA (0.45 mmol), DCE (3 mL), 70 C, 12 h. Isolated
2
2
8
c
d
o
e
yields based on 1. 24 h. 80 C. 3.0 mmol scale.
1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Next, we investigated the reaction of representative racemic N-benzoyl α-
amino acid derivative 1j with a variety of α-oxocarboxylic acids 2b−k to further
explore the substrate scope and limitation, which demonstrated wide generality
and good yields, as depicted in Table 3. Phenylglyoxylic acids bearing electron-
rich or electron-deficient groups at the para-position proceeded smoothly and
provided the desired products 3jb−jd in 55−78% yields. Meta-substituted
phenylglyoxylic acids with different functional groups also worked well under
the optimal conditions, delivering the corresponding products 3je−jh in 58−81%
yields. The reaction could be extended to ortho-substituted phenylglyoxylic acids
to give oxazoloisoindolinones 3ji and 3jj in 75% and 60% yields, respectively.
The disubstituted phenylglyoxylic acids proved to be feasible for this procedure
and afforded product 3jk in 73% yield. Unfortunately, the attempt to extend the
substrates from aromatic oxocarboxylic acids to aliphatic oxocarboxylic acids
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(such as pyruvic acid) under our optimized conditions failed to give the desired
products.
Table 3. Scope of α-Oxocarboxylic Acidsa,b
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O
O
O
Pd(OAc)2
N
OH
K S O , PTSA
2
2
8
N
COOH
O
H
+
o
O
R
DCE, 70 C, 12 h
O
R
(rac)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1j
2b-k
3jb-jk
O
O
O
O
O
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
OMe
MeO
(rac)
F
(rac)
(
rac)
(rac)
(rac)
3
jb, 78%
3jc, 55%
3jd, 60%
3je, 75%
3jf, 69%
O
N
O
O
N
O
O
N
O
O
N
O
O
N
O
O
O
O
O
O
Cl
Br
CF3
Cl
Cl
(rac)
(rac)
(rac)
(rac)
(rac)
3
jg, 81%
3jh, 58%
3ji, 75%
3jj, 60%
3jk, 73%
a
Reaction conditions: 1j (0.3 mmol), 2 (0.6 mmol), Pd(OAc) (0.03 mmol), K S O
8
2
2
2
o
b
(
0.75 mmol), PTSA (0.45 mmol), DCE (3 mL), 70 C, 12 h. Isolated yields based on
1j.
To probe whether the chirality of α-amino acids could be efficiently
transferred to products, and hence facile access to chiral oxazoloisoindolinones
with two stereogenic centers, including a quaternary one, enantiomerically pure
N-benzoyl-L-alanine (L-1b) was employed under the same reaction conditions
used for the racemic substrate DL-1b (Scheme 1). To our great delight, the
reaction proceeded well to afford the corresponding chiral oxazoloisoindolinone
1
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3ba with excellent diastereomeric excess (>99%), guaranteeing the practical
importance of our method.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1. Determination of the Diastereoselectivity of Pure N-Benzoyl-L-
alanine
O
O
O
Pd(OAc)2
(R)N
(S)
OH
K S O , PTSA
2
2
8
N
COOH
O
H
+
o
O
DCE, 70 C, 12 h
O
L-1b
99% ee
2a
(3S,9bR)-3ba
>
61% yield
>
99% de
1
13
The structures of the obtained products 3 were identified by H NMR, C
NMR, and HRMS. Particularly, all products 3 were formed as a single
1
diastereoisomer by the analyses of their H NMR spectra. For products 3ra−ta,
3
ya, and 3za, the regioselectivities could be established by the diagnostic singlets
1
at 7.33−8.18 ppm in their H NMR spectra, indicating that the C−H bond
cleavage primarily occurred at the less hindered position. Furthermore, the
stereoscopic configurations of the products were unambiguously established by
the single-crystal X-ray diffraction analyses of representative 3aa and 3ra
2
4
(
Figure 2), showing that the phenyl ring at C4 and the isopropyl group at C15
(for 3aa) or C11 (for 3ra) were in the cis-form.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
3
aa
3ra
CCDC 1819885
CCDC 1829339
Figure 2. Single-crystal X-ray structures of compounds 3aa and 3ra
Control experiments were performed to gain insight into the reaction
mechanism of this transformation (Scheme 2). First, the reaction of 1a and 2a
under our optimal conditions was retarded severely in the presence of 3.0 equiv.
of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and the corresponding
TEMPO-2a adduct was isolated in 29% yield, indicating that this reaction
probably involved a free radical process. Second, the kinetic isotope effect (KIE)
was determined as k /k = 3.8 by an intermolecular competition experiment with
H
D
1a and [D ]-1a, hinting that the C−H cleavage might be involved in our catalytic
5
system as the rate-determining step. In order to further probe the source of the
18
ester oxygen atom in the product, the O-labeled experiment was also performed
1
8
18
under the standard conditions. When [ O]-2a (20% O-labled) was employed
1
8
in the reaction, no O incorporation was observed in product 3aa by analysis of
its HRMS, indicating that the ester oxygen atom introduced into the products
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
came from the α-amino acids. This result also implied that a cationic intermediate
might be involved in the second intramolecular cyclization process.25
Scheme 2. Preliminary Mechanistic Studies
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
a) Trapping experiment with TEMPO
O
O
O
N
OH
O
standard conditions
TEMPO (3.0 equiv)
N
COOH
O
H
+
+
N
O
O
O
1a
2a
3aa
,
TEMPO-2a, 29%
trac
e
(
b) Kinetic isotope effect experiment
O
N
H
COOH
O
O
N
O
Pd(OAc)2
1a
N
OH
K S O , PTSA
2
2
8
+
O
+
o
O
D4
O
O
DCE, 70 C, 1 h
3% yield
k /k = 3.8
O
O
1
N
H
COOH
2a
D5
H
D
[D4]-
3aa
3aa
[
D ]-1a
5
c) 18O-labeled experiment
(
O
O
18O
N
OH
standard conditions
N
COOH
O
H
+
O
O
[18
0% 18O-labled
O]-2a
3aa
no 18O incorporation
1a
2
Based on the above experimental results and the previous literature, a
plausible reaction mechanism is proposed (Scheme 3). First, the palladium
intermediate I is generated by the coordination of nitrogen atom and oxygen atom
of substrate 1 to the Pd catalyst, followed by concerted metalation deprotonation
2
0
process to produce intermediate II. Then, II undergoes oxidative coupling with
1
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the acyl radical III, which is produced by decarboxylation of 2 with the aid of
1
7,26
K S O ,
to furnish a high-valent Pd intermediate IV. After reductive
2
2
8
elimination, a new C−C bond is formed, and the Pd atom coordinates to the
nitrogen atom of benzamide, as shown in species V. Intramolecular cyclization
of V provides intermediate VI, which is followed by protonation to give
hydroxyisoindolinone VII with the simultaneous release of a Pd(II) species to
complete the catalytic cycle.16,17 Finally, intramolecular lactonization of the
hydroxyisoindolinone VII generated the desired product 3 via a cationic
intermediate VIII promoted by PTSA.25
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Plausible Mechanism
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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5
5
5
5
5
5
6
O
O
R2
R2
R1
PTSA
- H2O
R1
R2
N
N
O
O
COOH
OH
N
H
COOH
HO
R1
VII
R3
R3
1
VIII
Pd(II)X2
HX
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
H
R2
O
R2
N
COOH
O
O
R1
R2
O
O
N
Pd
X
N
R1
Pd
R3
X
O
X
R1
O
O
VI
I
R3
R2
O
HX
3
N
COOH
R2
R1
O
Pd
X
O
O
N
R1
Pd
X
O
R2
R3
O
K S O
II
2
2
8
O
V
N
R1
O
O
Pd
O
K S O
X
2
2
8
OH
O
IV
O
R3
R3
R3
III
CO2
2
Trapped by TEMPO
O
N
O
TEMPO-2a
CONCLUSIONS
In conclusion, we have successfully developed the first one-step synthesis of
oxazoloisoindolinones via cascade Pd-catalyzed ortho-acylation of N-benzoyl α-amino
acid derivatives and subsequent double intramolecular cyclizations. This reaction
features broad substrate scope, good functional group tolerance, high regioselectivity,
and excellent diastereoselectivity. Of practical importance is the complete
stereoretention of enantiomerically pure α-amino acids and hence chiral induction to
oxazoloisoindolinones with two stereogenic centers, including a quaternary one. We
anticipate that this efficient method will be of great importance to drug synthesis for
medicinal chemists.
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EXPERIMENTAL SECTION
General Information. NMR spectra were recorded on a 400 MHz NMR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
1
spectrometer (400 MHz for H NMR; 101 MHz for C NMR). H NMR chemical shifts
1
3
were determined relative to internal TMS at δ 0.0 ppm. C NMR chemical shifts were
1
13
determined relative to CDCl at δ 77.16 ppm. Data for H NMR and C NMR are
3
reported as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet). High-resolution mass spectra (HRMS) were
measured with FTMS-ESI or TOF-ESI in positive mode on a LTQ-Orbitrap or Q-
TOF mass spectrometer. HPLC analysis was performed on Agilent 1260. Chiralpak IC
and IE columns from Daicel Chemical Industries, LTD were employed for the chiral
HPLC analyses. Optical rotation was measured with a polarimeter. K S O , PTSA, 1,2-
2
2
8
dichloroethene (DCE), N-benzoyl-L-alanine (L-1b), and 2a were purchased from J&K,
Adamas-beta, Alfa Aesar, Sinopharm Chemical Reagent Co. Ltd., and TCI and used
1
8
20,27,28
directly. 1, 2b−k, and [ O]-2a were prepared according to the reported protocols.
General Procedure for the Palladium-Catalyzed Decarboxylative ortho-
Acylation of N-Benzoyl α-Amino Acids with α-Oxocarboxylic Acids. A mixture of
N-benzoyl α-amino acid 1 (0.3 mmol), α-oxocarboxylic acid 2 (0.6 mmol), Pd(OAc)2
(6.9 mg, 0.03 mmol), K S O (202.8 mg, 0.75 mmol), and PTSA (85.8 mg, 0.45 mmol)
2
2
8
o
o
in DCE (3 mL) was stirred at 70 C or 80 C in an oil bath for 12−24 h. After this, the
reaction mixture was cooled to room temperature. Then, the reaction mixture was
filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in vacuo.
1
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Product 3 was purified by column chromatography over silica gel using petroleum ether
and ethyl acetate (10:1−6:1) as the eluent.
3
-Isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3aa). By
0
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following the general procedure, the reaction of 1a (66.8 mg, 0.3 mmol) with 2a (90.0
o
mg, 0.6 mmol) at 70 C for 12 h gave 3aa (77.5 mg, 84% yield): white solid, mp
o
1
142.1−142.5 C; H NMR (400 MHz, CDCl ) δ 7.94−7.89 (m, 1H), 7.62−7.56 (m, 2H),
3
7
1
.52−7.47 (m, 2H), 7.43−7.37 (m, 3H), 7.36−7.33 (m, 1H), 4.22 (d, J = 9.9 Hz, 1H),
13
1
.68−1.58 (m, 1H), 1.11 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); C{ H} NMR
(101 MHz, CDCl ) δ 174.3, 172.6, 146.6, 138.1, 134.2, 131.2, 130.3, 129.5, 129.1 (2C),
3
1
25.2 (2C), 124.8, 124.7, 98.9, 63.6, 29.9, 20.3, 18.9; HRMS (FTMS-ESI) calcd for
+
C H NO Na [M+Na] 330.1101, found 330.1092.
1
9
17
3
3
-Methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3ba).
By
following the general procedure, the reaction of 1b (58.0 mg, 0.3 mmol) with 2a (90.6
o
mg, 0.6 mmol) at 70 C for 12 h gave 3ba (50.4 mg, 60% yield): white solid,
o
1
1
53.9−154.6 C; H NMR (400 MHz, CDCl ) δ 7.94−7.88 (m, 1H), 7.64−7.52 (m, 4H),
3
1
3
1
7.45−7.36 (m, 4H), 4.75 (q, J = 7.4 Hz, 1H), 1.32 (d, J = 7.4 Hz, 3H); C{ H} NMR
(
101 MHz, CDCl ) δ 174.5, 173.7, 146.0, 137.8, 134.3, 131.3, 130.4, 129.7, 129.1 (2C),
3
1
25.4 (2C), 124.9, 124.7, 99.4, 53.3, 17.0; HRMS (FTMS-ESI) calcd for C H NO
17 14 3
+
[M+H] 280.0968, found 280.0962. When N-benzoyl-L-alanine (L-1b) was employed
as the substrate, the corresponding chiral product (3S,9bR)-3ba was obtained (50.9 mg,
61% yield). Diastereomeric excess: >99%, determined by HPLC (Daicel Chirapak IE
o
column, hexane/isopropanol = 70/30 v/v, flow rate 0.7 mL/min, T = 30 C, 254 nm): t
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(minor) = 14.276 min; t (major) = 16.946 min. [α] = +262.1 (c = 0.314, CHCl3).
R
D
3
-(Tert-butyl)-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ca). By
following the general procedure, the reaction of 1c (70.6 mg, 0.3 mmol) with 2a (90.4
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1
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1
1
2
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0
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8
9
0
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2
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4
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6
7
8
9
0
o
mg, 0.6 mmol) at 70 C for 12 h gave 3ca (70.7 mg, 73% yield): white solid, 94.9−96.1
o
1
C; H NMR (400 MHz, CDCl ) δ 7.93−7.88 (m, 1H), 7.60−7.54 (m, 2H), 7.51−7.42
3
1
3
1
(m, 2H), 7.41−7.33 (m, 3H), 7.33−7.28 (m, 1H), 4.29 (s, 1H), 0.90 (s, 9H); C{ H}
NMR (101 MHz, CDCl ) δ 175.6, 172.1, 147.9, 139.1, 134.3, 131.1, 129.8, 129.2, 129.0
3
(
2C), 125.3 (2C), 124.72, 124.71, 98.8, 67.8, 34.7, 27.3 (3C); HRMS (FTMS-ESI) calcd
+
for C H NO Na [M+Na] 344.1257, found 344.1249.
2
0
19
3
9
b-Phenyl-3-propyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3da).
By
following the general procedure, the reaction of 1d (66.7 mg, 0.3 mmol) with 2a (90.3
o
mg, 0.6 mmol) at 70 C for 12 h gave 3da (58.2 mg, 63% yield): white colloidal solid;
1
H NMR (400 MHz, CDCl ) δ 7.94−7.88 (m, 1H), 7.62−7.57 (m, 2H), 7.56−7.50 (m,
3
2H), 7.44−7.36 (m, 4H), 4.59 (dd, J = 11.2, 4.6 Hz, 1H), 1.74−1.64 (m, 1H), 1.62−1.51
1
3
1
(
m, 2H), 1.31−1.20 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H); C{ H} NMR (101 MHz, CDCl )
3
δ 174.02, 173.97, 146.2, 137.9, 134.2, 131.3, 130.4, 129.7, 129.1 (2C), 125.2 (2C),
1
24.9, 124.7, 99.4, 57.7, 32.3, 19.6, 13.3; HRMS (FTMS-ESI) calcd for C H NO
19 18
3
+
[
M+H] 308.1281, found 308.1278.
3-Isobutyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3ea).
By
following the general procedure, the reaction of 1e (70.8 mg, 0.3 mmol) with 2a (90.2
o
mg, 0.6 mmol) at 70 C for 24 h gave 3ea (49.2 mg, 51% yield): white solid,
o
1
1
11.9−112.7 C; H NMR (400 MHz, CDCl ) δ 7.93−7.88 (m, 1H), 7.62−7.57 (m, 2H),
3
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7.56−7.50 (m, 2H), 7.44−7.36 (m, 4H), 4.67 (dd, J = 12.1, 4.0 Hz, 1H), 1.94−1.83 (m,
1
H), 1.53−1.45 (m, 1H), 1.23−1.13 (m, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.8
13
1
Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ 173.3, 172.9, 145.1, 136.8, 133.2, 130.3,
3
0
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2
3
4
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7
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9
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1
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3
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129.5, 128.7, 128.1 (2C), 124.2 (2C), 123.9, 123.7, 98.4, 55.6, 37.7, 24.6, 21.9, 20.1;
+
HRMS (FTMS-ESI) calcd for C H NO Na [M+Na] 344.1257, found 344.1249.
2
0
19
3
3,9b-Diphenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3fa). By following
the general procedure, the reaction of 1f (76.6 mg, 0.3 mmol) with 2a (90.3 mg, 0.6
o
o
mmol) at 70 C for 24 h gave 3fa (57.3 mg, 56% yield) : white solid, 147.6−148.3 C;
1
H NMR (400 MHz, CDCl ) δ 8.02−7.96 (m, 1H), 7.68−7.63 (m, 2H), 7.44−7.39 (m,
3
1
3
1
1
H), 7.37−7.32 (m, 2H), 7.29−7.20 (m, 5H), 7.18−7.12 (m, 3H), 5.81 (s, 1H); C{ H}
NMR (101 MHz, CDCl ) δ 174.0, 171.8, 146.4, 137.2, 134.5, 132.7, 131.5, 130.4, 129.5,
3
1
28.8 (2C), 128.5 (2C), 128.3, 126.8 (2C), 125.7 (2C), 125.0, 124.9, 99.8, 60.3; HRMS
+
(
TOF-ESI) calcd for C H NO [M+H] 342.1130, found 342.1127.
2
2
16
3
3,3-Dimethyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3ga). By
following the general procedure, the reaction of 1g (62.3 mg, 0.3 mmol) with 2a (90.3
o
mg, 0.6 mmol) at 70 C for 12 h gave 3ga (48.4 mg, 55% yield): white solid,
o
1
1
7
52.2−153.1 C; H NMR (400 MHz, CDCl ) δ 7.90−7.85 (m, 1H), 7.60−7.54 (m, 2H),
3
13
1
.53−7.49 (m, 2H), 7.42−7.35 (m, 4H), 1.88 (s, 3H), 1.27 (s, 3H); C{ H} NMR (101
MHz, CDCl ) δ 177.2, 170.8, 145.6, 138.5, 133.9, 131.4, 131.0, 129.5, 129.1 (2C),
3
1
25.1 (2C), 124.6, 124.1, 97.9, 61.3, 25.3, 23.0; HRMS (FTMS-ESI) calcd for
+
C H NO Na [M+Na] 316.0944, found 316.0938.
1
8
15
3
9
b'-Phenyl-2'H-spiro[cyclopentane-1,3'-oxazolo[2,3-a]isoindole]-2',5'(9b'H)-
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dione (3ha). By following the general procedure, the reaction of 1h (70.2 mg, 0.3 mmol)
o
with 2a (90.6 mg, 0.6 mmol) at 80 C for 12 h gave 3ha (64.2 mg, 67% yield): white
o
1
solid, 168.1−169.8 C; H NMR (400 MHz, CDCl ) δ 7.90−7.85 (m, 1H), 7.60−7.54
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
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4
5
5
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5
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5
5
5
5
5
6
0
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7
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(m, 2H), 7.50−7.46 (m, 2H), 7.40−7.34 (m, 4H), 3.11−3.02 (m, 1H), 2.28−2.15 (m,
1
H), 2.14−2.04 (m, 1H), 2.00−1.75 (m, 3H), 1.71−1.61 (m, 1H), 1.58−1.50 (m, 1H);
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 177.5, 170.5, 145.2, 138.4, 133.8, 131.7, 131.0,
3
1
29.5, 129.1 (2C), 125.3 (2C), 124.6, 124.1, 98.0, 70.4, 39.0, 32.4, 25.2, 24.6; HRMS
+
(
FTMS-ESI) calcd for C H NO Na [M+Na] 342.1101, found 342.1095.
2
0
17
3
9b'-Phenyl-2'H-spiro[cyclohexane-1,3'-oxazolo[2,3-a]isoindole]-2',5'(9b'H)-
dione (3ia). By following the general procedure, the reaction of 1i (74.4 mg, 0.3 mmol)
o
with 2a (90.4 mg, 0.6 mmol) at 70 C for 12 h gave 3ia (66.1 mg, 66% yield): colorless
1
oil; H NMR (400 MHz, CDCl ) δ 7.89−7.83 (m, 1H), 7.58−7.49 (m, 4H), 7.41−7.31
3
(m, 4H), 2.69−2.60 (m, 1H), 2.34−2.22 (m, 1H), 2.06−1.93 (m, 2H), 1.65−1.39 (m,
1
3
1
6H); C{ H} NMR (101 MHz, CDCl ) δ 175.6, 171.2, 145.5, 139.0, 133.8, 131.4,
3
1
30.9, 129.3, 129.2 (2C), 124.8 (2C), 124.5, 124.0, 97.8, 65.2, 33.9, 30.3, 24.8, 22.3,
+
21.4; HRMS (FTMS-ESI) calcd for C H NO Na [M+Na] 356.1257, found 356.1250.
2
1
19
3
3
-Isopropyl-8-methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3ja). By following the general procedure, the reaction of 1j (70.8 mg, 0.3 mmol) with
o
2a (90.6 mg, 0.6 mmol) at 70 C for 12 h gave 3ja (88.2 mg, 91% yield): white solid,
o
1
1
50.2−151.6 C; H NMR (400 MHz, CDCl ) δ 7.79 (d, J = 7.8 Hz, 1H), 7.52−7.48 (m,
3
2H), 7.43−7.36 (m, 4H), 7.12 (s, 1H), 4.20 (d, J = 9.8 Hz, 1H), 2.38 (s, 3H), 1.67−1.56
1
3
1
(
m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); C{ H} NMR (101 MHz,
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CDCl ) δ 174.4, 172.7, 147.0, 145.6, 138.3, 132.3, 129.4, 129.0 (2C), 127.7, 125.2 (2C),
3
1
25.0, 124.6, 98.9, 63.5, 29.9, 22.1, 20.2, 18.9; HRMS (FTMS-ESI) calcd for
+
C H NO Na [M+Na] 344.1257, found 344.1250.
2
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0
1
2
3
4
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9
0
8-(Tert-butyl)-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3ka). By following the general procedure, the reaction of 1k (83.6 mg, 0.3 mmol) with
o
2a (90.7 mg, 0.6 mmol) at 70 C for 12 h gave 3ka (80.2 mg, 74% yield): white solid,
o
1
1
76.4−177.1 C; H NMR (400 MHz, CDCl ) δ 7.83 (d, J = 8.1 Hz, 1H), 7.63 (dd, J =
3
8
.1, 1.6 Hz, 1H), 7.53−7.48 (m, 2H), 7.44−7.37 (m, 3H), 7.31 (d, J = 1.6 Hz, 1H), 4.19
(d, J = 9.9 Hz, 1H), 1.66−1.56 (m, 1H), 1.27 (s, 9H), 1.10 (d, J = 6.6 Hz, 3H), 0.92 (d,
1
3
1
J = 6.6 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ 174.3, 172.7, 158.7, 146.9, 138.3,
3
129.4, 129.0 (2C), 128.8, 127.7, 125.2 (2C), 124.4, 121.1, 99.1, 63.5, 35.7, 31.2 (3C),
+
2
9.9, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C H NO Na [M+Na] 386.1727,
2
3
25
3
found 386.1719.
3-Isopropyl-8-methoxy-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3la). By following the general procedure, the reaction of 1l (75.9 mg, 0.3 mmol) with
o
2a (90.0 mg, 0.6 mmol) at 70 C for 12 h gave 3la (77.3 mg, 76% yield): white colloidal
1
solid; H NMR (400 MHz, CDCl ) δ 7.82 (d, J = 8.5 Hz, 1H), 7.52−7.46 (m, 2H),
3
7
.44−7.37 (m, 3H), 7.07 (dd, J = 8.5, 1.9 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 4.18 (d, J
= 9.7 Hz, 1H), 3.80 (s, 3H), 1.70−1.55 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.90 (d, J =
1
3
1
6
.6 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ 174.2, 172.7, 164.8, 149.2, 138.3,
3
129.5, 129.1 (2C), 126.4, 125.2 (2C), 122.6, 118.2, 109.0, 98.5, 63.5, 56.0, 30.0, 20.2,
+
1
9.0; HRMS (FTMS-ESI) calcd for C H NO Na [M+Na] 360.1206, found 360.1201.
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8-Fluoro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(
3ma). By following the general procedure, the reaction of 1m (72.0 mg, 0.3 mmol)
o
with 2a (90.3 mg, 0.6 mmol) at 70 C for 12 h gave 3ma (82.0 mg, 84% yield): white
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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4
4
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0
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3
4
5
6
7
8
9
0
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7
8
9
0
1
colloidal solid; H NMR (400 MHz, CDCl ) δ 7.91 (dd, J = 8.3, 4.7 Hz, 1H), 7.52−7.46
3
(
m, 2H), 7.45−7.39 (m, 3H), 7.31−7.24 (m, 1H), 7.01 (d, J = 7.5 Hz, 1H), 4.21 (d, J =
1
9
9.8 Hz, 1H), 1.68−1.57 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); F
1
3
1
NMR (376 MHz, CDCl ) δ −101.87 (s, 1F); C{ H} NMR (101 MHz, CDCl ) δ 173.1,
3
3
1
72.2, 166.4 (d, JC−F = 257.0 Hz), 149.2 (d, JC−F = 9.6 Hz), 137.6, 129.8, 129.2 (2C),
127.1 (d, JC−F = 9.8 Hz), 126.3 (d, JC−F = 2.1 Hz), 125.1 (2C), 119.2 (d, JC−F = 23.7 Hz),
1
12.2 (d, JC−F = 24.4 Hz), 98.0 (d, JC−F = 2.4 Hz), 63.6, 29.9, 20.2, 18.9; HRMS (TOF-
+
ESI) calcd for C H FNO [M+H] 326.1192, found 326.1195.
1
9
17
3
8
-Chloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(
3na). By following the general procedure, the reaction of 1n (76.9 mg, 0.3 mmol) with
o
2a (90.4 mg, 0.6 mmol) at 70 C for 12 h gave 3na (92.3 mg, 90% yield): white colloidal
1
solid; H NMR (400 MHz, CDCl ) δ 7.84 (d, J = 8.1 Hz, 1H), 7.56 (dd, J = 8.1, 1.7 Hz,
3
1H), 7.51−7.46 (m, 2H), 7.46−7.39 (m, 3H), 7.31 (d, J = 1.7 Hz, 1H), 4.21 (d, J = 9.8
1
3
1
Hz, 1H), 1.69−1.55 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); C{ H}
NMR (101 MHz, CDCl ) δ 173.1, 172.1, 148.1, 140.7, 137.4, 131.9, 129.8, 129.2 (2C),
3
128.7, 126.0, 125.1 (3C), 98.1, 63.6, 29.8, 20.2, 18.9; HRMS (FTMS-ESI) calcd for
3
5
+
C H ClNO [M+H] 342.0892, found 342.0887.
1
9
17
3
8-Bromo-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
3oa). By following the general procedure, the reaction of 1o (90.2 mg, 0.3 mmol) with
(
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6
o
2a (90.1 mg, 0.6 mmol) at 70 C for 12 h gave 3oa (91.1 mg, 79% yield): white colloidal
1
solid; H NMR (400 MHz, CDCl ) δ 7.77 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 8.1, 1.5 Hz,
3
1
H), 7.51−7.46 (m, 3H), 7.46−7.39 (m, 3H), 4.21 (d, J = 9.9 Hz, 1H), 1.67−1.56 (m,
0
1
2
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8
9
0
1
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0
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 173.2, 172.1, 148.1, 137.4, 134.7, 129.8, 129.2 (2C), 129.1 (2C), 128.0, 126.1,
3
125.1 (2C), 98.1, 63.5, 29.8, 20.2, 18.8; HRMS (FTMS-ESI) calcd for
7
9
+
C H BrNO Na [M+Na] 408.0206, found 408.0196.
1
9
16
3
3
-Isopropyl-9b-phenyl-8-(trifluoromethyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)-
dione (3pa). By following the general procedure, the reaction of 1p (86.8 mg, 0.3 mmol)
o
with 2a (90.1 mg, 0.6 mmol) at 70 C for 12 h gave 3pa (77.2 mg, 69% yield): pale
1
yellow colloidal solid; H NMR (400 MHz, CDCl ) δ 8.05 (d, J = 8.0 Hz, 1H), 7.87 (d,
3
J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.53−7.49 (m, 2H), 7.46−7.42 (m, 3H), 4.24 (d, J = 10.0
Hz, 1H), 1.68−1.57 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 19F
1
3
1
NMR (376 MHz, CDCl ) δ −62.71 (s, 3F); C{ H} NMR (101 MHz, CDCl ) δ 172.6,
3
3
1
71.9, 147.0, 137.0, 135.9 (q, JC−F = 33.1 Hz), 133.5, 130.0, 129.4 (2C), 128.6 (q, JC−F
= 3.4 Hz), 125.6, 125.1 (2C), 123.1 (q, JC−F= 273.5 Hz), 121.9 (q, JC−F= 3.8 Hz), 98.3,
+
6
3
3.6, 29.8, 20.2, 18.8; HRMS (FTMS-ESI) calcd for C H F NO Na [M+Na]
20 16 3 3
98.0975, found 398.0965.
3-Isopropyl-8-nitro-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione (3qa).
By following the general procedure, the reaction of 1q (80.0 mg, 0.3 mmol) with 2a
o
(90.4 mg, 0.6 mmol) at 70 C for 24 h gave 3qa (57.4 mg, 54% yield): pale yellow
o
1
solid, 153.8−155.0 C; H NMR (400 MHz, CDCl ) δ 8.47 (d, J = 8.3 Hz, 1H), 8.16 (s,
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1H), 8.10 (d, J = 8.3 Hz, 1H), 7.54−7.42 (m, 5H), 4.25 (d, J = 10.0 Hz, 1H), 1.69−1.58
1
3
1
(
m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 171.7, 171.5, 151.6, 147.7, 136.5, 135.2, 130.3, 129.5 (2C), 126.8, 126.1,
3
1
1
1
1
1
1
1
1
1
1
2
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2
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0
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8
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0
1
2
3
4
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7
8
9
0
125.1 (2C), 120.3, 97.9, 63.8, 29.8, 20.3, 18.8; HRMS (FTMS-ESI) calcd for
+
C H N O [M+H] 353.1132, found 353.1125.
1
9
17
2
5
3-Isopropyl-7-methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3ra). By following the general procedure, the reaction of 1r (70.6 mg, 0.3 mmol) with
o
2
a (90.9 mg, 0.6 mmol) at 70 C for 12 h gave 3ra (71.7 mg, 74% yield): white solid,
o
1
154.1−155.0 C; H NMR (400 MHz, CDCl ) δ 7.70 (s, 1H), 7.51−7.45 (m, 2H),
3
7
.42−7.35 (m, 4H), 7.22 (d, J = 7.8 Hz, 1H), 4.20 (d, J = 9.9 Hz, 1H), 2.46 (s, 3H),
1
3
1
1.68−1.56 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); C{ H} NMR
(
101 MHz, CDCl ) δ 174.5, 172.7, 144.1, 141.9, 138.3, 135.2, 130.5, 129.4, 129.0 (2C),
3
1
25.2 (2C), 124.9, 124.4, 98.9, 63.6, 29.9, 21.6, 20.3, 18.9; HRMS (FTMS-ESI) calcd
+
for C H NO Na [M+Na] 344.1257, found 344.1251.
2
0
19
3
7
-Chloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3sa). By following the general procedure, the reaction of 1s (77.0 mg, 0.3 mmol) with
o
2
a (90.6 mg, 0.6 mmol) at 70 C for 12 h gave 3sa (84.4 mg, 82% yield): white solid,
o
1
1
32.2−133.7 C; H NMR (400 MHz, CDCl ) δ 7.87 (d, J = 1.4 Hz, 1H), 7.55 (dd, J =
3
8.1, 1.4 Hz, 1H), 7.50−7.45 (m, 2H), 7.44−7.38 (m, 3H), 7.28 (d, J = 8.1 Hz, 1H), 4.21
d, J = 9.9 Hz, 1H), 1.67−1.56 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz,
(
1
3
1
3H); C{ H} NMR (101 MHz, CDCl ) δ 172.7, 172.1, 144.7, 137.7, 137.5, 134.3,
3
1
32.1, 129.7, 129.1 (2C), 125.9, 125.1 (2C), 124.8, 98.3, 63.6, 29.8, 20.2, 18.8; HRMS
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+
(FTMS-ESI) calcd for C H ClNO Na [M+Na] 364.0711, found 364.0706.
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3
3
-Isopropyl-9b-phenyl-7-(trifluoromethyl)oxazolo[2,3-a]isoindole-2,5(3H,9bH)-
dione (3ta). By following the general procedure, the reaction of 1t (86.8 mg, 0.3 mmol)
0
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8
9
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2
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4
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6
7
8
9
0
o
with 2a (90.3 mg, 0.6 mmol) at 70 C for 12 h gave 3ta (68.7 mg, 61% yield): pale
1
yellow colloidal solid; H NMR (400 MHz, CDCl ) δ 8.18 (s, 1H), 7.85 (d, J = 8.0 Hz,
3
1H), 7.53−7.48 (m, 3H), 7.45−7.40 (m, 3H), 4.24 (d, J = 9.9 Hz, 1H), 1.70−1.59 (m,
1
9
1
H), 1.12 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H); F NMR (376 MHz, CDCl ) δ
3
13
1
−
62.68 (s, 3F); C{ H} NMR (101 MHz, CDCl ) δ 172.6, 171.9, 149.5, 137.2, 133.8
3
(q, JC−F = 33.4 Hz), 131.2, 131.1 (q, JC−F = 3.4 Hz), 130.0, 129.3 (2C), 125.5, 125.1
(
2C), 123.3 (q, JC−F = 273.2 Hz), 122.2 (q, JC−F = 3.8 Hz), 98.2, 63.6, 29.8, 20.2, 18.8;
+
HRMS (FTMS-ESI) calcd for C H F NO Na [M+Na] 398.0975, found 398.0968.
2
0
16
3
3
3
-Isopropyl-6-methyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(
3ua). By following the general procedure, the reaction of 1u (71.0 mg, 0.3 mmol) with
o
2a (90.3 mg, 0.6 mmol) at 70 C for 12 h gave 3ua (73.8 mg, 77% yield): white solid,
o
1
1
42.5−144.0 C; H NMR (400 MHz, CDCl ) δ 7.53−7.47 (m, 2H), 7.43 (t, J = 7.5 Hz,
3
1H), 7.41−7.35 (m, 3H), 7.32 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 4.21 (d, J =
.8 Hz, 1H), 2.74 (s, 3H), 1.69−1.57 (m, 1H), 1.11 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6
9
13
1
Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ 175.2, 172.8, 147.1, 139.1, 138.5, 133.7,
3
133.1, 129.4, 129.0 (2C), 127.4, 125.2 (2C), 122.2, 98.5, 63.6, 29.8, 20.3, 19.0, 17.6;
+
HRMS (FTMS-ESI) calcd for C H NO Na [M+Na] 344.1257, found 344.1254.
2
0
19
3
3-Isopropyl-6-methoxy-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(
3va). By following the general procedure, the reaction of 1v (75.3 mg, 0.3 mmol) with
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o
2a (90.1 mg, 0.6 mmol) at 80 C for 24 h gave 3va (62.3 mg, 62% yield): white solid,
o
1
1
41.4−142.8 C; H NMR (400 MHz, CDCl ) δ 7.55−7.46 (m, 3H), 7.42−7.35 (m, 3H),
3
7
.01 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.21 (d, J = 9.6 Hz, 1H), 4.02 (s, 3H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
4
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5
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5
5
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0
1
2
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
1.67−1.55 (m, 1H), 1.09 (d, J = 5.9 Hz, 3H), 0.89 (d, J = 5.8 Hz, 3H); C{ H} NMR
(
101 MHz, CDCl ) δ 173.0, 172.7, 157.8, 148.8, 138.3, 136.2, 129.4, 129.0 (2C), 125.2
3
(2C), 117.2, 116.6, 113.2, 98.2, 63.4, 56.3, 29.8, 20.1, 18.9; HRMS (FTMS-ESI) calcd
+
for C H NO Na [M+Na] 360.1206, found 360.1200.
2
0
19
4
6
-Fluoro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(3wa). By following the general procedure, the reaction of 1w (71.9 mg, 0.3 mmol)
o
with 2a (90.5 mg, 0.6 mmol) at 70 C for 12 h gave 3wa (76.4 mg, 78% yield): white
1
colloidal solid; H NMR (400 MHz, CDCl ) δ 7.58 ( td, J = 7.9, 4.6 Hz, 1H), 7.53−7.48
3
(
m, 2H), 7.45−7.39 (m, 3H), 7.23 (t, J = 8.5 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 4.22 (d,
J = 9.9 Hz, 1H), 1.68−1.56 (m, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H);
1
9
13
1
F NMR (376 MHz, CDCl ) δ −113.75 (s, 1F); C{ H} NMR (101 MHz, CDCl ) δ
3
3
1
72.2, 170.8, 158.7 (d, JC−F = 264.8 Hz), 148.6, 137.7, 136.5 (d, JC−F = 7.6 Hz), 129.7,
129.2 (2C), 125.1 (2C), 120.8 (d, JC−F = 4.3 Hz), 118.5 (d, JC−F = 19.2 Hz), 117.6 (d,
JC−F = 14.0 Hz), 98.2, 63.5, 29.8, 20.2, 18.9; HRMS (FTMS-ESI) calcd for C H FNO
3
19
17
+
[
M+H] 326.1187, found 326.1187.
6-Chloro-3-isopropyl-9b-phenyloxazolo[2,3-a]isoindole-2,5(3H,9bH)-dione
(
3xa). By following the general procedure, the reaction of 1x (76.8 mg, 0.3 mmol) with
o
2a (90.8 mg, 0.6 mmol) at 70 C for 12 h gave 3xa (80.3 mg, 78% yield): white colloidal
1
solid; H NMR (400 MHz, CDCl ) δ 7.55−7.47 (m, 4H), 7.45−7.38 (m, 3H), 7.24 (dd,
3
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