Regioselective Synthesis of Isocoumarins via Iridium(III)-Catalyzed Oxidative Cyclization of Aromatic Acids with Propargyl Alcohols

Article abstract of DOI:10.1021/acs.joc.8b03077

An Ir(III)-catalyzed oxidative cyclization of benzoic acids with propargyl alcohols to give substituted isocoumarins in a highly regioselective manner is described. This protocol has a broad substrate scope with high functional group tolerance. The observed isocoumarins were converted into biologically active tetracyclic indeno[2,1-c]isocoumarins by Lewis acid-mediated cyclization. A possible reaction mechanism is proposed and strongly supported by the detailed mechanistic investigation and DFT.

Full text of DOI:10.1021/acs.joc.8b03077

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Article
Regioselective Synthesis of Isocoumarins via Iridium(III)-Catalyzed
Oxidative Cyclization of Aromatic Acids with Propargyl Alcohols
Pinki Sihag, and Masilamani Jeganmohan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Feb 2019
Downloaded from http://pubs.acs.org on February 7, 2019
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Regioselective Synthesis of Isocoumarins via Iridium(III)-Catalyzed
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Oxidative Cyclization of Aromatic Acids with Propargyl Alcohols
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Pinki Sihag and Masilamani Jeganmohan*
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Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil
Nadu, India
E-mail: mjeganmohan@iitm.ac.in
Table of Contents/Abstract Graphic
Abstract
An Ir(III)-catalyzed oxidative cyclization of benzoic acids with propargyl alcohols to
give substituted isocoumarins in a highly regioselective manner is described. This protocol
has broad substrate scope with high functional group tolerance. The observed isocoumarins
were converted into biologically active tetracyclic indeno[2,1-c]isocoumarins by Lewis acid
mediated cyclization. A possible reaction mechanism is proposed and strongly supported by
the detailed mechanistic investigation and DFT.
Introduction
Isocoumarins are privileged oxygen containing heterocyclic molecules and also the benzo
derivative of α-pyranones. These are naturally occurring unsaturated lactones and its
structural motifs are present in many natural products and biologically active molecules.1
These molecules exhibit the wide range of biological activities as well as serve as a key
intermediate for various synthetic transformations.2 Considering all these importance,
enormous effort has been devoted to synthesize isocoumarins.3 In recent years, by using
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metal catalysts, isocoumarins are prepared very efficiently. Generally, isocoumarins are
prepared by the metal-catalyzed cyclization of o-haloaromatic esters or acid with π-
components, carbonylative cyclization of o-halophenols with π-components and electrophilic
cyclization of substituted alkynes.3
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Transition-metal-catalyzed oxidative cyclization of substituted benzoic acids with alkynes via
C-H bond activation is an efficient method for synthesizing isocoumarins in a highly atom-
economical manner as compared with other metal-catalyzed reactions.4 A few reports are
available in the literature for synthesizing isocoumarins in the presence of Ru,5b-c Rh,5d-i Co5j
and Ir5k-l complexes via C-H bond activation. In the known methodologies, Rh, Ir and Co
metals provided regioisomeric mixtures of isocoumarin derivatives in the reaction of
aromatic acids with unsymmetrical alkynes (Scheme 1). In the observed major product, the
aryl substituted carbon of an alkyne prefers to stay at the C3 position. In the meantime, the
ruthenium metal provides the cyclized product in a highly regioselective manner.
Subsequently, the iridium metal also selectively provided naphthalene derivatives apart from
isocoumarins.
Scheme 1. Cyclization of Benzoic Acids with Alkynes
Herein, we report a diverse regioselective oxidative cyclization of benzoic acids with
propargyl alcohols in the presence of metal catalysts such as Ru or Rh or Ir (Scheme 2). It is
interesting to note that in the Ru and Ir metal catalysts; the phenyl group is attached at the C4
position and the alkyl group at the C3 position very selectively which is the diverse
selectivity as compared with previous methods. However, in the rhodium-catalyzed reaction,
mixture of regioisomeric products was observed. In the present cyclization reaction, the steric
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as well as coordinating ability of tertiary hydroxyl group of propargyl alcohol plays a
significant role for the high regioselectivity by coordinating with the Ir metal forming a
seven-membered metalacycle intermediate. It is important to note that the other competitive
reaction such as ortho allenylation followed by cyclization via β-hydroxyl elimination was
not observed.6
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Scheme 2. Metal-Catalyzed Oxidative Cyclization
Results and Discussion
Treatment of 4-methoxybenzoic acid (1a) with propargyl alcohol 2a in the presence of
[Cp*IrCl2]2 (3 mol %), LiOAc.2H2O (1.0 equiv) and Ag2CO3 (1.2 equiv) in ClCH2CH2Cl at
80 C for 20 h gave isocoumarin derivative 3aa in 86% isolated yield in a highly selective
manner (Scheme 2). In the reaction, the other possible regioisomer 3aa’ was not observed. In
product 3aa, the alkyl substituted carbon of 2a is attached at the C3 position and Ph group at
the C4 position. Initially, the cyclization reaction of 1a with 2a was examined in the presence
of [{Ru(CH3CN)3(p-cymene)}{SbF6}2] (10 mol %) in ClCH2CH2Cl at 100 C for 24 h. In the
reaction, product 3aa was observed in 25% yield. The reaction was examined with various
solvents and acetate sources. However, no improvement was observed in the yield (for
detailed optimization studies, see Supporting Information (SI)). Meanwhile, the reaction was
examined with various oxidants including Ag2CO3 along with LiOAc.2H2O. The yield of
product 3aa was not increased. Next, the reaction was examined with other metal catalysts
such as rhodium and iridium. The cyclization reaction of 1a with 2a in the presence of
[{Rh(CH3CN)3(Cp*)}{SbF6}2] (10 mol %), LiOAc.2H2O (1.0 equiv) and Ag2CO3 (1.2 equiv)
in ClCH2CH2Cl at 100 C for 24 h provided mixture of regioisomeric products 3aa and 3aa’
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in 76% and 8% yields, respectively. It is very interesting to note that the same reaction was
examined in the presence of [Cp*IrCl2]2 (3 mol %). In the reaction, exclusively product 3aa
was observed in 86% yield. The reaction was examined without LiOAc.2H2O. In the reaction,
product 3aa was observed in 61% yield. Product 3aa was not observed without Ag2CO3.
Meanwhile, the product yield 3aa was observed in 63% yield in the presence of 0.6 equiv of
Ag2CO3. The optimization study clearly reveals that both Ag2CO3 and LiOAc are crucial for
getting 3aa in more yields and also [Cp*IrCl2]2 is crucial for the high regioselectivity (see SI
for the detailed optimization studies).
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The scope of annulation reaction was examined with assorted substituted benzoic acids
(Table 1). 4-Methyl benzoic acid (1b) or benzoic acid (1c) reacted with 2a giving the
expected products 3ba and 3ca in 89% and 88% yields, respectively (entries 1-2). Halogen I,
Br, Cl, F substituent at the para position of benzoic acids 1d-g effectively participated in the
reaction, giving 3da-3ga in 60%, 77%, 87% and 81% yields, respectively (entries 3-6).
Electron-withdrawing 4-nitro and 4-cyano benzoic acids 1h-i provided the expected products
3ha and 3ia in moderate 42% and 32% yields, respectively (entries 7 and 8). ortho Methyl
and phenyl benzoic acids 1j-k was also efficiently involved in the reaction, affording
products 3ja and 3ka in 82% and 56%, respectively (entries 9 and 10). Interestingly, a free
hydroxyl group substituted 3,5-dihydroxy benzoic acid 1l as well as 1m also efficiently
participated in the reaction, yielding products 3la and 3ma in 53% and 75% yields,
respectively. 1-Naphthoic acid (1n) reacted with 2a giving 3na in moderate 31% yield.
Heterocyclic, thiophene 2-carboxylic acid 1o, also efficiently participated in the reaction,
giving product 3oa in 40% yield.
Table 1. Scope of Aromatic Acids 1b-oa
Entry
product 3
yield (%)b
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1b: R1 = Me
1c: R1 = H
1d: R1 = I
3ba: R1 = Me
3ca: R1 = H
3da: R1 = I
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1e: R1 = Br
1f: R1 = Cl
1g: R1 = F
1h: R1 = NO2
3ea: R1 = Br
3fa: R1 = Cl
3ga: R1 = F
3ha: R1 = NO2
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1i: R1 = CN
3ia: R1 = CN
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1j: R1 = Me
1k: R1 = Ph
3ja: R1 = Me
3ka: R1 = Ph
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1l: R1 = OH
3la: R1 = OH
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1m: R1 = OMe
3ma: R1 = OMe
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aAll reactions were carried out using 1b-o (0.057 gm, 0.37 mmol), 2a (0.050 gm, 0.3
mmol), [Cp*IrCl2]2 (0.007 gm, 0.009 mmol), LiOAc.2H2O (0.032 gm, 0.3 mmol) and
Ag2CO3 (0.103 gm, 0.37 mmol) in ClCH2CH2Cl (2.0 mL) under N2 at 80 C for 20 h.
bIsolated yield.
Interestingly, meta Cl 1p and Br 1q substituted benzoic acids reacted with 2a providing
single regioisomeric products 3pa and 3qa in 50% and 63% yields, respectively (Scheme 3).
However, 3-methoxy benzoic acid 1r provided mixture of regioisomeric products 3ra and
3ra’ in 82% combined yields in a 1:1 ratio. 3,4-Dimethoxy benzoic acid 1s reacted with 2a
giving cyclized product 3sa in 92% in a highly selective manner. However, piperonylic acid
(1t) afforded regioisomeric products 3ta and 3ta’ in combined 73% yields in 3:1 ratio. At
present, the exact rationale behind the observation of difference in the regioselectivity of
benzoic acids 1p-t is unclear. It is believed that the steric hindrance could play an important
role for the high regioselectivity.
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Scheme 3. Scope of Unsymmetrical Benzoic Acids
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Table 2. Scope of Propargyl Alcohols 2b-ia
Entry
product 3
yield (%)b
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2b: R1 = OMe
2c: R1 = Me
2d: R1 = Br
3sb: R1 = OMe
3sc: R1 = Me
3sd: R1 = Br
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aAll reactions were carried out using 1s (0.057 gm, 0.37 mmol), 2b-i (0.050 gm, 0.3
mmol), [Cp*IrCl2]2 (0.007 gm, 0.009 mmol), LiOAc.2H2O (0.032 gm, 0.3 mmol) and
Ag2CO3 (0.103 gm, 0.37 mmol) in ClCH2CH2Cl (2.0 mL) under N2 at 80 C for 20 h.
bIsolated yield.
The scope of cyclization reaction was examined with substituted propargyl alcohols (Table
2). The reaction of OMe, Me, Br substituent on the aryl ring of propargyl alcohols 2b-d with
1s gave cyclized products 3sb-3sd in 92%, 75% and 78% yields, respectively (entries 1-3).
ortho Bromo substituent on the aryl ring of propargyl alcohol 2e also efficiently participated
in the reaction, giving cyclized product 3se in 94% yield. Heterocyclic 2-thienyl 2f and alkyl
2g substituted propargyl alcohols also efficiently reacted with 1s, affording cyclized products
3sf and 3sg in 75% and 92% yields, respectively. α-Disubstituted propargyl alcohols 2h and
2i reacted with 1s, giving cyclized products 3sh and 3si in 80% and 90% yields, respectively.
The structure of 3ba (CCDC 1875730) is confirmed by a single crystal XRD (see SI).
However, 3-phenylprop-2-yn-1-ol, but-2-yn-1-ol, α-methyl substituted 4-phenylbut-3-yn-2-
ol, (3,3-dimethylbut-1-yn-1-yl)benzene as well as 3,3-dimethylbut-1-yne were not suitable
for the reaction.
The isocoumarin derivatives were further converted into biologically active tetracyclic
systems indeno[2,1-c]isocoumarin by intramolecular Lewis acid mediated cyclization.
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.
Treatment of 3aa with BF3 O(Et)2 in DCE at 100 C for 12 h gave tetracyclic product 4a in
excellent 93% yield (Scheme 4). In a similar fashion, products 3aa, 3ba, 3ca, 3ga, 3sb and
3sc were converted into the expected products 4b-f in excellent 93%, 93%, 92%, 90%, 89%
and 90% yields, respectively. This type of tetracyclic molecules shows various biological
properties including anticancer and cytotoxic properties.7 The structure of 4a (CCDC
1875796) is confirmed by a single crystal XRD (see SI).
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Scheme 4. Preparation of Indeno[2,1-c]isocoumarins
The reaction of 4-methoxy benzoic acid (1a) with d4-AcOH provided [D]-1a in 80% yield in
which the deuterium incorporation was observed at the both ortho carbons in 40% (Scheme
5). Further, in the reaction of 1a with 2a in the presence of d4-AcOH, product [D]-3aa was
observed in 87% yield, in which 88% of deuterium incorporation was observed at the ortho
C-H position. This result reveals that the C-H bond activation is a reversible process. Further,
the kinetic isotopic effect study was carried by using deuterated benzoic acid [D]-1c and
benzoic acid 1c in the competitive version and independent version. In the competitive
reaction, kH/kD was observed to be around 2.83. Similarly, in parallel two pot reaction, kH/kD
was observed around 2.2. This result reveals that the C-H activation could be the rate
determining step in the reaction. Next, the competitive reaction was carried out with equal
amount of 4-F 1g and 4-OMe 1a benzoic acids. In the reaction, 3aa was observed in 28% and
3ha in 33% yields, respectively. This indicates that the electrophilic iridiation is unlikely.
.
Further, the metalacycle intermediate C was isolated in the reaction of Cp*Ir(OAc)2 DMSO
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with 1a. Later, the metalacycle intermediate C was treated with 2a yielding product 3aa in
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75% yield. This result suggests that the metalacycle is key intermediate in the reaction.
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Scheme 5. Mechanistic Studies
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A plausible mechanism is proposed for the cyclization reaction in Scheme 6. The [Cp*IrCl2]2
complex reacted with LiOAc giving the active catalyst [Cp*Ir(OAc)2] 5. The benzoic acid 1
reacted with one of the acetate groups of complex 5 affording benzoate-Ir complex 6. The
ortho C-H bond of benzoate is deprotonated by an acetate group in complex 6 provides
iridiacycle intermediate 7. The regioselective coordinative insertion of propargyl alcohol 2
into the Ir-C bond of complex 7 gives a seven membered iridiacycle intermediate 9. The
reductive elimination of intermediate 9 giving product 3 and Ir(I) species. The active Ir(III)
species 5 can be regenerated by the reaction of Ir(I) with Ag(I) and AcOH
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Scheme 6. Proposed Mechanism
DFT calculations were carried out for understanding the proposed reaction mechanism using
M06 density functional theory (Figure 1). The active catalyst [Cp*Ir(OAc)2] 5 can be
generated by the reaction of [Cp*IrCl2]2 with LiOAc. In the first step, lithium benzoate
replaces one of the acetate ligand in the active complex 5, gives int-6 which has coordination
of benzoate through the oxygen atom, one acetate moiety and Cp* ligand. Concerted
metalation-deprotonation of the ortho C-H bond of benzoate in int-6 takes place via TS-1,
forming int-7. The ortho C-H bond in intermediate int-6 is activated by an acetate moiety via
agostic interaction. The overall C-H activation barrier is found to be 16.0 kcal.mol-1. The
replacement of acetic acid by propargyl alcohol 2 in int-7 forms int-8a. It involves pre-
coordination of the hydroxyl group with an iridium metal centre which may be the reason for
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high regioselectivity. In next step, more stable int-8b is formed by coordination of Ir to
alkyne carbon of propargyl alcohol exergonically (-10.33 kcal.mol-1). It is noted that the
formation of isomer 8b is more favourable than the isomer 8b’ by -2 kcal. mol-1. Meanwhile,
the energy calculation for transition states was also performed. It was observed that the TS-2
(18.4 kcal/mol) has lower energy than the TS-2’ (21.2 kcal/mol). Both steric as well as weak
interaction between Ir-O play an important role for the selectivity. Since the distance between
Ir-O is 3.23 Å, there could be very weak interaction between metal and oxygen atom in TS-2.
Meanwhile, the steric factor may also play the major role in the selective formation of TS-2.
Further, more stable TS-2 results in int-9 exergonically (-42.0 kcal.mol-1). In the next step,
int-9 is rearranged into int-10a by absorption of 19.17 kcal.mol-1 of energy followed by
oxidation with AgOAc providing thermodynamically stable int-10b. The int-10b dissociates
product 3 and further oxidizes with AgOAc giving active catalyst 5.5k It is expected that the
pre-coordination of the OH group and steric effect of propargyl alcohol could be important
for the selectivity.
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Figure 1. DFT-computed energy profiles.
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Conclusion
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In conclusion, we have demonstrated an iridium-catalyzed cyclization of benzoic acids with
propargyl alcohols. The reaction provides isocoumarins in a highly regioselective manner.
The hydroxyl group of propargyl alcohol plays crucial role for the high selectivity. The
observed isocoumarins were converted into tetracyclic indeno[2,1-c]isocoumarins by Lewis
acid mediated cyclization. A possible reaction mechanism was proposed and strongly
supported by the detailed mechanistic investigation and DFT studies.
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Experimental Section
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General information: All reactions were carried out under the N2 atmosphere in flame-dried
glassware. Syringes which were used to transfer anhydrous solvents or reagents were purged
with nitrogen prior to use (three times). Dry solvents are used for the reaction. Column
chromatographical purifications were performed using SiO2 (120- 200 mesh ASTM) from
Merck if not indicated otherwise. Abbrevations for signal coupling are as follows: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet. The starting materials, propargyl alcohols 2a-i,
were prepared according to the literature procedures.8 Commercially available metal salts and
acids were purchased from Sigma-Aldrich and Spectrochem. Pvt. Ltd., India and used
without further purification.
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General Procedure 1 for the Synthesis of Isocoumarins.
A 15 ml schlenk tube with septum containing propargyl alcohol 2a (0.050 gm, 0.3 mmol), 4-
methoxy benzoic acid 1a (0.057 gm, 0.37 mmol), LiOAc.2H2O (0.032 gm, 0.3 mmol),
Ag2CO3 (0.103 gm, 0.37 mmol) and [Cp*IrCl2]2 (0.007 gm, 0.009 mmol) was evacuated and
purged with nitrogen gas three times. Followed by 1,2-Dichloroethane (2 mL) was added via
syringe and the reaction mixture was evacuated and purged with nitrogen gas three times.
Then rubber septum was taken out and screw cap was used to cover the tube. The reaction
mixture was allowed to stir at 80 ºC for 20 h. Then the reaction mixture was allowed to reach
ambient temperature and diluted with CH2Cl2, followed by filteration through celite and the
filtrate was concentrated. The crude residue was purified through a silica gel column using
hexane and ethyl acetate as eluent to give pure 3aa in 86% isolated yield. The yield of
product was calculated based on propargyl alcohol 2a.
General Procedure 2 for the Synthesis of Indeno[2,1-c] isocoumarins.
A 15 ml schlenk tube with septum containing isocoumarin 3aa (0.050 gm, 0.2 mmol) was
dissolved in 2 mL of 1,2-Dichloroethane. Then, BF3.O(C2H5)2 (0.02 mL, 0.16 mmol) was
added via syringe. Then, rubber septum was taken out and screw cap was used to cover the
tube. The reaction mixture was allowed to stir at 100 ºC for 12 h. After cooling to ambient
temperature, the reaction mixture was diluted with EtOAc. The crude residue was purified
through a silica gel column using hexane and ethyl acetate as eluent to give pure 4a in 93%
isolated yield.
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Deuterium labelling studies:
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(i) Preparation of ortho-deuterated 4-OMe benzoic acid [D]-1a:
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A 15 mL schlenk tube with septum containing 1a (0.050 gm, 0.3 mmol), [Cp*IrCl2]2 (0.009
gm, 0.009 mmol), Ag2CO3 (0.108 gm, 0.4 mmol). was evacuated and purged with nitrogen
gas three times. Followed by solvent ClCH2CH2Cl (2 mL) and CD3COOH (1 mL) were
added via syringe and again the reaction mixture was evacuated and purged with nitrogen gas
three times. Then rubber septum was taken out and screw cap was used to cover the tube. The
reaction mixture was allowed to stir at 80 oC for 16 h. After cooling to ambient temperature,
the reaction mixture was diluted with CH2Cl2, filtered through celite and the filtrate was
concentrated and product [D]-1a was observed in 87% yield with 40% of deuterium
incorporation at both ortho carbons, respectively.
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Reaction of ortho-deuterated 4-OMe benzoic acid [D]-1a with 2a:
A 15 mL schlenk tube with septum containing propargyl alcohol 2a (0.050 gm, 0.3 mmol),
[D]-1a (0.049 gm, 0.4 mmol), LiOAc.2H2O (0.032 gm, 0.3 mmol) and [Cp*IrCl2]2 (0.007
gm, 0.009 mmol) was evacuated and purged with nitrogen gas three times. Followed
ClCH2CH2Cl (2 mL) was added via syringe and again the reaction mixture was evacuated
and purged with nitrogen gas three times. Then rubber septum was taken out and screw cap
was used to cover the tube. The reaction mixture was allowed to stir at 80 ºC for 20 h. After
cooling to ambient temperature, the reaction mixture was diluted with CH2Cl2, filtered
through celite and the filtrate was concentrated. The crude residue was purified through a
silica gel column using hexane and ethyl acetate as eluent to give pure [D]-3aa product was
observed in 80% yield with 88% of deuterium incorporation at ortho hydrogen.
(ii) Kinetic isotopic effect studies (KIE):
For one pot reaction:
In 15 mL schlenk tube, 1c (0.038 gm, 0.3 mmol), [D]-1c (0.040 gm, 0.3 mmol), 2a (1.0
equiv, 0.3 mmol), [Cp*IrCl2]2 (0.007gm, 0.009 mmol), Ag2CO3 (0.103 gm, 0.4 mmol),
LiOAc.2H2O (0.032 gm, 0.3 mmol), was added and then purged with nitrogen gas three
times. Then 2 mL of ClCH2CH2Cl was added via syringe. After that, the tube was purged and
evacuated with N2 gas three times and screw cap was used to cover the tube. Then, the
reaction mixture was allowed to stir at 80 ºC for 10 h. Then the reaction mixture was allowed
to reach ambient temperature and diluted with CH2Cl2, followed by filteration through celite
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and the filtrate was concentrated. The crude residue was purified through a silica gel column
using hexane and ethyl acetate as eluent to give combined products 3ca and [D]-3ca with
75% yield. From 1H-NMR, the KIE value was found to be 2.83.
For independent reaction:
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In separate 15 mL schlenk tubes, 1c (0.076 gm, 0.6 mmol), [D]-1c (0.079 gm, 0.6 mmol), 2a
(0.100 gm, 0.6 mmol), [Cp*IrCl2]2 (0.014 gm, 0.009 mmol), Ag2CO3 (0.103 gm, 0.4 mmol),
LiOAc.2H2O (0.032 gm, 0.3 mmol), was added. 1,3,5-trimethoxybenzene(0.105gm, 0.625
mmol) was also added as internal reference.Then 3 mL of ClCH2CH2Cl was added via
syringe. After that, the tube was purged and evacuated with N2 gas three times and screw cap
was used to cover the tube. Then, the reaction mixture was allowed to stir at 80 °C. After 60
minutes, an aliquot (0.1 mL) was removed by a syringe every 20 min for 1 hour,filtered and
concentrated under reduced pressure. Yields of products were determined by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal reference. Data from independent
kinetic isotope studies are collected in Table S2 (see SI) and using plot, KIE was found to be
kH/kD ≈ 2.2.
Procedure for Competitive reaction between 1a and 1c:
In 15 mL schlenk tube, 1a (0.048 gm, 0.3mmol), 1g (0.044 gm, 0.3mmol), 2a (0.050 gm 0.3
mmol), [Cp*IrCl2]2 (0.007 gm, 0.009 mmol), Ag2CO3 (0.103 gm, 0.4 mmol), LiOAc.2H2O
(0.032 gm, 0.3 mmol), was added and then purged with nitrogen gas three times. Then 2 mL
of ClCH2CH2Cl solvent was added using syringe. After that, the tube was purged and
evacuated with N2 gas three times and screw cap was used to cover the tube. Then, the
reaction mixture was allowed to stir at 80 oC for 20 h. Then the reaction mixture was allowed
to reach ambient temperature and diluted with CH2Cl2, followed by filteration through celite
and the filtrate was concentrated. The crude residue was purified through a silica gel column
using hexane and ethyl acetate as eluent to get product 3aa and 3ga in 28% and 33%.
Procedure for Intermediate Isolation.
Intermediate C was isolated according to literature procedure.5m Followed by its reaction
with 2a taking equal equivalents of both in a 15 mL schlenk tube at 80 oC for 16 h and
product was isolated with 75% yield.
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Computational Details.
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DFT computations were carried out using the Gaussian 09 program (revision A.02).9 The
model systems have been fully optimized using the B3LYP density functional theory via
vibrational frequency calculations as either minima (all positive frequency) or transition
states (one negative frequency) obtained the zero-point energy (ZPE), and thermal correction.
The valence orbitals of iridium were described using the SDD basis set, non-metal centers
were described using the 6-31G* basis set. IRC calculations and subsequent geometry
optimizations were used to confirm the minima linked by each transition state. A solvent
correction (for DCE) was performed using the polarized continuum model (PCM).10 The
M06 functional has been used to improve the treatment of non-covalent interactions in the
model systems.11 Single point energies including solvent effects were evaluated at the PCM
(in DCE)/M06/6-31G(d), SDD(Ir). The energy profile diagram of the reaction pathway is
presented as Gibbs free energy changes (ΔG’s) involving zero-point vibrational energy
(ZPVE) and thermal corrections obtained at 298.15 K and 1 atm pressure. To estimate the
Gibbs free energies of M06 calculations, the ZPVE and thermal corrections obtained from
the B3LYP calculations have been used.
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Spectral Data of All Compounds:
3-(2-Hydroxypropan-2-yl)-6-methoxy-4-phenyl-1H-isochromen-1-one (3aa)
Prepared according to GP 1; white solid. 84 mg, 86% yield, eluent (10 % ethyl acetate in
hexane), mp: 124-125 ºC. 1H NMR (400 MHz, CDCl3): δ 8.27 (dd, J = 8.8, 3.6Hz, 1H), 7.68
– 7.41 (m, 3H), 7.43 – 7.19 (m, 2H), 7.02 (d, J = 8.8 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 3.69
(s, 3H), 1.47 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 164.8, 161.6, 157.6, 142.2, 134.5,
131.8, 130.8, 129.1, 128.6, 115.6, 114.3, 113.4, 108.8, 73.6, 55.5, 30.4. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C19H19O4 311.1283; Found 311.1271.
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Prepared according to GP 1; white solid. 82 % yield, 75 mg, eluent (8 % ethyl acetate in
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hexane), mp: 164-165 ºC. H NMR (500 MHz, CDCl3): δ 8.22 (d, J = 8.0 Hz, 1H), 7.52 –
7.44 (m, 3H), 7.32 – 7.27 (m, 3H), 6.56 (s, 1H), 2.31 (s, 3H), 1.98 (s, 1H), 1.46 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3): δ 161.7, 156.8, 145.8, 139.6, 134.4, 130.7, 129.3, 129.2,
128.8, 128.3, 125.3, 117.5, 114.2, 73.4, 29.8, 22.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C19H19O3 295.1334; Found 295.1331.
3-(2-Hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3ca)
Prepared according to GP 1; white solid. 81 mg, 92 % yield, eluent (8 % ethyl acetate in
hexane), mp: 100-101 ºC. 1H NMR (500 MHz, CDCl3): δ 8.34 (dd, J = 8.0, 1.1 Hz, 1H),
7.60 – 7.55 (m, 1H), 7.52 – 7.45 (m, 4H), 7.32 – 7.28 (m, 2H), 6.81 (d, J = 8 Hz, 1H), 1.90 (s,
1H), 1.48 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.7, 156.8, 139.6, 134.6, 134.3,
130.7, 129.2, 128.9, 128.4, 127.9, 125.3, 119.9, 114.3, 73.6, 29.9. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C18H17O3 281.1178; Found 281.1172.
3-(2-Hydroxypropan-2-yl)-6-iodo-4-phenyl-1H-isochromen-1-one (3da)
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Prepared according to GP 1; white solid.76 mg, 60% yield, eluent (8 % ethyl acetate in
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hexanes), mp: 170-171 ºC. H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 8.5 Hz, 1H), 7.82
(dd, J = 8.5, 1.6 Hz, 1H), 7.54 – 7.47 (m, 3H), 7.30 – 7.25 (m, 2H), 7.14 (d, J = 1.5 Hz, 1H),
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1.84 (s, 1H), 1.46 (s, 6H). C{1H} NMR (126 MHz, CDCl3): δ 161.3, 158.1, 140.8, 137.3,
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134.3, 133.4, 130.5, 130.4, 129.1, 128.7, 119.1, 113.2, 103.6, 3.5, 29.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H16 IO3 407.0144; Found 407.0138.
6-Bromo-3-(2-hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3ea)
Prepared according to GP 1; white solid. 86 mg, 60% yield, eluent (8 % ethyl acetate in
hexane), mp: 176-177 ºC. 1H NMR (500 MHz, CDCl3):δ 8.17 (d, J = 8 Hz, 1H), 7.60 (dd, J
= 8.5, 1.5 Hz, 1H), 7.54 – 7.48 (m, 3H), 7.30 – 7.27 (m, 2H), 6.93 (d, J = 1.8 Hz, 1H), 1.87
(s, 1H), 1.47 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3):δ 161.0, 158.3, 141.1, 133.4, 131.4,
130.8, 130.5, 130.5, 129.1, 128.7, 128.1, 128.1, 118.6, 113.7,73.5, 29.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H16 BrO3 359.0283; Found 359.0277.
6-Chloro-3-(2-hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3fa)
Prepared according to GP 1; white solid. 75 mg, 87% yield, eluent (8 % ethyl acetate in
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hexane), mp: 178-179 ºC. H NMR (500 MHz, CDCl3): δ 8.25 (d, J = 8.5 Hz, 1H), 7.55 –
7.47 (m, 3H), 7.44 (dd, J = 8.5, 1.9 Hz, 1H), 7.31 – 7.27 (m, 2H), 6.76 (d, J = 1.9 Hz, 1H),
1.91 (s, 1H), 1.47 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.9, 158.3, 141.6, 141.1,
133.5, 130.8, 130.5, 129.1, 128.7, 128.5, 125.0, 118.2, 113.6, 73.5, 29.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H16 ClO3 315.0788; Found 315.0785.
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6-Fluoro-3-(2-hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3ga)
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Prepared according to GP 1; white solid. 75 mg, 81 % yield, eluent (8 % ethyl acetate in
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hexanes), mp: 148-149 ºC. H NMR (500 MHz, CDCl3): δ 8.34 (dd, J = 8.7, 5.8 Hz, 1H),
7.54 – 7.45 (m, 3H), 7.29 (dd, J = 8.0, 2 Hz, 2H), 7.17 (td, J = 8.0, 2.5 Hz, 1H), 6.44 (dd, J =
10.1, 2.5 Hz, 1H), 1.96 (s, 1H), 1.48 (s, 6H). 13C {1H} NMR (126 MHz, CDCl3): δ 167.8,
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165.7 (d, J=256 Hz), 160.7, 158.2, 142.,142.6(d, J=10Hz), 133.7, 132.5 ,132.4 (d, J
=10Hz), 130.5, 129.1, 128.6, 116.4,116.2 (d, 2J=23.5Hz), 113.9, 111.5 ,111.28(d, 2J=24.0Hz),
73.4, 29.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H16FO3 299.1083; Found
299.1077.
3-(2-Hydroxypropan-2-yl)-6-nitro-4-phenyl-1H-isochromen-1-one (3ha)
Prepared according to GP 1; yellow solid. 43 mg, 42% yield, eluent (15 % ethyl acetate in
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hexane), mp: 126-127 ºC. H NMR (500 MHz, CDCl3): δ 8.44 (d, J = 8.5 Hz, 1H), 8.18 (dd,
J = 8.5, 2.0 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.51 – 7.45 (m, 3H), 7.25 – 7.21 (m, 2H), 1.44
(s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 159.9, 159.4, 151.8, 141.0, 132.8, 131.2, 130.4,
129.45, 129.2, 123.8, 121.9, 120.5, 113.9, 73.6, 29.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C18H16 NO5 326.1028; Found 326.1013.
3-(2-Hydroxypropan-2-yl)-1-oxo-4-phenyl-1H-isochromene-6-carbonitrile (3ia)
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Prepared according to GP 1; yellow solid. 30 mg, 32% yield, eluent (15 % ethyl acetate in
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hexane), mp: 124-125 ºC. H NMR (500 MHz, CDCl3): δ 8.36 – 8.33 (m, 1H), 7.64 (dd, J =
8.1, 1.5 Hz, 1H), 7.50 – 7.43 (m, 3H), 7.24 – 7.20 (m, 2H), 7.04 (d, J = 1.0 Hz, 1H), 1.42 (s,
6H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.2, 159.1, 140.2, 132.9, 130.4, 130.2, 129.7,
129.4, 129.1, 122.6, 118.2, 117.5, 113.6, 113.3, 73.6, 29.8. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C19H16 NO3 306.1130; Found 306.1115.
3-(2-Hydroxypropan-2-yl)-8-methyl-4-phenyl-1H-isochromen-1-one (3ja)
Prepared according to GP 1; white solid. 72 mg, 82% yield, eluent (8% ethyl acetate in
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hexane), mp: 110-111 ºC. H NMR (500 MHz, CDCl3): δ 7.51 – 7.43 (m, 3H), 7.39 (t, J =
7.5 Hz, 1H), 7.27 (ddd, J = 8.5, 5.0, 1.5 Hz, 3H), 6.63 (d, J = 8.0 Hz, 1H), 2.86 (s, 3H), 1.96
(s, 1H), 1.45 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.9, 156.4, 143.2, 141.1, 134.9,
133.7, 130.9, 130.8, 128.9, 128.3, 123.5, 118.5, 114.2, 73.2, 29.8, 23.4. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C19H19O3 295.1334; Found 295.1330.
3-(2-Hydroxypropan-2-yl)-4,8-diphenyl-1H-isochromen-1-one (3ka)
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Prepared according to GP 1; white solid. 75 mg, 56% yield, eluent (10 % ethyl acetate in
hexane) mp: 140-141 ºC. 1H NMR (400 MHz, CDCl3): δ 7.43 (m, 4H), 7.38 – 7.30 (m, 3H),
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7.30 – 7.21 (m, 6H), 6.74 (d, J = 10 Hz, 1H), 1.36 (s, 1H). C{1H} NMR (101 MHz,
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CDCl3): δ 159.8, 157.0, 145.7, 141.6, 141.1, 134.7, 133.4, 131.2, 130.9, 129.0, 128.4, 127.7,
127.3, 125.0, 117.2, 114.0, 73.3, 29.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H21O3
357.1491; Found 357.1515.
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5,7-Dihydroxy-3-(2-hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3la)
Prepared according to GP 1; white solid. 52 mg, 53% yield, eluent (20 % ethyl acetate in
hexane), mp: 128-129 ºC. 1H NMR (400 MHz, CDCl3): δ 11.09 (s, 1H), 7.42 – 7.33 (m, 3H),
7.19 (s, 2H), 6.35 (s, 1H), 5.54 (s, 1H), 1.37 (s, 13H). 13C{1H} NMR (101 MHz, CDCl3): δ
165.1, 163.8, 163.7, 156.5, 142.3, 134.0, 130.4, 129.9, 128.5, 115.2, 103.6, 102.3, 99.7, 73.5,
29.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H17O5 313.1076 ; Found 313.1070.
3-(2-Hydroxypropan-2-yl)-5,7-dimethoxy-4-phenyl-1H-isochromen-1-one (3ma)
Prepared according to GP 1; white solid. 78 mg, 75% yield, eluent (20 % ethyl acetate in
hexane), mp: 134-135 ºC. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 2.0 Hz, 1H), 7.27 (m,
3H), 7.24 – 7.19 (m, 2H), 6.54 (d, J = 3 Hz, 1H), 3.82 (s, 3H), 3.14 (s, 3H), 1.36 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 161.7, 160.1, 157.6, 154.1, 137.2, 130.2, 127.4, 127.2,
122.4, 122.2, 112.9, 107.0, 101.8, 73.9, 55.8, 55.7, 30.1. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C20H21O5 341.1389; Found 341.1393.
3-(2-Hydroxypropan-2-yl)-4-phenyl-1H-benzo[g]isochromen-1-one (3na)
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Prepared according to GP 1; white solid. 32 mg, 31% yield, eluent (15 % ethyl acetate in
hexane), mp: 180-181 ºC. 1H NMR (500 MHz, CDCl3): δ 9.72 (d, J = 9.0 Hz, 1H), 7.89 (d, J
= 8.5 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.72 (ddd, J = 8.5, 7.0, 1.0 Hz, 1H), 7.58 – 7.54 (m,
1H), 7.48 – 7.40 (m, 3H), 7.29 – 7.25 (m, 2H), 6.83 (d, J = 8.9 Hz, 1H), 1.45 (s, 6H). 13C{1H}
NMR (126 MHz, CDCl3): δ 160.9, 158.6, 141.9, 135.9, 134.7, 132.5, 131.3, 131.0, 129.5,
129.0, 128.5, 128.5, 127.0, 126.9, 122.5, 73.5, 30.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C22H19O3 331.1334; Found 331.1317.
6-(2-Hydroxypropan-2-yl)-7-phenyl-4H-thieno[3,2-c]pyran-4-one (3oa)
Prepared according to GP 1; white solid. 36 mg, 40% yield, eluent (15 % ethyl acetate in
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hexane), mp: 138-139 ºC. H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 5.5 Hz, 1H), 7.42 –
7.34 (m, 3H), 7.26 – 7.22 (m, 2H), 6.49 – 6.46 (m, 1H), 1.87 (s, 1H), 1.43 (s, 6H). 13C{1H}
NMR (126 MHz, CDCl3): δ 159.5, 157.6, 150.5, 136.1, 135.0, 129.9, 128.8, 128.4, 125.1,
121.7, 113.8, 73.5, 30.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H15O3S 287.0742 ;
Found 287.0751.
7-Bromo-3-(2-hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3pa)
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Prepared according to GP 1; white solid. 70 mg, 63% yield, eluent (15 % ethyl acetate in
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hexane), mp: 168-169 ºC. H NMR (500 MHz, CDCl3): δ 8.45 (d, J = 2.1 Hz, 1H), 7.64
(dd, J = 8.5, 2.2 Hz, 1H), 7.53 – 7.45 (m, 3H), 7.30 – 7.26 (m, 2H), 6.68 (d, J = 8.5 Hz, 1H),
1.88 (s, 1H), 1.47 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 160.4, 157.4, 138.3, 137.7,
133.7, 131.6, 130.5, 129.0, 128.6, 127.1, 121.8, 121.3, 113.9, 73.5, 29.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H16 BrO3 359.0283; Found 359.0274.
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7-Chloro-3-(2-hydroxypropan-2-yl)-4-phenyl-1H-isochromen-1-one (3qa)
Prepared according to GP 1; white solid. 48 mg, 50% yield, eluent (15 % ethyl acetate in
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hexane) mp: 152-153 ºC. H NMR (500 MHz, CDCl3): δ 8.22 (d, J = 2.5 Hz, 1H), 7.44 –
7.40 (m, 4H), 7.21 (dd, J = 7.5, 1.5 Hz, 2H), 6.68 (d, J = 8.7 Hz, 1H), 1.40 (s, 6H). 13C{1H}
NMR (126 MHz, CDCl3): δ 160.6, 157.2, 138.0, 135.0, 134.1, 133.9, 130.6, 129.0, 128.5,
127.0, 121.1, 113.8, 73.5, 29.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H16 ClO3
315.0788 ; Found 315.0770.
3-(2-Hydroxypropan-2-yl)-7-methoxy-4-phenyl-1H-isochromen-1-one (3ra)
Prepared according to GP 1; white solid. 42 mg, 43% yield, eluent (10 % ethyl acetate in
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hexane) mp: 140-141 ºC. H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 3.0 Hz, 1H), 7.50 –
7.43 (m, 3H), 7.31 – 7.27 (m, 2H), 7.15 (dd, J = 9.0, 2.0 Hz, 1H), 6.75 – 6.72 (d,J=9.0Hz,
1H), 3.90 (s, 3H), 1.47 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.8, 159.4, 154.8,
134.5, 133.2, 130.6, 128.9, 128.3, 127.0, 124.2, 121.0, 114.1, 109.6, 73.3, 55.8, 29.9. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C19H19O4 311.1283; Found 311.1276.
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3-(2-Hydroxypropan-2-yl)-5-methoxy-4-phenyl-1H-isochromen-1-one (3ra’)
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Prepared according to GP 1; white solid. 42 mg, 43% yield, eluent (10 % ethyl acetate in
hexane) mp: 120-121 ºC. 1H NMR (500 MHz, CDCl3): δ 7.92 (dd, J = 8.0, 1.0 Hz, 1H), 7.37
(t, J = 8.0 Hz, 1H), 7.32 – 7.27 (m, 3H), 7.26 – 7.22 (m, 2H), 6.99 (dd, J = 8.0, 1.0 Hz, 1H),
3.18 (s, 3H), 1.71 (s, 1H), 1.38 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.6, 156.3,
156.2, 137.3, 130.2, 129.0, 127.9, 127.5, 127.3, 121.7, 121.6, 117.7, 113.0, 74.1, 56.0, 30.1.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H19O4 311.1283,measured 311.1284.
3-(2-Hydroxypropan-2-yl)-6,7-dimethoxy-4-phenyl-1H-isochromen-1-one (3sa)
Prepared according to GP 1; white solid. 98 mg, 92% yield, eluent (15 % ethyl acetate in
hexane), mp: 128-129 ºC. 1H NMR (500 MHz, CDCl3): δ 7.61 (s, 1H), 7.44 – 7.36 (m, 3H),
7.23 (m, 2H), 6.06 (s, 1H), 3.91 (s, 3H), 3.56 (s, 3H), 1.39 (s, 6H). 13C{1H} NMR (126 MHz,
CDCl3): δ 161.5, 155.8, 154.8, 149.5, 135.3, 134.6, 130.6, 128.8, 128.4, 114.0, 113.1, 109.0,
106.1, 73.3, 56.3, 55.7, 29.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H21O5 341.1389
; Found 341.1381.
7-(2-Hydroxypropan-2-yl)-8-phenyl-5H-[1,3]dioxolo[4,5-g]isochromen-5-one (3ta)
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Prepared according to GP 1; white solid. 74 mg for inseparable mixture of two regioisomers
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in the ratio (3:1), 73 % yield, eluent (15 % ethyl acetate in hexane), mp: 130-131 ºC. H
NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.4 Hz, 1H), 7.58 (s, 0.24H), 7.48 – 7.36 (m, 1H),
7.31 (m, 3H), 7.25 (m, 2H), 7.20 (d, J = 4.0Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.08 (s, 0.26H),
5.96 (s, 0.59H), 5.62 (s, 2H), 1.37 (s, 8H). 13C{1H} NMR (101 MHz, CDCl3):δ 161.0, 156.7,
153.2, 142.7, 134.8, 130.6, 130.5, 128.9, 128.4, 128.2, 128.1, 125.8, 125.8, 122.2, 114.4,
111.0, 109.4, 107.0, 104.2, 102.2, 101.9, 73.7, 29.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C19H17O5 325.1071; Found 325.1068.
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3-(2-Hydroxypropan-2-yl)-6,7-dimethoxy-4-(4-methoxyphenyl)-1H-isochromen-1-one
(3sb)
Prepared according to GP 1; white solid.93 mg, 92% yield, eluent (25 % ethyl acetate in
hexanes); mp: 160-161 ºC.1H NMR (500 MHz, CDCl3): δ 7.61 (s, 1H), 7.16 – 7.11 (dd,
J=8.5, 1.5 Hz, 2H), 6.98 – 6.92 (m, 2H), 6.13 (s, 1H), 3.91 (s, 3H), 3.81 (s,, 3H), 3.59 (s, 3H),
1.39 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.6, 159.5, 156.2, 154.9, 149.5, 135.7,
131.8, 126.2, 114.3, 113.7, 113.1, 109.1, 106.2, 73.4, 56.3, 55.9, 55.3, 30.0. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for [M+H]+ C21H22O6 371.1495 ; Found 371.1504.
3-(2-Hydroxypropan-2-yl)-6,7-dimethoxy-4-(p-tolyl)-1H-isochromen-1-one (3sc)
Prepared according to GP 1; white solid. 114 mg, 75% yield, eluent (20 % ethyl acetate in
hexane) mp: 140-141 ºC. 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.19 (dd, J = 8.0, 6.0
Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 6.11 (s, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 2.37 (s, 3H), 1.90
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(s, 1H), 1.39 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.6, 156.0, 154.9, 149.5, 138.2,
135.5, 131.3, 130.4, 129.6, 114.0, 113.1, 109.1, 106.2, 73.4, 56.3, 55.9, 29.9, 21.3. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C21H23O5 355.1545 ; Found 355.1540.
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Prepared according to GP 1; white solid. 86 mg, 78% yield, eluent (15 % ethyl acetate in
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hexane) mp: 142-143 ºC. H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.55 (d, J = 8.4 Hz,
2H), 7.11 (d, J = 8.0 Hz, 2H), 6.05 (s, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 1.80 (s, 1H), 1.40 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 161.3, 157.0, 155.0, 149.7, 134.8, 133.8, 132.3,
132.0, 122.5, 113.1, 113.0, 109.2, 105.9, 73.3, 56.4, 55.9, 30.0. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C20H20 BrO5 419.0494; Found 419.0483.
4-(2-Bromophenyl)-3-(2-hydroxypropan-2-yl)-6,7-dimethoxy-1H-isochromen-1-one(3se)
Prepared according to GP 1 (2a is taken as 0.5 mmol); white solid. 104 mg, 94% yield, eluent
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(15 % ethyl acetate in hexane) mp: 142-143 ºC. H NMR (500 MHz, CDCl3): δ 7.65 (m,
1H), 7.63 (s, 1H), 7.39 – 7.34 (m, 1H), 7.27 – 7.23 (m, 2H), 5.96 (s, 1H), 3.91 (s, 3H), 3.58
(s, 3H), 1.75 (s, 1H), 1.44 (d, J = 7.0 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.5,
156.1, 155.1, 149.7, 136.3, 133.9, 133.0, 132.2, 129.9, 127.7, 125.4, 113.5, 113.2, 109.3,
73.4, 56.4, 55.8, 29.4, 29.04. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H20BrO5
419.0494 ; Found 419.0480.
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3-(2-Hydroxypropan-2-yl)-6,7-dimethoxy-4-(thiophen-2-yl)-1H-isochromen-1-one (3sf)
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Prepared according to GP 1; 75 mg, 72% yield, eluent (15 % ethyl acetate in hexane), mp:
114-115 ºC.1H NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 7.45 (s, 1H), 7.09 (s, 1H), 6.99 (s,
1H), 6.27 (s, 1H), 3.91 (s, 3H), 3.65 (s, 3H), 2.24 (s, 1H), 1.46 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 161.1, 158.5, 155.1, 149.7, 135.5, 134.6, 129.7, 127.7, 127.3, 112.7, 108.9,
106.8, 105.7, 73.5, 56.3, 55.8, 29.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H19O5S
347.0953 ; Found 347.0950.
4-Butyl-3-(1-hydroxycyclopentyl)-6,7-dimethoxy-1H-isochromen-1-one (3sg)
Prepared according to GP 1; white solid. 105 mg, 92% yield, eluent (15 % ethyl acetate in
hexane), mp: 106-107 ºC. 1H NMR (500 MHz, CDCl3):δ 7.65 (s, 1H), 6.92 (s, 1H), 4.00 (d,
J = 5.6 Hz, 6H), 3.05 – 2.94 (m, 2H), 2.32 (d, J = 10.6 Hz, 1H), 1.67 (s, 6H), 1.63 – 1.56 (m,
2H), 1.51 (dt, J = 14.4, 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3): δ 161.8, 155.4, 154.9, 149.2, 134.5, 114.1, 113.1, 109.5, 104.1,73.9, 56.2, 56.0,
32.5, 30.0, 25.2, 23.1, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H25O5 321.1702 ;
Found 321.1695.
3-(1-Hydroxycyclopentyl)-6,7-dimethoxy-4-phenyl-1H-isochromen-1-one (3sh)
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Prepared according to GP 1; white solid. 78 mg, 80% yield, eluent (20 % ethyl acetate in
hexane) mp: 130-131 ºC. 1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1H), 7.47 (m, 3H), 7.38 –
7.26 (m, 2H), 6.35 – 6.12 (m, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 2.34 (s, 1H), 2.02 (m, 2H), 1.72
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(m, 5H). C{1H} NMR (126 MHz, CDCl3): δ 161.7, 154.8, 154.7, 149.5, 135.2, 134.6,
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130.7, 128.8, 128.3, 115.2, 113.2 109.1, 106.1, 83.5, 56.3, 55.7, 40.0, 23.3. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C22H23O5 367.1545 ; Found 367.1543.
3-(1-Hydroxycyclohexyl)-6,7-dimethoxy-4-phenyl-1H-isochromen-1-one (3si)
Prepared according to GP 1; white solid. 86 mg, 90% yield, eluent (20 % ethyl acetate in
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hexane) mp: 158-159 ºC. H NMR (500 MHz, CDCl3): δ 7.69 (s, 1H), 7.52 – 7.43 (m, 3H),
7.31 (m, 2H), 6.12 (s, 1H), 3.98 (s, 3H), 3.63 (s, 3H), 2.02 (td, J = 13.2, 4.9 Hz, 2H), 1.71 (d,
J = 12.7 Hz, 2H), 1.63 – 1.48 (m, 6H). 13C{1H} NMR (126 MHz, CDCl3): δ 161.7, 156.5,
154.7, 149.4, 135.5, 134.9, 130.5, 128.8, 128.2, 114.4, 113.0, 109.0, 106.0, 74.9, 56.3, 55.7,
36.5, 24.9, 21.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H25O5 381.1702 ; Found
381.1693.
2-Methoxy-7,7-dimethylindeno[2,1-c]isochromen-5(7H)-one (4a)
Prepared according to GP 2; white solid. 44 mg, 93 % yield, eluent (2 % ethyl acetate in
hexane), mp: 146-147 ºC. 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J = 8.9 Hz, 1H), 7.74 (d, J
= 7.6 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.31 (dd, J = 14.8, 7.5 Hz, 2H), 7.21 (t, J = 7.4 Hz,
1H), 6.99 (dd, J = 8.9, 2.2 Hz, 1H), 3.93 (s, 3H), 1.42 (s, 6H). 13C{1H} NMR (126 MHz,
CDCl3): δ 167.9, 165.0, 162.4, 148.3, 137.0, 136.6, 133.5, 127.2, 125.5, 121.9, 120.4, 114.6,
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113.3, 110.8, 106.1, 55.7, 46.1, 23.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H16 O3
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293.1178 ; Found 293.1176.
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Prepared according to GP 2; white solid. 44 mg, 90% yield, eluent (2 % ethyl acetate in
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hexane) mp: 150-151 ºC. H NMR (400 MHz, CDCl3): δ 7.73 (s, 1H), 7.59 (d, J = 7.8 Hz,
1H), 7.42 (s, 1H), 7.16 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 4.06 (s, 3H), 3.94 (s, 3H), 1.42 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.6, 162.8, 155.3, 148.9, 148.7, 135.4, 133.8,
130.7, 127.7, 127.7, 123.0, 119.9, 113.4, 111.2, 110.9, 103.7, 56.3, 45.9, 23.6. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C21H21O4 337.1440 ; Found 337.1421.
7,7-Dimethylindeno[2,1-c]isochromen-5(7H)-one (4c)
Prepared according to GP 2; white solid. 34 mg, 92% yield, eluent (2 % ethyl acetate in
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hexane) mp: 110-111 ºC. H NMR (500 MHz, CDCl3): δ 8.35 (dd, J = 8.0, 1.1 Hz, 1H),
8.09 (d, J = 8.0 Hz, 1H), 7.80 (d,J = 7.5 Hz, 1H), 7.77 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 – 7.44
(m, 1H), 7.36 – 7.29 (m, 2H), 7.22 (td, J = 7.5, 1.0 Hz, 1H), 1.43 (s, 6H). 13C{1H} NMR (126
MHz, CDCl3): δ 167.1, 162.7, 148.3, 135.1, 134.9, 131.3, 127.5, 127.3, 125.6, 122.5, 121.9,
120.7, 120.3, 111.0, 46.1, 23.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H15 O2
263.1072 ; Found 263.1064.
2-Fluoro-7,7-dimethylindeno[2,1-c]isochromen-5(7H)-one (4d)
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