Preparation of Spiro[indene-1,1′-isoindolin]-3′-ones via Sulfuric Acid-Promoted Cascade Cyclization

Article abstract of DOI:10.1021/acs.joc.7b00958

The sulfuric acid-promoted cascade cyclization of 2-(3-hydroxyprop-1-ynyl)benzonitriles led to an efficient synthesis of spiro[indene-1,1′-isoindolin]-3′-ones. This class of spiro compounds could also be prepared by the sulfuric acid-catalyzed cyclization of 2-(phenylacryloyl)benzonitriles, which were readily derived from 2-(3-hydroxyprop-1-ynyl)benzamides using trifluoroacetic acid as a catalyst.

Full text of DOI:10.1021/acs.joc.7b00958

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Article
Preparation of Spiro[indene-1,1'-isoindolin]-3'-ones
via Sulfuric Acid-Promoted Cascade Cyclization
Lang Sun, Peng Liu, Jing Wang, Ping Lu, and Yanguang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00958 • Publication Date (Web): 21 Jul 2017
Downloaded from http://pubs.acs.org on July 21, 2017
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Preparation of Spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones via
Sulfuric AcidꢀPromoted Cascade Cyclization
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Lang Sun, Peng Liu, Jing Wang, Ping Lu,* Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
pinglu@zju.edu.cn; orgwyg@zju.edu.cn
ABSTRACT: The sulfuric acidꢀpromoted
cascade
cyclization
of
2
ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)benzonitriles led to an efficient synthesis of
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones. This class of spiro compounds could also be
prepared by the sulfuric acidꢀcatalyzed cyclization of 2ꢀ(phenylacryloyl)benzonitriles,
which were readily derived from 2ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)benzamides using
trifluroacetic acid as catalyst.
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INTRODUCTION
Isoindolinones are an important class of nitrogenꢀcontaining heterocyclic
compounds duo to their impressive bioactivities, such as antipsychotic, antiviral,
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anxiolytic, antifungal and anticancer activities. Some of them have been clinically
used as pharmaceuticals. For instance, lenalidomide is being used in the treatment of
1
e
multiple myeloma (Figure 1). It has also shown efficacy in the class of
hematological disorders known as myelodysplastic syndromes (MDS). Furthermore,
2
isoindolinones are also useful building blocks for the synthesis of several drugs and
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naturally occurring alkaloids. Among a variety of isoindolinones, spiroisoindolinones
have their own importance as they exhibit various properties such as anticancer
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5
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activity and aldose reductase inhibition or can act as chemical sensors (Figure 1).
Consequently, the development of highly efficient methods for the preparation of this
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class of heterocycles has attracted much attention in recent years. However, very
limited methodologies for the construction of spiroisoindolinones with a
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀone skeleton have been reported so far. The early
examples
ꢀ(9ꢀhydroxyꢀ9Hꢀfluorenꢀ9ꢀyl)ꢀNꢀmethylbenzamide (Scheme 1, Previous work A)
and the Pdꢀcatalyzed cyclization of enamides of 2ꢀiodobenzoic acid (Scheme 1,
include
the
dehydration
of
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2
12
Previous work B). Theses transformations suffer from low yields and limited
substrate scope. More recently, Nishimura and Kim’s groups independently reported
more efficient syntheses of spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀone skeletons by the
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transitionꢀmetalꢀcatalyzed [3+2] annulation reactions of the in situ generated
1
3
4
ketimines with alkynes or activated olefins (Scheme 1, Previous work C).
Therefore, the synthesis of spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀone skeletons has been an
attractive area for synthetic chemists.
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O
O
O
NH
N
O
NH
O
NH2
Lenalidomide
O
(
a drug used to treat
multiple myeloma)
anticancer agent
O
H
O
N Me
O
NH
N
Cl
N
Cl
N
O
NEt2
Et N
2
O
H
aldose reductase inhibitor
fluorescent chemosensor
Figure 1. Typical examples of isoindolinone and spiroisoindolinone scaffolds.
In this context, propargylic alcohols are versatile building blocks in organic
synthesis as they could be easily accessed from terminal alkynes and carbonyl
compounds through simple nucleophilic addition and could be readily converted into
a variety of important organic compounds, such as α,βꢀunsaturated ketones,
alleneamides, allenesulfonamides, allenephosphoramides, carbocycles, and
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heterocycles. These transformations normally proceed through a Lewis acid or
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Brønsted acid catalyzed MeyerꢀSchuster rearrangement and related cascade process.
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As part of our ongoing program of the cascade reactions of propargylic alcohols,
herein we report the acidꢀcatalyzed cyclization reactions of
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ꢀ(2ꢀcyanophenyl)propargylic alcohols and 2ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)benzamides,
furnishing class of isoindolinone derivatives with
a
a
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀone skeleton (Scheme 1, This work). In comparison
with the published methods, the features of our cascade approach to
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones are more facile, metalꢀfree and efficient.
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Scheme 1. Previous Works and Our Design to Spiro[indene-1,1'-isoindolin]-3'-
ones
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RESULTS AND DISCUSSIONS
In our primary investigations, BF ·Et O was used as the catalyst for the electrophilic
3
2
cyclization of 3ꢀ(2ꢀcyanophenyl)propargylic alcohol 1a. By refluxing 1a with
BF
3
·Et
2
O in nitromethane for 30 minutes, spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀone 2a was
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isolated in 66% yield (Table 1, entry 1). Structure of 2a was established by single
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crystal analysis. In order to obtain a satisfied yield of 2a, the reaction conditions
were optimized and the results are summarized in Table 1. Firstly, we screened several
Lewis acids and Brønsted acids, such as BF ·Et O, TsOH, TfOH, and H SO (Table 1,
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entries 1ꢀ4). Concentrated sulfuric acid was found to be the best catalyst. 2a was not
detected when CF COOH, AcOH, HCl, Cu(OTf) , and AgOTf were used as the
catalyst, although 1a was completely consumed afterwards (Table 1, entries 5ꢀ9).
Only trace amount of 2a was detected when Yb(OTf) was used as the catalyst (Table
, entry 10). By altering the solvent from nitromethane to THF, we did not observe the
3
2
3
1
desired product (Table 1, entry 11). The best result (97% yield) was achieved in
dichloroethane (DCE) (Table 1, entry 12). 1a was recovered when the reaction was
performed in water (Table 1, entry 13). The reaction in methanol also did not provide
2a, although 1a was completely consumed (Table 1, entry 14). Dichloromethane
(
DCM), toluene and MeCN were also screened, but they did not improve the yield
(Table 1, entries 15ꢀ17). Both decreasing the catalyst amount and lowering the
reaction temperature led to a decrease in the yield (Table 1, entries 18ꢀ20).
a
Table 1. Optimization of the Reaction Conditions
o
b
temp. ( C)
entry
catalyst
solvent
time (h)
yield (%)
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100
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BF ·Et O
CH NO
0.5
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0.5
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0.5
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2
66
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2
2
100
TsOH
CH
CH
CH
CH
CH
CH
CH
CH
CH
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3
3
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NO
NO
NO
NO
NO
NO
NO
NO
NO
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1
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1
1
00
00
00
00
TfOH
68
H
2
SO
4
90
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CF CO
3
2
H
ND
NR
ND
ND
ND
trace
ND
97
AcOH
HCl
100
100
Cu(OTf)
2
1
1
6
8
00
00
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AgOTf
0
Yb(OTf)
3
11
H
2
SO
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THF
DCE
3
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H SO
2
100
65
H
H
2
2
SO
SO
H
2
O
NR
ND
81
3
CH OH
4
0
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H SO
DCM
PhMe
2
110
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a
H
H
2
2
SO
SO
89
81
83
83
83
CH
3
CN
24
c
H SO
DCE
DCE
DCE
95
2
d
H
H
2
2
SO
SO
ND
e
2
82
2 4
Reaction conditions: 1a (0.20 mmol), catalyst (0.24 mmol), solvent (4 mL), reflux temperature, H SO
b
c
d
2 4 2 4
is concentrated sulfuric acid. Isolated yield referred to 1a. H SO (0.20 mmol). H SO (0.01 mmol).
e
Room temperature.
With the optimized reaction conditions in hand, we tested the substrate diversity
(
Schemes 2ꢀ4). Firstly, we tested the symmetrical propargylic alcohols 1a-f (Scheme
2). Good yields 2b (81%) and 2d (87%) were obtained for those substrates with a
moderate electronꢀwithdrawing (Cl, 1b) or electronꢀdonating group (Me, 1d). Strong
electronꢀdonating group (OMe) or strong electronꢀwithdrawing group (F) substituted
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propargylic alcohols 1c and 1e provided the corresponding products 2c (53%) and 2e
65%) in relative lower yields. For asymmetrical propargylic alcohols, such as
(
2
ꢀ(3ꢀ(4ꢀChlorophenyl)ꢀ3ꢀhydroxyꢀ3ꢀphenylpropꢀ1ꢀynꢀ1ꢀyl)benzonitrile
ꢀ(3ꢀHydroxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ3ꢀphenylpropꢀ1ꢀynꢀ1ꢀyl)benzonitrile
(1g)
and
the
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(1h),
reaction took place to give the corresponding spiro products 2g (94%) and 2h (79%)
in good to excellent yields. Asymmetric propargylic alcohols 1i and 1j were also
tested (Scheme 3). In these cases, however, poor regioselectivity was observed. Thus,
the cyclization of 1i gave a mixture of 2ia and 2ib in 2.2 to 1 ratio, while a 1:1
mixture of 2ja and 2jb was obtained from 1j.
Scheme 2. Preparation of Compounds 2a-h
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Scheme 3. Preparation of Compounds (2ia + 2ib) and (2ja + 2jb)
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3
As shown in Scheme 4, the R group in propargylic alcohols 1 could be altered to
2 3
3ꢀF (1k), 4ꢀBr (1l), 4ꢀNO (1m), 4ꢀMeO (1n), 5ꢀCF (1o), and 6ꢀF (1p). In these cases,
the corresponding products 2k-p were obtained in good to excellent yields and the
electronic effect of these substituted groups was not apparent. In comparison to 2l and
2
n, 2q and 2r were isolated in lower yields duo to the decreased electron density of
4ꢀchlorophenyl of propargylic alcohols 1q and 1r, which should be adverse to the
final cyclization.
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Scheme 4. Preparation of Compounds 2k-r
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Practically, this transformation could be scaled up to gram scale. By refluxing the
mixture of 1a (4 mmol, 1.236 g) and sulfuric acid (4.8 mmol) in DCE (50 mL) for 30
minutes, 1.065 g (86% yield) of 2a was isolated by silica gel column chromatograph.
If a strong electrophile such as NIS was added to the reaction mixture after
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones 2 were formed, iodination occurred on the
indene ring of 2 to furnish 2ꢀiodospiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones 3aꢀg in good to
1
1
excellent yields (Table 2). Structure of 3a was established by single crystal analysis.
The reaction was carried in a oneꢀpot without the isolation step. Electronic effect of
the substituted group on indene ring was significant. With 3ꢀ(4ꢀnitrophenyl)
substituted on indene, 3e was obtained in the lowest yield. Electron withdrawing
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group on isoindoline ring did not affect the electrophilic substitution on the indene
ring. Thus, 3f (4ꢀBr) and 3g (5ꢀCF ) were prepared in 90% and 94% yields,
respectively. With similar strategy, we also obtained
ꢀbromspiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones 3hꢀk in yields varying from 73% to 87%.
With excess amount of NIS, diiodination occurred to generate 4a and 4b in 77% and
4% yields, respectively (Scheme 5). However, excess amount of NBS did not give
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the dibrominated products.
a
Table 2. Preparation of Compounds 3
a
o
2 4
Reaction conditions: 1 (0.2 mmol), DCE (4 mL), H SO (0.24 mmol), 83 C, 0.5 h; then NIS (0.2
mmol), room temperature, 0.5 h.
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Scheme 5. Preparation of Compounds 4a and 4b
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In order to get insight into the reaction mechanism, we synthesized the substrate
5
a and subjected it to the standard conditions. Unfortunately, only 23% yield of 2a
was afforded. Surprisingly, when trifluoroacetic acid instead of sulfuric acid was used
as catalyst, α,βꢀunsaturated ketone 6a was prepared in 84% yield. The structure of 6a
11
was established by single crystal analysis. 6a also could be easily synthesized from
1a using trifluoroacetic acid as catalyst. Moreover, further treatment of 6a with
sulfuric acid in DCE for 5 min led to the formation of 2a in 94% yield (Scheme 6).
Scheme 6. Preparation of 6a and Its Transformation to 2a
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As an extension, we optimized the conversion of 5a to 6a. Several acids and
solvents (e.g. DCE, CH NO , THF, CH CN, toluene, and DCM) were screened and
3
2
3
trifluoroacetic acid was found to be the most efficient catalyst while toluene was the
best solvent. Lowing the reaction temperature did not improve the yield, whereas
decreasing the amount of trifluoroacetic acid to 0.8 equivalent could increase the yield
of 6a up to 91% yield. Under the optimized reaction conditions, the substrate scope
was investigated and nine α,βꢀunsaturated ketones 6aꢀi were prepared (Table 3).
When both R and R' were aryl groups, good to excellent yields (76%ꢀ98%) were
obtained (Table 3, products 6a-f). When R was phenyl and R' was methyl or hydrogen,
the corresponding products 6g and 6h were prepared in relatively lower yields.
However, poor yield of 6i was isolated in the case where both R and R' were methyl
group.
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1
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1
2
2
2
2
2
2
2
2
2
2
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5
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5
6
a
Table 3. Preparation of Compounds 6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
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2
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8
9
0
a
o
b
Reaction conditions: 5 (0.2 mmol), toluene (4 mL), CF COOH (0.16 mmol), 110 C, 0.5 h. Reaction
3
c
d
for 1 h. Reaction for 3 h. Reaction for 4 h.
As next step, we tried to convert the 2ꢀ(3ꢀhydroxyꢀ1ꢀpropyne)benzamides 5 into
the corresponding spiro products 2 through a twoꢀstep oneꢀpot procedure. Thus,
compounds 2a, 2b and 2d were successfully obtained from compounds 5a, 5c, and
5f, respectively (Scheme 7). The asymmetric 2ꢀ(3ꢀhydroxyꢀ1ꢀpropyne)benzamide 5j
could also work and furnished the desired product 2h in a relatively lower yield.
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Scheme 7. Preparation of Compounds 2 from 5
O
R'
NH
1. CF CO H (0.8 equiv)
3
2
o
PhMe, 110 C, 0.5 h
OH
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CONH2
2
. H SO (1.2 equiv)
DCE, 83 C, 0.5 h
R'
2
4
o
R
R
2a, R = H, R' = H, 81%
5
5
a, R = R' = H,
c, R = R' =Cl
2
2
2
b, R = Cl, R' = Cl, 73%
d, R = Me, R' = Me, 64%
h, R = NO , R' = H, 42%
5f, R = R' =Me
5j, R = NO , R' = H
2
2
On the basis of these results, we propose a possible mechanism for the formation
of spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones 2 and 3 as well as α,βꢀunsaturated ketones 6 in
Scheme 8. Firstly, the MeyerꢀSchuster rearrangement of propargylic alcohol 1a in the
5
presence of sulfuric acid forms α,βꢀunsaturated ketone 6a. Subsequently, the
hydrolysis of cyano group of 6a generates amide A, which then undergoes an
intramolecular condensation to form B. Finally, the intramolecular FriedelꢀCraft
alkylation occurs to generate the spiro product 2a. In the presence of an electrophile,
such as NIS, 2a subsequently undergoes an electrophilic substitution to produce 3a.
For the transformation of 5a to 6a, the allene intermediate C might be involved in the
cascade rearrangement process. In the presence of trifluoroacetic acid, 5a undergoes
an electrophilic cyclization to form C. Then, the ringꢀopening of C occurs to give the
more stable product 6a.
Scheme 8. Proposed Mechanism for the Formation of 2a, 3a and 6a
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7
8
9
0
For asymmetric propargylic alcohols, it is possible that there is equilibrium
between the intermediates (E)ꢀB and (Z)ꢀB under strong acid condition (Scheme 9).
Since the cyclization undergoes an intramolecular FriedelꢀCrafts reaction, the relative
electronꢀrich phenyl ring should react faster than the electronꢀdeficient phenyl ring.
For strong electronꢀwithdrawing group (NO
(Scheme 2), 2h was obtained as a sole product because it is very difficulty that the
NO substituted phenyl ring undergoes the FriedelꢀCraftsꢀtype cyclization. In the case
2
) substituted propargylic alcohol 1h
2
where OMe substituted propargylic alcohol 1j was used (Scheme 3), OMe substituent
does not works as electronꢀdonation group since the cyclization happens at
metaꢀposition, which led to formation of 2ja and 2jb with poor regiochemistry.
Similar reason can be used to explain the fact that the yield of 2c is much lower than
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that of 2a.
Scheme 9. Possible Explanation for the Regioselectivity of Asymmetric
Propargylic Alcohols
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Furthermore, the synthesized 2ꢀiodospiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀone 3a could
be extended to 2ꢀarylspiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones under the standard Suzuki
coupling reaction conditions (Scheme 10). Thus, 7a, 7b, and 7c were obtained from
3a in excellent yields.
Scheme 10. Conversion from 3a to 7
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6
CONCLUSION
In conclusion, we developed an efficient method for the synthesis of
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones from 2ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)benzonitriles.
The cascade process was triggered by sulfuric acid and occurred in a sequence of
MeyerꢀSchuster rearrangement, hydrolysis of cyano, imide formation, and
FriedelꢀCraft alkylation. The spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones were obtained in
moderate to excellent yields with 100% atom efficiency and high bond formation
efficiency. Alternatively, 2ꢀ(3ꢀhydroxyꢀ1ꢀpropyne)benzamides could also be
converted into the spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones in a twoꢀstep oneꢀpot
procedure. The starting materials, 2ꢀ(3ꢀhydroxypropꢀ1ꢀynyl)benzonitriles and
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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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
2
ꢀ(3ꢀhydroxyꢀ1ꢀpropyne)benzamides, could be conveniently prepared by the
Sonogashira coupling reaction of 1,1ꢀdiarylpropynꢀ1ꢀols with 2ꢀiodobenzonitriles and
2
ꢀiodobenzamides,
respectively.
Moreover,
be
the
synthesized
extended to
spiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones
could
in
situ
2
2
ꢀiodospiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones, which could be further derived to
ꢀarylspiro[indeneꢀ1,1'ꢀisoindolin]ꢀ3'ꢀones through Pdꢀcatalyzed Suzuki coupling
reaction.
EXPERIMENTAL SECTION
General Considerations. Unless otherwise mentioned, solvents and reagents were
1
purchased from commercial sources and used as received. H NMR spectra were
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recorded on 400 MHz or 500 MHz spectrometer. The chemical shifts were reported
relative to internal standard TMS (0 ppm) in CDCl . The following abbreviations
3
were used to describe peak patterns where appropriate: b = broad, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet. Coupling constants were reported in
10
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60
1
3
Hertz (Hz). C NMR spectra were recorded on 100 MHz or 125 MHz spectrometer
and referenced to the internal solvent signals (77.27 ppm for CDCl ). Infrared spectra
3
were obtained on an FTIR spectrometer. Highꢀresolution mass spectra (HRMS) data
were obtained by using an EIꢀTOF or ESI mass spectrometer. Melting points were
measured with a micro melting point apparatus.
Typical Procedure for the Preparation of Substrates 1. To a stirred suspension
of PdCl
2 3 2
(PPh ) (0.1 mmol), CuI (0.1 mmol), 2ꢀiodobenzonitrile (2 mmol), and
iꢀPr NH (6 mL) in THF (10 mL) under N
2
2
atmosphere was added a solution of
o
1,1ꢀdiphenylpropynꢀ1ꢀol (2.2 mmol) in THF (4 mL) via syringe at 50 C. The reaction
mixture was stirred for 3 hours and then concentrated in vacuo. The residue was
washed with saturated NH
4
Cl solution (5 mL) and extracted with AcOEt (20 mL). The
SO . After filtered and
organic layer was washed with brine and dried over Na
2
4
concentrated in vacuo, the crude was purified by column chromatography over silica
gel with hexane/ AcOEt as the eluent.
2-(3-Hydroxy-3,3-diphenylprop-1-yn-1-yl)benzonitrile (1a). Purified on silica gel
1
with hexane/ AcOEt (3:1, v/v) as the eluent. 96% Yield (593 mg); Brown oil; H
NMR (400 MHz, CDCl
3
): δ 7.75ꢀ7.70 (m, 4H), 7.67 (dd, J = 7.8, 0.6 Hz, 1H),
7
.60ꢀ7.52 (m, 2H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.39ꢀ7.34 (m, 4H), 7.32ꢀ7.26 (m,
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5
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7
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9
1
1
1
1
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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
4
4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
1
3
2
1
1
H), 3.07 (s, 1H); C NMR (100 MHz, CDCl
3
): δ 144.5, 132.9, 132.8, 132.7, 129.0,
28.7, 128.2, 126.7, 126.4, 117.9, 115.6, 98.4, 83.4, 75.2; IR (film): 3440, 3062, 2229,
ꢀ1
+
592, 1481, 1449, 1165, 1031, 992, 762 cm ; HRMS (EIꢀTOF) m/z: M Calcd for
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
C H NO 309.1154; found 309.1157.
22
15
2
-(3,3-Bis(4-chlorophenyl)-3-hydroxyprop-1-yn-1-yl)benzonitrile (1b). Purified on
silica gel with hexane/ AcOEt (4:1, v/v) as the eluent. 93% Yield (701 mg); Brown oil;
1
H NMR (400 MHz, CDCl
3
): δ 7.68 (d, J = 7.6 Hz, 1H), 7.64ꢀ7.59 (m, 4H), 7.58ꢀ7.55
13
(
m, 2H), 7.48ꢀ7.42 (m, 1H), 7.35ꢀ7.30 (m, 4H), 3.25 (s, 1H); C NMR (100 MHz,
CDCl ): δ 142.7, 134.3, 132.9, 132.8, 132.7, 129.3, 128.9, 127.8, 126.2, 117.9, 115.6,
3
9
7.2, 83.9, 74.3; IR (film): 3428, 3069, 2231, 1592, 1488, 1403, 1165, 1092, 993, 762
ꢀ1
+
cm ; HRMS (EIꢀTOF) m/z: M Calcd for C22
2
H13Cl NO 377.0374; found 377.0370.
2
-(3-Hydroxy-3,3-bis(4-methoxyphenyl)prop-1-yn-1-yl)benzonitrile (1c). Purified
on silica gel with hexane/ AcOEt (3:1, v/v) as the eluent. 90% Yield (664 mg); Brown
1
oil; H NMR (400 MHz, CDCl ): δ 7.67ꢀ7.58 (m, 5H), 7.57ꢀ7.48 (m, 2H), 7.40 (td, J
3
1
3
= 7.6, 1.6 Hz, 1H), 6.90ꢀ6.84 (m, 4H), 3.78 (s, 6H), 3.12 (s, 1H); C NMR (100 MHz,
CDCl ): δ 159.4, 137.0, 132.8, 132.7, 132.6, 128.8, 127.7, 126.8, 118.0, 115.4, 113.9,
98.9, 83.0, 74.5, 55.5; IR (film): 3444, 2959, 2837, 2229, 1607, 1506, 1251, 1173,
3
ꢀ1
+
1
033, 831 cm ; HRMS (EIꢀTOF) m/z: M Calcd for C24
3
H19NO 369.1365; found
369.1366.
2
-(3-Hydroxy-3,3-di-p-tolylprop-1-yn-1-yl)benzonitrile (1d). Purified on silica gel
1
with hexane/ AcOEt (4:1, v/v) as the eluent. 94% Yield (634 mg); Brown oil; H
NMR (400 MHz, CDCl
3
): δ 7.66 (dd, J = 7.8, 0.6 Hz, 1H), 7.62ꢀ7.55 (m, 5H), 7.53 (td,
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J = 7.6, 1.2 Hz, 1H), 7.41 (td, J = 7.6, 1.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 4H), 2.97 (s,
1
3
1
1
2
H), 2.33 (s, 6H); C NMR (100 MHz, CDCl
3
): δ 141.8, 137.9, 132.9, 132.8, 132.6,
29.3, 128.9, 126.8, 126.3, 117.9, 115.6, 98.8, 83.1, 75.0, 21.3; IR (film): 3451, 2921,
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
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43
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45
46
47
48
49
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51
52
53
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55
56
57
58
59
60
ꢀ
1
+
229, 1592, 1508, 1482, 1164, 1052, 995, 763 cm ; HRMS (EIꢀTOF) m/z: M Calcd
19NO 337.1467; found 337.1464.
-(3,3-Bis(4-fluorophenyl)-3-hydroxyprop-1-yn-1-yl)benzonitrile (1e)
for C24
H
2
. Purified on
silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 89% Yield (614 mg); Brown oil;
1
3
H NMR (400 MHz, CDCl ): δ 7.71ꢀ7.62 (m, 5H), 7.59ꢀ7.52 (m, 2H), 7.46ꢀ7.41 (m,
13
1
1
H), 7.07ꢀ6.99 (m, 4H), 3.41 (s, 1H); C NMR (100 MHz, CDCl ): δ 162.6 (d, J
=
CF
3
4
3
2
46 Hz), 140.2 (d, JCF = 3 Hz), 132.9, 132.8, 132.7, 129.2, 128.2 (d, JCF = 8 Hz),
2
126.3, 118.0, 115.528, 115.526 (d, JCF = 22 Hz), 97.8, 83.7, 74.3; IR (film): 3428,
ꢀ1
3
073, 2231, 1603, 1505, 1412, 1228, 1158, 1054, 995, 836 cm ; HRMS (EIꢀTOF)
+
m/z: M Calcd for C22
H
13
F
2
NO 345.0965; found 345.0965.
2
-(3,3-Bis(4-bromophenyl)-3-hydroxyprop-1-yn-1-yl)benzonitrile (1f). Purified on
silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 92% Yield (856 mg); Brown
1
solid, mp 146ꢀ147 °C; H NMR (400 MHz, CDCl
3
): δ 7.71ꢀ7.67 (m, 1H), 7.59ꢀ7.53
): δ 143.1,
32.9, 132.8, 132.7, 131.9, 129.3, 128.1, 126.2, 122.6, 117.9, 115.6, 97.0, 84.0, 74.4;
13
(m, 6H), 7.51ꢀ7.43 (m, 5H), 3.20 (s, 1H); C NMR (100 MHz, CDCl
3
1
ꢀ1
IR (film): 3427, 3068, 2231, 1592, 1483, 1398, 1164, 1071, 1010, 994, 904, 807 cm ;
+
HRMS (EIꢀTOF) m/z: M Calcd for C22
2
H13Br NO 464.9364; found 464.9364.
2-(3-(4-Chlorophenyl)-3-hydroxy-3-phenylprop-1-yn-1-yl)benzonitrile
(1g).
Purified on silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 93% Yield (638 mg);
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2
1
2
3
4
5
6
7
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
1
Brown solid, mp 102ꢀ103 °C; H NMR (400 MHz, CDCl
3
): δ 7.71ꢀ7.62 (m, 5H),
7
3
1
7
.57ꢀ7.49 (m, 2H), 7.44ꢀ7.38 (m, 1H), 7.38ꢀ7.33 (m, 2H), 7.32ꢀ7.26 (m, 3H),
13
.34ꢀ3.33 (m, 1H); C NMR (100 MHz, CDCl
3
): δ 144.1, 143.1, 134.0, 132.8, 132.72,
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
32.70, 129.1, 128.75, 128.74, 128.4, 127.8, 126.4, 126.2, 117.9, 115.5, 97.8, 83.6,
ꢀ
1
4.7; IR (film): 3435, 3065, 2230, 1592, 1488, 1448, 1402, 1165, 1092, 993, 761 cm ;
+
HRMS (EIꢀTOF) m/z: M Calcd for C22
H14ClNO 343.0764; found 343.0766.
2
-(3-Hydroxy-3-(4-nitrophenyl)-3-phenylprop-1-yn-1-yl)benzonitrile (1h). Purified
on silica gel with hexane/ AcOEt (4:1, v/v) as the eluent. 91% Yield (644 mg); Brown
1
oil; H NMR (400 MHz, CDCl ): δ 8.21ꢀ8.15 (m, 2H), 7.92ꢀ7.87 (m, 2H), 7.73ꢀ7.65
3
(
m, 3H), 7.60ꢀ7.53 (m, 2H), 7.49ꢀ7.43 (m, 1H), 7.41ꢀ7.34 (m, 2H), 7.34ꢀ7.28 (m, 1H),
13
3.57 (s, 1H); C NMR (100 MHz, CDCl
3
): δ 151.3, 147.6, 143.4, 132.9, 132.8, 132.7,
1
29.4, 129.0, 128.8, 127.3, 126.2, 126.0, 123.9, 117.9, 115.6, 96.8, 84.3, 74.7; IR
ꢀ1
(film): 3432, 3068, 2230, 1593, 1519, 1448, 1346, 1165, 1052, 995, 764 cm ; HRMS
+
(
EIꢀTOF) m/z: M Calcd for C H N O 354.1004; found 354.1004.
22
14
2
3
2-(3-Hydroxy-3-phenyl-3-(p-tolyl)prop-1-yn-1-yl)benzonitrile (1i). Purified on
silica gel with hexane/ AcOEt (4.5:1, v/v) as the eluent. 92% Yield (594 mg); Yellow
1
oil; H NMR (400 MHz, CDCl
3
): δ 7.71 (d, J = 8.0 Hz, 2H), 7.65 (dd, J = 7.8, 0.6 Hz,
1
H), 7.62ꢀ7.54 (m, 3H), 7.52 (td, J = 7.2, 1.2 Hz, 1H), 7.40 (td, J = 7.6, 1.6 Hz, 1H),
7.38ꢀ7.32 (m, 2H), 7.30ꢀ7.25 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 3.08 (s, 1H), 2.32 (s,
13
3
H); C NMR (100 MHz, CDCl
3
): δ 144.6, 141.6, 138.0, 132.9, 132.8, 132.6, 129.3,
128.9, 128.6, 128.1, 126.7, 126.30, 126.29, 117.9, 115.5, 98.6, 83.2, 75.1 21.3; IR
(
film): 3445, 3061, 2921, 2229, 1592, 1509, 1481, 1448, 1335, 1164, 1049, 994, 896,
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3
1
2
3
4
5
6
7
8
9
ꢀ
1
+
7
60 cm ; HRMS (EIꢀTOF) m/z: M Calcd for C23
H
17NO 323.1310; found 323.1311.
2
-(3-Hydroxy-3-(4-methoxyphenyl)-3-phenylprop-1-yn-1-yl)benzonitrile
(1j).
Purified on silica gel with hexane/ AcOEt (4:1, v/v) as the eluent. 83% Yield (563 mg);
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
1
Brown oil; H NMR (400 MHz, CDCl ): δ 7.72ꢀ7.67 (m, 2H), 7.63ꢀ7.57 (m, 3H),
3
7
3
1
5
9
3
.51ꢀ7.42 (m, 2H), 7.37ꢀ7.30 (m, 3H), 7.28ꢀ7.21 (m, 1H), 6.87ꢀ6.82 (m, 2H), 3.73 (s,
1
3
3
H), 3.50 (s, 1H); C NMR (100 MHz, CDCl ): δ 159.3, 144.7, 136.8, 132.7, 132.64,
32.59, 128.8, 128.5, 127.9, 127.7, 126.6, 126.2, 117.9, 115.2, 113.8, 98.6, 83.0, 74.7,
5.4; IR (film): 3445, 3065, 2837, 2229, 1607, 1506, 1447, 1304, 1250, 1174, 1033,
ꢀ
1
+
92, 909, 761 cm ; HRMS (EIꢀTOF) m/z: M Calcd for C H NO 339.1259; found
23 17
2
39.1263.
2-Fluoro-6-(3-hydroxy-3,3-diphenylprop-1-yn-1-yl)benzonitrile (1k). Purified on
silica gel with hexane/ AcOEt (4:1, v/v) as the eluent. 89% Yield (582 mg); Yellow
1
solid, mp 134ꢀ135 °C; H NMR (400 MHz, CDCl
3
): δ 7.73ꢀ7.67 (m, 4H), 7.56ꢀ7.49
(
m, 1H), 7.40ꢀ7.33 (m, 5H), 7.32ꢀ7.27 (m, 2H), 7.18 (td, J = 8.6, 0.9 Hz, 1H), 3.04 (s,
1
3
1
3
1H); C NMR (100 MHz, CDCl
3
): δ 163.4 (d, JCF = 259 Hz), 144.2, 134.5 (d, JCF =
4
3
9
Hz), 128.7, 128.6 (d, JCF = 3 Hz), 128.33, 128.29 (d, JCF = 2 Hz), 126.3, 116.6 (d,
2
2
4
J
CF = 20 Hz), 113.1, 104.7 (d, JCF = 16 Hz), 99.4, 82.5 (d, JCF = 4 Hz), 75.2; IR
ꢀ1
(
film): 3452, 3060, 2234, 1603, 1567, 1470, 1250, 1065, 1011, 796 cm ; HRMS
+
(EIꢀTOF) m/z: M Calcd for C H FNO 327.1059; found 327.1059.
22
14
5
-Bromo-2-(3-hydroxy-3,3-diphenylprop-1-yn-1-yl)benzonitrile (1l). Purified on
silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 85% Yield (658 mg); Brown
1
solid, mp 81ꢀ82 °C. H NMR (400 MHz, CDCl
3
): δ 7.70ꢀ7.62 (m, 5H), 7.52 (dd, J =
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6
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8
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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
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
8
1
7
.4, 2.0 Hz, 1H), 7.34ꢀ7.19 (m, 7H), 3.58 (s, 1H); C NMR (100 MHz, CDCl
3
): δ
44.2, 135.9, 135.1, 133.7, 128.5, 128.1, 126.2, 125.4, 122.5, 116.7, 116.5, 99.6, 82.3,
ꢀ
1
5.0; IR (film): 3451, 3062, 2232, 1598, 1482, 1450, 1274, 1183, 1031, 992, 740 cm ;
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
+
HRMS (EIꢀTOF) m/z: M Calcd for C H BrNO 387.0259; found 387.0259.
22
14
2
-(3-Hydroxy-3,3-diphenylprop-1-yn-1-yl)-5-nitrobenzonitrile (1m). Purified on
silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 81% Yield (573 mg); Brown oil;
1
H NMR (400 MHz, CDCl
3
): δ 8.45 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 8.6, 2.2 Hz, 1H),
13
7
.70ꢀ7.63 (m, 5H), 7.38ꢀ7.31 (m, 4H), 7.30ꢀ7.25 (m, 2H), 3.43 (s, 1H); C NMR (100
MHz, CDCl ): δ 146.9, 143.7, 133.8, 132.6, 128.7, 128.4, 127.8, 127.3, 126.2, 116.6,
3
1
15.9, 104.0, 82.0, 75.2; IR (film): 3459, 3085, 2237, 1602, 1531, 1450, 1352, 1165,
ꢀ1
+
1032, 911, 743 cm ; HRMS (EIꢀTOF) m/z: M Calcd for C22
14 2 3
H N O 354.1004;
found 354.1008.
2-(3-Hydroxy-3,3-diphenylprop-1-yn-1-yl)-5-methoxybenzonitrile (1n). Purified on
silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 19% Yield (129 mg); Brown oil;
1
H NMR (400 MHz, CDCl
3
): δ 7.74ꢀ7.67 (m, 4H), 7.44 (d, J = 8.8 Hz, 1H), 7.38ꢀ7.31
(
m, 4H), 7.29ꢀ7.23 (m, 2H), 7.10 (d, J = 2.8 Hz, 1H), 7.02 (dd, J = 8.6, 2.6 Hz, 1H),
13
3.79 (s, 3H), 3.19 (s, 1H); C NMR (100 MHz, CDCl
3
): δ 159.6, 144.7, 134.2, 128.6,
1
28.1, 126.3, 119.3, 118.7, 117.8, 117.6, 116.5, 96.6, 83.2, 75.2, 56.0; IR (film): 3454,
ꢀ1
3060, 2230, 1601, 1501, 1450, 1315, 1162, 1043, 991, 746 cm ; HRMS (EIꢀTOF)
+
m/z: M Calcd for C23
H17NO
2
339.1259; found 339.1262.
2-(3-Hydroxy-3,3-diphenylprop-1-yn-1-yl)-4-(trifluoromethyl)benzonitrile
(1o).
Purified on silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 93% Yield (701 mg);
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1
2
3
4
5
6
7
8
9
1
Yellow solid, mp 120ꢀ121 °C. H NMR (400 MHz, CDCl
3
): δ 7.78 (s, 1H), 7.72ꢀ7.65
(
m, 5H), 7.59 (dd, J = 8.4, 0.8 Hz, 1H), 7.37ꢀ7.30 (m, 4H), 7.28ꢀ7.22 (m, 2H), 3.55 (s,
13
2
1
3
H); C NMR (100 MHz, CDCl ): δ 144.0, 134.6 (q, JCF = 34 Hz), 133.4, 129.5 (q,
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
1
JCF = 4 Hz), 128.6, 128.2, 127.7, 126.3, 125.5 (q, J = 4 Hz), 122.8 (q, J = 272
CF
CF
Hz), 118.6, 116.7, 100.5, 82.0, 75.2; IR (film): 3459, 3061, 2237, 1598, 1490, 1417,
ꢀ1
+
1
332, 1177, 1070, 996, 906, 700 cm ; HRMS (EIꢀTOF) m/z: M Calcd for
NO 377.1027; found 377.1024.
-Fluoro-2-(3-hydroxy-3,3-diphenylprop-1-yn-1-yl)benzonitrile (1p). Purified on
23 14 3
C H F
3
silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 16% Yield (105 mg); Brown oil;
1
3
H NMR (400 MHz, CDCl ): δ 7.73ꢀ7.68 (m, 4H), 7.46 (dd, J = 7.6, 1.2 Hz, 1H),
1
3
7.39ꢀ7.33 (m, 5H), 7.32ꢀ7.26 (m, 3H), 3.18 (s, 1H); C NMR (100 MHz, CDCl
3
): δ
1
3
4
1
62.7 (d, JCF = 254 Hz), 144.2, 130.6 (d, JCF = 9 Hz), 128.8 (d, JCF = 4 Hz), 128.7,
2
4
3
128.3, 126.3, 120.4 (d, JCF = 21 Hz), 117.1 (d, JCF = 3 Hz), 116.7 (d, JCF = 4 Hz),
2
3
1
15.5 (d, J = 19 Hz), 103.7 (d, J = 4 Hz), 77.2, 75.3; IR (film): 3444, 3060, 2239,
CF CF
ꢀ1
+
1567, 1464, 1269, 1164, 1031, 992, 766 cm ; HRMS (EIꢀTOF) m/z: M Calcd for
14FNO 327.1059; found 327.1058.
2-(3,3-Bis(4-chlorophenyl)-3-hydroxyprop-1-yn-1-yl)-5-bromobenzonitrile
22
C H
(1q).
Purified on silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 90% Yield (819 mg);
1
Yellow oil; H NMR (400 MHz, CDCl ): δ 7.80 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.4,
3
2
.0 Hz, 1H), 7.62ꢀ7.56 (m, 4H), 7.42 (d, J = 8.8 Hz, 1H), 7.35ꢀ7.30 (m, 4H), 3.26 (s,
13
1H); C NMR (100 MHz, CDCl
3
): δ 142.4, 136.2, 135.5, 134.5, 133.8, 129.0, 127.7,
1
25.1, 123.2, 117.1, 116.6, 98.4, 83.1, 74.3; IR (film): 3434, 3068, 2234, 1580, 1482,
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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
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ꢀ
1
+
1
402, 1182, 1093, 1014, 993, 831 cm ; HRMS (EIꢀTOF) m/z: M Calcd for
NO 454.9479; found 454.9483 .
-(3,3-Bis(4-chlorophenyl)-3-hydroxyprop-1-yn-1-yl)-5-methoxybenzonitrile (1r).
22 2
C H12BrCl
2
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
Purified on silica gel with hexane/ AcOEt (6:1, v/v) as the eluent. 14% Yield (114 mg);
1
Brown oil; H NMR (400 MHz, CDCl
3
): δ 7.65ꢀ7.58 (m, 4H), 7.45 (d, J = 8.8 Hz, 1H),
7
3
1
2
.34ꢀ7.28 (m, 4H), 7.13 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 8.6, 2.6 Hz, 1H), 3.84 (s,
1
3
H), 3.32 (s, 1H); C NMR (100 MHz, CDCl
3
): δ 159.9, 142.9, 134.21, 134.18,
28.8, 127.8, 119.4, 118.2, 117.8, 117.7, 116.7, 95.5, 83.9, 74.3, 56.1; IR (film): 3436,
ꢀ1
941, 2840, 2231, 1602, 1489, 1403, 1316, 1234, 1092, 1014, 905, 835 cm ; HRMS
+
(EIꢀTOF) m/z: M Calcd for C23
H
15Cl
2
NO
2
407.0480; found 407.0482.
General Procedure for the Synthesis of 2. To a stirred solution of 1 (0.2 mmol) in
2 4
DCE (4 mL) was added concentrated H SO (12.8 ꢁL, 0.24 mmol). The reaction
o
mixture was stirred at 83 C for 30 min. After the reaction completed, the mixture was
concentrated under reduced pressure and the residue was purified by column
chromatography over silica gel with hexane/ AcOEt as the eluent to give pure 2.
3
-Phenylspiro[indene-1,1'-isoindolin]-3'-one (2a). Purified on silica gel with
hexane/ AcOEt (3:1, v/v) as the eluent. 97% yield (60 mg); Yellow solid ); mp
1
115ꢀ116 °C; H NMR (500 MHz, CDCl
3
): δ 7.92 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 7.5
Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.52ꢀ7.40 (m, 5H), 7.34 (td, J = 7.5, 0.5 Hz, 1H),
.19 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.25 (s,
7
1
3
1H), 6.21 (s, 1H); C NMR (125 MHz, CDCl
3
): δ 171.1, 146.9, 146.4, 145.8, 142.6,
1
34.4, 133.5, 132.7, 131.8, 129.07, 129.05, 129.0, 128.9, 127.8, 127.4, 124.4, 123.2,
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2
3
4
5
6
7
8
9
ꢀ1
1
22.1, 121.6, 72.6; IR (film): 3399, 3224, 3066, 1694, 1466, 1313, 909, 733 cm ;
+
HRMS (EIꢀTOF) m/z: M Calcd for C22
H15NO 309.1154; found 309.1147.
6
-Chloro-3-(4-chlorophenyl)spiro[indene-1,1'-isoindolin]-3'-one (2b). Purified on
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
silica gel with hexane/ AcOEt (3:1, v/v) as the eluent. 81% Yield (61 mg); White solid,
1
mp 271ꢀ272 °C; H NMR (500 MHz, CDCl
3
): δ 7.91 (d, J = 7.0 Hz, 1H), 7.57ꢀ7.53
(m, 2H), 7.52ꢀ7.44 (m, 4H), 7.42 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.3, 1.8 Hz, 1H),
1
3
7
.02 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 6.53 (s, 1H), 6.22 (s, 1H); C NMR
): δ 171.1, 147.8, 145.4, 145.1, 140.6, 135.1, 134.2, 133.8, 133.0,
32.4, 131.7, 129.4, 129.3, 129.0, 124.6, 124.0, 122.3, 122.0, 72.2; IR (film): 3410,
(125 MHz, CDCl
3
1
3
ꢀ1
+
222, 3075, 2926, 1698, 1489, 1463, 1312, 1088, 731 cm ; HRMS (EIꢀTOF) m/z: M
NO 377.0374; found 377.0370.
-Methoxy-3-(4-methoxyphenyl)spiro[indene-1,1'-isoindolin]-3'-one (2c). Purified
Calcd for C22H13Cl
2
6
on silica gel with hexane/ AcOEt (2:1, v/v) as the eluent. 53% Yield (39 mg); White
1
solid, mp 215ꢀ217 °C; H NMR (500 MHz, CDCl ): δ 7.89 (d, J = 7.0 Hz, 1H), 7.57
3
(d, J = 8.5 Hz, 2H), 7.48ꢀ7.38 (m, 3H), 6.99 (d, J = 8.5 Hz, 3H), 6.83 (dd, J = 8.5, 2.0
Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 6.47 (s, 1H), 6.00 (s, 1H), 3.86 (s, 3H), 3.69 (s, 3H);
1
3
C NMR (125 MHz, CDCl
31.7, 129.9, 128.9, 128.7, 127.1, 124.3, 122.2, 122.1, 114.4, 114.1, 109.5, 72.3, 55.8,
55.6; IR (film): 3390, 3227, 3071, 2936, 1698, 1611, 1509, 1467, 1249, 1030, 910,
3
): δ 171.2, 160.1, 159.7, 147.9, 146.9, 146.0, 135.3, 132.7,
1
ꢀ1
+
7
32 cm ; HRMS (EIꢀTOF) m/z: M Calcd for C24
3
H19NO 369.1365; found 369.1364.
6-Methyl-3-(p-tolyl)spiro[indene-1,1'-isoindolin]-3'-one (2d). Purified on silica gel
with hexane/ AcOEt (3:1, v/v) as the eluent. 87% Yield (58 mg); White solid, mp
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8
1
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3
4
5
6
7
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
1
2
32ꢀ233 °C; H NMR (500 MHz, CDCl
3
): δ 7.90 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.0
Hz, 2H), 7.48ꢀ7.38 (m, 3H), 7.28 (d, J = 7.5 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.99 (d,
1
3
J = 7.0 Hz, 1H), 6.84 (s, 1H), 6.36 (s, 1H), 6.09 (s, 1H), 2.42 (s, 3H), 2.25 (s, 3H); C
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
NMR (125 MHz, CDCl ): δ 171.2, 146.8, 146.7, 146.1, 140.0, 138.8, 137.4, 132.6,
3
1
2
31.84, 131.81, 131.7, 129.7, 129.5, 128.7, 127.6, 124.3, 124.0, 122.1, 121.4, 72.4,
ꢀ1
1.6, 21.5; IR (film): 3391, 3226, 3068, 2921, 1694, 1468, 1311, 909, 732 cm ;
+
HRMS (EIꢀTOF) m/z: M Calcd for C24
H
19NO 337.1467; found 337.1467.
6
-Fluoro-3-(4-fluorophenyl)spiro[indene-1,1'-isoindolin]-3'-one (2e). Purified on
silica gel with hexane/ AcOEt (3:1, v/v) as the eluent. 65% Yield (45 mg); Brown
1
solid, mp 207ꢀ208 °C; H NMR (400 MHz, CDCl
3
): δ 7.92ꢀ7.85 (m, 1H), 7.64ꢀ7.56
(m, 2H), 7.52ꢀ7.40 (m, 3H), 7.22ꢀ7.13 (m, 2H), 7.06ꢀ6.97 (m, 2H), 6.92 (s, 1H), 6.75
13
(
dd, J = 7.8, 2.2 Hz, 1H), 6.16 (s, 1H); C NMR (100 MHz, CDCl
3
): δ 171.4, 163.2
1
1
3
(d, JCF = 247 Hz), 162.8 (d, JCF = 247 Hz), 148.4 (d, JCF = 8 Hz), 145.8, 145.2,
4
4
4
1
38.2 (d, J = 3 Hz), 133.1 (d, J = 3 Hz), 132.9, 131.7, 130.2 (d, J = 3 Hz),
CF CF CF
3
3
2
129.5 (d, JCF = 8 Hz), 129.1, 124.5, 122.3 (d, JCF = 8 Hz), 122.0, 116.2 (d, JCF = 22
2
2
4
Hz), 115.7 (d, JCF = 23 Hz), 111.4 (d, JCF = 24 Hz), 72.2 (d, JCF = 2 Hz); IR (film):
ꢀ
1
3407, 3218, 3072, 1698, 1607, 1506, 1476, 1344, 1226, 1159, 909, 733 cm ; HRMS
+
(
EIꢀTOF) m/z: M Calcd for C22
H
13
F
2
NO 345.0965; found 345.0964.
6-Bromo-3-(4-bromophenyl)spiro[indene-1,1'-isoindolin]-3'-one (2f). Purified on
silica gel with hexane/ AcOEt (3:1, v/v) as the eluent. 63% Yield (59 mg); Brown
1
solid, mp 277ꢀ278 °C; H NMR (400 MHz, CDCl
3
): δ 7.96ꢀ7.90 (m, 1H), 7.65ꢀ7.60
(
m, 2H), 7.55ꢀ7.44 (m, 5H), 7.36 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.00 (d,
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The Journal of Organic Chemistry
2
9
1
2
3
4
5
6
7
8
9
1
3
J = 6.8 Hz, 1H), 6.21 (s, 1H), 6.14 (s, 1H); C NMR (100 MHz, CDCl
3
): δ 170.9,
47.9, 145.3, 145.2, 141.0, 134.1, 133.0, 132.7, 132.4, 132.2, 131.6, 129.33, 129.30,
26.8, 124.7, 123.3, 122.7, 122.1, 121.9, 72.2; IR (film): 3409, 3208, 3074, 1698,
1
1
1
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
ꢀ1
485, 1464, 1398, 1337, 1315, 1263, 1070, 1010, 908, 823, 731 cm ; HRMS
+
(
EIꢀTOF) m/z: M Calcd for C22
H
13Br
2
NO 464.9364; found 464.9363.
3
-(4-Chlorophenyl)spiro[indene-1,1'-isoindolin]-3'-one (2g). Purified on silica gel
1
with hexane/ AcOEt (3:1, v/v) as the eluent. 94% Yield (64 mg); oil; H NMR (400
MHz, CDCl
3
): δ 7.89 (dd, J = 6.6, 1.4 Hz, 1H), 7.60ꢀ7.54 (m, 2H), 7.51ꢀ7.39 (m, 5H),
7
.34 (td, J = 7.6, 0.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.98
13
(
dd, J = 6.4, 1.2 Hz, 1H), 6.64 (s, 1H), 6.20 (s, 1H); C NMR (100 MHz, CDCl
171.4, 146.1, 145.8, 145.7, 142.1, 134.7, 134.0, 132.8, 132.7, 131.9, 129.2, 129.1,
29.0, 128.9, 127.5, 124.4, 123.3, 122.0, 121.4, 72.6; IR (film): 3400, 3218, 3069,
3
): δ
1
ꢀ1
+
1694, 1610, 1489, 1314, 1086, 909, 732 cm ; HRMS (EIꢀTOF) m/z: M Calcd for
C H ClNO 343.0764; found 343.0760.
22
14
3-(4-Nitrophenyl)spiro[indene-1,1'-isoindolin]-3'-one (2h). Purified on silica gel
with hexane/ AcOEt (3:1, v/v) as the eluent. 79% Yield (56 mg); Pale brown solid, mp
1
244ꢀ245 °C; H NMR (400 MHz, CDCl
3
): δ 8.39ꢀ8.33 (m, 2H), 7.92 (dd, J = 6.4, 1.2
Hz, 1H), 7.85ꢀ7.80 (m, 2H), 7.53ꢀ7.43 (m, 3H), 7.39 (td, J = 7.6, 0.8 Hz, 1H), 7.25 (t,
J = 7.2 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.60 (s, 1H), 6.39
13
(
s, 1H); C NMR (100 MHz, CDCl
3
): δ 171.2, 148.1, 145.64, 145.61, 145.0, 141.4,
140.9, 136.5, 132.9, 131.8, 129.4, 129.2, 128.7, 128.1, 124.6, 124.4, 123.6, 122.0,
1
21.3, 72.6; IR (film): 3399, 3196, 3069, 1694, 1599, 1516, 1464, 1347, 1315, 1107,
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