Domino [Pd]-Catalysis: One-Pot Synthesis of Isobenzofuran-1(3H)-ones

Article abstract of DOI:10.1021/acs.joc.6b01396

An efficient domino [Pd]-catalysis for the synthesis of isobenzofuran-1(3H)-ones is presented. The strategy shows broad substrate scope and is amenable to o-bromobenzyl tertiary/secondary/primary alcohols. Significantly, the method was applied to the synthesis of antiplatelet drug n-butyl phthalide and cytotoxic agonist 3a-[4′-methoxylbenzyl]-5,7-dimethoxyphthalide.

Full text of DOI:10.1021/acs.joc.6b01396

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Article
Domino [Pd]-Catalysis: One-pot Synthesis of Isobenzofuran-1(3H)-ones
Lodi Mahendar, and Gedu Satyanarayana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01396 • Publication Date (Web): 10 Aug 2016
Downloaded from http://pubs.acs.org on August 11, 2016
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Domino [Pd]ꢀCatalysis: Oneꢀpot Synthesis of Isobenzofuranꢀ1(3H)ꢀones
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Lodi Mahendar and Gedu Satyanarayana
*
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Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi–502 285, Sangareddy, Medak District,
Telangana, India.
Fax: +91(40) 2301 6032
Eꢀmail: gvsatya@iith.ac.in
Abstract:
An efficient domino [Pd]ꢀcatalysis for the synthesis of isobenzofuranꢀ1(3H)ꢀones, is presented. The strategy showed
broad substrate scope and amenable to orthoꢀbromobenzyl tertiary/secondary/primary alcohols. Significantly, the
method was applied to the synthesis of antiꢀplatelet drug
methoxylbenzyl]ꢀ5,7ꢀdimethoxyphthalide.
nꢀbutyl phthalide and cytotoxic agonist 3aꢀ[4’ꢀ
Introduction
Isobenzofuranones (phthalides) are emerging class of compounds in medicinal chemistry. Phthalides are
found in many naturally occurring compounds that exhibit interesting biological activities (Figure 1).1
They are proven to be useful in the treatment of circulatory and heart diseases.1a Phthalides also act as key
structural units in organic synthesis, particularly, in the synthesis of functionalized anthracenes,
naphthalenes, and naphthacene based natural products.2 As a result, their synthesis has attracted much
attention from organic as well as pharmaceutical chemists.3 In this context, reasonable attempts have been
made on the synthesis of isobenzofuranꢀ1(3H)ꢀones.4 Nevertheless, some of reported methods are still
lacking the simplicity and generality.5
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Figure 1: Biologically active natural isobenzofuranones.
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Domino processes are extremely useful in organic synthesis as they can be performed under simple oneꢀ
step conditions, thus eliminating tedious isolation and purification of intermediate products(s). Therefore,
such processes are ultimately useful in saving energy and minimizing the waste formation.6 Transition
metal catalysis has been proven to be an efficient tool for the development of new synthetic methods,
especially in the creation of new CꢀC and CꢀX heteroatom bonds with increasing molecular complexity.7
In continuation of our onꢀgoing research interests in domino processes using transition metalꢀcatalysis,8
we have reported an efficient [Cu]ꢀcatalyzed domino oneꢀpot method for the synthesis of isobenzofuranꢀ
1(3H)ꢀones using nontoxic K4[Fe(CN)6] as the source of CO, under environmentally benign conditions
(Scheme 1).4i However, this process was limited to the orthoꢀbromobenzyl tertiary alcohols. Though
carbon monoxide (CO)9 is an inexpensive and readily available carbonylation source, its toxicity and the
requirement of high pressure operations limits its synthetic applications. CO remains significant to the
advancement of carbonylation reactions.10 On these grounds, Skrydstrup et al. reported COꢀfree
carbonylations using inꢀsitu generated carbon monoxide.11 Also, the research group of Beller et al.
developed new methods using CO surrogates, such as, aryl formates and [Mo(CO)6].12 However,
compared to all CO surrogates used in previous reports, paraformaldehyde was found superior, because it
is cheap, stable and also ease of use. As a result, the research group of Beller disclosed an elegant
approach demonstrating the palladiumꢀcatalyzed reductive carbonylations and alkoxycarbonylations using
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paraformaldehyde as an external CO source.13a Subsequently, XiaoꢀFeng Wu et al. disclosed
paraformaldehyde mediated carbonylations for the synthesis of benzoxazinones.13b Paraformaldehyde had
also been used in Rhꢀcatalyzed COꢀfree carbonylations of alkynes.14 However, paraformaldehyde has not
been properly explored for the [Pd]ꢀcatalyzed carbonylation.13,15 In continuation of our research interests
on domino transition metalꢀcatalysis, herein, we report an efficient [Pd]ꢀcatalyzed concise approach for
the syntheses of phthalides, using paraformaldehyde as the source of CO (Scheme 1). Significantly, the
strategy was extended to the synthesis of isobenzofuranone based natural products, from simple orthoꢀ
bromobenzyl alcohols. Remarkably, unlike our previous report,4i the present strategy was proved to be
much versatile, as it was amenable to primary/secondary/tertiary orthoꢀbromobenzyl alcohols and also
applied to the synthesis of natural/drug products. To the best of our knowledge, there are no reports on the
synthesis of isobenzofuranꢀ1(3H)ꢀones using paraformaldehyde as carbonylating agent.
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Scheme 1: Present study and our previous approach for the synthesis of isobenzofuranones.
Result and Discussions
To initiate the synthetic study, we have chosen orthoꢀbromobenzyl tertiary alcohol 1aa as a model. Thus
the reaction was carried out with paraformaldehyde as CO source in the presence of Pd(OAc)2, base
KOAc in H2O, and with PPh3 and XanthꢀPhos, respectively. The desired product 2aa was formed, albeit
in poor to moderate yields (Table 1, entries 1 to 2). The reaction was then conducted under different
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solvents using XanthꢀPhos as the ligand (Table 1, entries 3 to 10). Gratifyingly, orthoꢀxylene was found
as the best solvent, afforded the product 2aa in excellent yield (Table 1, entry 6). Other varying
conditions, such as with different bases in orthoꢀxylene were found inferior to the conditions of entry 6
(Table 1, entries 11ꢀ18).
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Table 1: Screening conditions for the synthesis of 2aa.
Ligand
(10 mol %)
Base
(2 equiv)
2aa (%)b
Entrya
3
Solvent
H2O
PPh3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K3PO4
K2CO3
Na2CO3
NaOAc
Cs2CO3
NEt3
36d
51d
2
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
XantꢀPhos
H2O
c
3
DMA
−
4
DMSO
DMF
45d
41d
93
5
6
oꢀxylene
dioxane
CH3CN
pꢀxylene
DCE
7
42d
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60
9
87
c
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18
−
oꢀxylene
oꢀxylene
oꢀxylene
oꢀxylene
oꢀxylene
oꢀxylene
oꢀxylene
oꢀxylene
71
61
c
−
66
48d
46d
48d
26d
HNEt2
DMED
a All reactions were carried out on (0.5 mol) scale of 1aa and (2.5 mol) of (CH2O)n and solvent (0.5 mL). b Isolated yields of
chromatographically pure products. c Starting material was recovered. d Starting material 1aa was recovered along with the
product 2aa.
With the optimized conditions in hand (Table 1, entry 6), to check the scope and generality of the method,
the reaction was explored with other orthoꢀbromobenzyl tertiary alcohols 1aa−1bd. To our delight, the
reaction showed broad substrate scope and furnished the benzofuranones 2aa−2bd, in very good to
excellent yields (Table 2). Interestingly, the reaction was successful with diꢀalkyl substituents (entries
2aaꢀ2ar), cyclic tertiary alcohol 1as (entry 2as), alkylꢀaryl groups (entries 2atꢀ2az), alkylꢀheteroaryl
groups (entries 2ba & 2ab) as well as diaryl substituents (entries 2bc & 2bd). Remarkably, the reaction
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showed broad functional group tolerance, such as, donating groups on the orthoꢀbromoarene moiety
(compare entries 2ae vs 2ar).
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Table 2: Syntheses of isobenzofuranones 2aaꢀ2bd from orthoꢀbromobenzyl tertiary alcohols 1aaꢀ1bd.a,b
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aReaction conditions: 1aa−1bd (0.50 mmol), (CH2O)n (2.5 mmol), Pd(OAc)2 (5 mol%), XanthꢀPhos (10 mol%), KOAc (2 equiv)
in 0.5 mL orthoꢀxylene, at 140 °C for 24 h. bIsolated yields of chromatographically pure products.
After successful synthesis of benzofuranones 2aa−2bd (Table 2) with a quaternary carbon atom,
to demonstrate the scope and generality of the method, we planned to explore the reaction with orthoꢀ
bromobenzyl secondary alcohols. Thus, the reaction was performed with orthoꢀbromobenzyl secondary
alcohols 1be−1bo, under standard conditions. Gratifyingly, the reaction was quite successful and
furnished the desired lactones 2be−2bo, in fair to good yields (Table 3). Notably, the reaction proceeded
smoothly with different alkyl substituents on the carbinol center (Table 3, entries 2be−2bo). Significantly,
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this strategy was successfully applied to the synthesis of an antiꢀplatelet drug nꢀbutylphthalide (NBP)16
2bm. Notably, the reaction was also amenable with cyclic alkyl as well as benzyl groups (entries 2bn &
2bo). Most significantly, demonstrating the utility of the current method over previous reported methods,
primary alcohols 1bp–1bs were successfully cyclized to give the desired lactones 2bp–2bs (Table 3). It is
worth noting that the reaction with primary alcohols 1bp–1bs was not successful with the base KOAc.
However, to our delight, changing the base from KOAc to Na2CO3, gave the desired lactones in good
yields (Table 3). It is worth noting that in contrast to our previous report,4i which was limited to orthoꢀ
bromobenzyl tertiary alcohols, the present protocol amenable to the orthoꢀbromobenzyl
secondary/primary alcohols.
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Table 3: Syntheses of isobenzofuranones 2beꢀ2bs from 1beꢀ1bs.a,b,c,d
aReaction conditions: 1be−1bo/1bp−1bs (0.50 mmol), (CH2O)n (2.5 mmol), Pd(OAc)2 (5 mol%), XanthꢀPhos (10 mol%), base
(2 equiv) in 0.5 mL orthoꢀxylene, at 140 °C for 24 h. bFor 1be−1bo; KOAc was used as the base. cIn case of 1bp−1bs; Na2CO3
d
was used as the base. Isolated yields of chromatographically pure products.
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To demonstrate the utility of the domino [Pd]ꢀcatalysis process, we applied the strategy to the
synthesis of a cytotoxic antagonist, 3aꢀ[4’ꢀmethoxybenzyl]5,7ꢀdimethoxypthalide 2bt17 (Scheme 2).
Therefore, the required secondary alcohol 1bt was synthesized using established conditions as depicted in
Scheme 2. Thus, NBS promoted bromination, methylmagnesium iodide addition followed by oxidation
protocol, afforded the acetophenone 4 (Scheme 2). The [Pd]ꢀcatalyzed αꢀarylation of acetophenone 4 and
reduction of the resultant ketone 3 with NaBH4, furnished the alcohol 1bt (Scheme 2). Finally, the key
[Pd]ꢀcatalyzed lactonization of 1bt was amenable and furnished the cytotoxic agonist 3aꢀ[4’ꢀ
methoxybenzyl]ꢀ5,7ꢀdimethoxyphthalide 2bt in its racemic form, in good yield (Scheme 2).
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Scheme 2: Synthesis of cytotoxic agonist 3aꢀ[4’ꢀmethoxybenzyl]ꢀ5,7ꢀdimethoxyphthalide 2bt.
Interestingly, when we attempted the reaction of silyl ether 9, the benzofuranone 2ai was obtained in 67%
yield (Scheme 3). This may be probably due to inꢀsitu deprotection of TMSꢀgroup which might feasible
under basic reaction conditions and then usual [Pd]ꢀcatalyzed lactonization process.
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Me
Me
Me
Me
TMSCl (3 equiv)
imidazole (3 equiv)
MeO
MeO
OTMS
OH
dry DCM
0 °C to rt, 4 h
Br
9 (89%)
Br
1ai
7
8
9
(CH2O)n (5 equiv)
Pd(OAc)2 (5 mol%)
Xanth-Phos (10 mol%)
KOAc (2 equiv)
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o-xylene, 140 °C, 24 h
Me
Me
MeO
O
O
2ai
(67%)
Scheme 3: Formation of isobenzofuranone 2ai from TMS ether 9.
Further the chemical structure of 2 was confirmed by single crystal Xꢀray diffraction analysis of 2bq and
2br as shown in Figure 2 (see; SI for Xꢀray data of 2bq & 2br).
Figure 2: Xꢀray crystal structures for products 2bq and 2br.
On the basis of established reports using paraformaldehyde as COꢀfree carbonylating agent and their
experimental studies probed to understand the mechanistic path,13 the plausible reaction mechanism for
the formation of isobenzofuranones 2 is shown in Scheme 4. Thus, the initial oxidative insertion of Pd0ꢀ
catalyst into the CꢀBr bond of 1 generates the arylꢀPdII species A. Then the migratory insertion of CO on
A furnishes new PdIIꢀspecies B. Subsequent intramolecular nucleophilic chelation of the OH group and
concomitant elimination of HBr leads to the six membered PdIIꢀintermediate C. Finally, reductive
elimination of C through the formation of Pd0ꢀ catalyst, gives isobenzofuranones 2, thus completes the
catalytic cycle. Presumably, CO might be formed via an independent path by the reaction of
paraformdaldehyde with the [Pd]ꢀcatalyst.
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Scheme 4: Plausible reaction path for the formation of 2.
Conclusions
In conclusion, we have described an efficient domino [Pd]ꢀcatalysis for oneꢀpot synthesis of
isobenzofuranꢀ1(3 )ꢀones. Unlike our previous report, the present strategy showed broad substrate
scope and amenable to orthoꢀbromobenzyl tertiary/secondary/primary alcohols. Significantly, the
H
method was also successfully applied to the synthesis of antiꢀplatelet drug
cytotoxic agonist 3aꢀ[4’ꢀmethoxylbenzyl]ꢀ5,7ꢀdimethoxyphthalide.
nꢀbutyl phthalide and
Experimental Section
General Considerations
1
IR spectra were recorded on a FTIR spectrophotometer. H NMR spectra were recorded on 400
MHz spectrometer at 295 K in CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are reported
in standard fashion with reference to either internal standard tetramethylsilane (TMS) (δH=0.00 ppm) or
CHCl3 (δH=7.25 ppm). 13C NMR spectra were recorded on 100 MHz spectrometer at RT in CDCl3;
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chemical shifts (δ ppm) are reported relative to CHCl3 [δC=77.00 ppm (central line of triplet)]. In the C
NMR, the nature of carbons (C, CH, CH2, and CH3) was determined by recording the DEPTꢀ135 spectra
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and is given in parentheses and noted as s = singlet (for C), d = doublet (for CH), t = triplet (for CH2) and
q = quartet (for CH3). In the 1H NMR, the following abbreviations were used throughout: s = singlet, d =
doublet, t = triplet, q = quartet, qui =quintet, m = multiplet and br s. = broad singlet. The assignment of
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1
13
signals was confirmed by H, C CPD (carbon proton decoupled), and DEPT spectra. Highꢀresolution
mass spectra (HRꢀMS) were recorded using QꢀTOF multimode source. Melting points were determined
on an electrothermal melting point apparatus and are uncorrected. Benzaldehydes, immidazole, aryl
halides, methyl iodide, bromoethane, Mg metal and Na2SO4 were commercially available (local made)
used without further purification, Pd(OAc)2, PPh3, XanthꢀPhos, (HCHO)n, Cs2CO3, KOAc, K3PO4, K2CO3,
Na2CO3, NaOAc, NEt3, NHEt2 and DMED (dimethyl ethelene diamine) purchased from commercial
source. All dry solvents were used, diethyl ether, toluene, Dioxane and THF were dried over sodium
metal, DCM, DMA, CH3CN, DCE and DMF were dried over calcium hydride.
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All the solvents (diethyl ether, THF, DCM, DMF, paraꢀxylene, DMSO and orthoꢀxylene) are
commercially available (LR Grade). All small scale dry reactions were carried out using standard syringeꢀ
septum technique. Reactions were monitored by TLC on silica gel using a combination of petroleum ether
and ethyl acetate as eluents. Solvents were distilled prior to use; petroleum ether with a boiling range of
40 to 60 °C was used. Acme’s silica gel (60–120 mesh) was used for column chromatography
(approximately 20 g per one gram of crude material).
General Procedure (For the synthesis of lactones) (2aaꢀ2bt):
In an ovenꢀdried Schlenk tube 2ꢀbromobenzyl alcohols 1 (0.50 mmol), paraformaldehyde (2.50
mmol), Pd(OAc)2 (0.02 mmol), XanthꢀPhos (0.05 mmol), base [(1.00 mmol) for primary alcohols Na2CO3
for tertiary and secondary alcohols KOAc] and solvent (othoꢀxylene) (0.5 mL) were added. The resulting
reaction mixture was stirred at 140 °C for 24 h. The progress of the reaction was monitored by TLC. After
completion of reaction, the reaction mixture was allowed to cool to room temperature, then diluted with
(10 mL) ethyl acetate and saturated NH4Cl was added fallowed by extraction with ethyl acetate. The
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organic layers were dried (Na2SO4) and concentrated in vacuo. Purification of the residue by silica gel
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column chromatography using petroleum ether/ethyl acetate as the eluent furnished the lactone 2.
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1ꢀ(2ꢀbromoꢀ3,5ꢀdimethoxyphenyl)ethanol (1bu):
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To a cold (0 °C), magnetically stirred solution of a bromobenzaldehyde 7f (1.29 mmol) in
dry dry ether (2 mL) was added methylmagnesium iodide (2.59 mmol) [prepared from magnesium (2.59
mmol) and methyl iodide (2.59 mmol) in 10 mL of dry ether]. The reaction mixture was stirred at 0 °C to
room temperature for 3 h. It was then poured into saturated aqueous NH4Cl solution and extracted with
ethyl acetate (3 × 15 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo.
The crude secondary alcohol 1bu was purified by column chromatography on silica using petroleum
ether/ethyl acetate (85:15) as eluent and isolated as white colored solid 89% yield (339 mg): mp 76–78
°C; [TLC (petroleum ether/ethyl acetate 8:2, Rf(7f)=0.40, Rf(1bu)=0.30, UV detection]. 1H NMR (CDCl3
400 MHz): δ=6.79 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 5.27 (q, J=6.3 Hz, 1H), 3.86 (s, 3H), 3.82
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(s, 3H), 2.00 (br. s, 1H), 1.45 (d, J=6.3 Hz, 3H) ppm. C NMR (CDCl3, 100 MHz): δ=160.1 (Cq), 156.4
(Cq), 146.8 (Cq), 102.4 (CH), 101.8 (Cq), 98.8 (Cq), 69.4 (CH), 56.3 (CH3), 55.6 (CH3), 23.4 (CH3) ppm.
IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=3320, 2932, 1490, 1345, 1286, 1181, 1050, 962, 758, 689 cmꢀ1. HRꢀ
MS (ESI+) m/z calculated for [C10H14BrO3]+=[M+H]+: 261.0121; found: 261.0125.
1ꢀ(2ꢀbromophenyl)butanꢀ1ꢀol (1bj):
To a cold (0 °C), magnetically stirred solution of a bromobenzaldehyde 7a (2.70 mmol) in dry
THF (2 mL) was added propylmagnesium bromide (5.40 mmol), [prepared from magnesium (5.40 mmol)
and 1ꢀbromopropane (5.40 mmol) and a catalytic amount of iodine in 10 mL of dry THF]. The reaction
mixture was stirred at 0 °C to room temperature for 3 h. It was then poured into saturated aqueous NH4Cl
solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The crude secondary alcohol 1bj was purified by column chromatography on
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silica using petroleum ether/ethyl acetate (92:08) as eluent and isolated as colorless liquid 78% yield (486
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mg); [TLC (petroleum ether/ethyl acetate 9:1, Rf(7a)=0.50, Rf(1bj)=0.40, UV detection]. H NMR
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(CDCl3 400 MHz): δ=7.58ꢀ7.40 (m, 2H), 7.31 (dd, J=7.3 and 7.3 Hz, 1H), 7.10 (dd, J=7.8 and 7.3 Hz,
1H), 5.10ꢀ5.00 (m, 1H), 2.23 (br. s, 1H), 1.80ꢀ1.60 (m, 2H), 1.58ꢀ1.35 (m, 2H), 0.95 (t, J=7.3 Hz, 3H)
ppm. 13C NMR (CDCl3, 100 MHz): δ=143.9 (Cq), 132.5 (CH), 128.6 (CH), 127.6 (CH), 127.3 (CH),
121.9 (Cq), 72.6 (CH), 39.8 (CH2), 18.9 (CH2), 13.8 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1):
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ν
max=3320, 2930, 1496, 1341, 1286, 1181, 1050, 962, 750, 687 cmꢀ1. HRꢀMS (ESI+) m/z calculated for
[C10H13OBrNa]+=[M+Na]+: 251.0042; found: 251.0046.
1ꢀ(2ꢀbromoꢀ3,4,5ꢀtrimethoxyphenyl)butanꢀ1ꢀol (1bl):
To a cold (0 °C), magnetically stirred solution of a bromobenzaldehyde 7d (2.0 mmol) in dry
THF (2 mL) was added propylmagnesium bromide (4.0 mmol) [prepared from magnesium (4.0 mmol)
and 1ꢀbromopropane (4.0 mmol) and a catalytic amount of iodine in 10 mL of dry THF]. The reaction
mixture was stirred at 0 °C to room temperature for 3 h. It was then poured into saturated aqueous NH4Cl
solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried (Na2SO4)
and concentrated in vacuo. The crude secondary alcohol 1bl was purified by column chromatography on
silica using petroleum ether/ethyl acetate (75:25) as eluent and isolated as brown colored viscous liquid
85% yield (549 mg); [TLC (petroleum ether/ethyl acetate 7:3, Rf(7d)=0.60, Rf(1bl)=0.50, UV detection].
1H NMR (CDCl3 400 MHz): δ=6.91 (s, 1H), 5.08ꢀ5.00 (m, 1H), 3.84 (s, 3H), 3.83 (s, 2 x 3H), 2.28 (br. s,
13
1H), 1.80ꢀ1.30 (m, 4H), 0.93 (t, J=7.3 Hz, 3H) ppm. C NMR (CDCl3, 100 MHz): δ=152.9 (Cq), 150.2
(Cq), 141.9 (Cq), 139.8 (Cq), 107.9 (Cq), 105.7 (CH), 72.5 (CH), 61.0 (CH3), 60.9 (CH3), 56.0 (CH3), 39.8
(CH2), 19.0 (CH2), 13.8 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=3349, 2930, 1493, 1355, 1276,
1181, 1052, 962, 759, 679 cmꢀ1. HRꢀMS (ESI+) m/z calculated for [C13H19O4BrNa]+=[M+Na]+: 341.0359;
found: 341.0350.
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1ꢀ(2ꢀbromoꢀ3,5ꢀdimethoxyphenyl)ethanone (4):
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To a magnetically stirred solution of the secondary alcohol 1bu (1.21 mmol) in dry CH2Cl2 (10
mL) was added a homogeneous mixture (1:1) of PCC (3.64 mmol) and silica gel. The resulting reaction
mixture was stirred at room temperature for 2 h. Filtration of the reaction mixture through a short silica
column with excess CH2Cl2 furnished the pure ketone 4 and isolated as pale yellow colored oil 94% yield
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1
(281 mg); [TLC (petroleum ether/ethyl acetate 8:2, Rf(1bu)=0.40, Rf(4)=0.50, UV detection]. H NMR
(CDCl3 400 MHz): δ=6.51 (d, J=2.9 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 2.59 (s,
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3H) ppm. C NMR (CDCl3, 100 MHz): δ=202.4 (Cq), 160.0 (Cq), 156.9 (Cq), 144.3 (Cq), 103.8 (CH),
101.1 (CH), 98.9 (Cq), 56.5 (CH3), 55.7 (CH3), 30.6 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1):
ν
max=2939, 1689, 1546, 1460, 1355, 1280, 1171, 1055, 962, 758, 680 cmꢀ1. HRꢀMS (ESI+) m/z calculated
for [C10H11BrO3Na]+=[M+Na]+: 280.9784; found: 280.9789.
1ꢀ(2ꢀbromoꢀ3,5ꢀdimethoxyphenyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)ethanone (3):
In an oven ꢀdried Schlenk tube under nitrogen atmosphere were added pꢀiodoanisole 5 (1.34
t
mmol), orthoꢀbromoacetophenone 4 (1.22 mmol), Pd(OAc)2 (2 mol%), xantphos (4 mol%) and BuOK
(2.44 mmol) followed by addition of dry toluene (4 mL). The resulting reaction mixture was stirred at 80
°C for 20 min. Progress of the reaction was monitored by TLC until the reaction is completed. The
reaction mixture was then quenched with saturated aqueous NH4Cl, and the aqueous layer was extracted
with ethyl acetate (3 × 20 mL). The combined organic layers were dried (Na2SO4) and concentrated in
vacuo. The crude ketone 3 was purified by column chromatography on silica using petroleum ether/ethyl
acetate (85:15) as eluent and isolated as pale yellow colored liquid 66% yield (296 mg); [TLC (petroleum
1
ether/ethyl acetate 8:2, Rf(4)=0.60, Rf(3)=0.50, UV detection]. H NMR (CDCl3 400 MHz): δ=7.15 (d,
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J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.49 (d, J=2.9 Hz, 1H), 6.27 (d, J=2.9 Hz, 1H), 4.13 (s, 2H), 3.87
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(s, 3H), 3.78 (s, 3H), 3.73 (s, 3H) ppm. C NMR (CDCl3, 100 MHz): δ=202.7 (Cq), 159.9 (Cq), 158.7
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(Cq), 156.7 (Cq), 144.0 (Cq), 130.8 (CH), 125.4 (Cq), 114.0 (CH), 103.9 (CH), 100.8 (CH), 98.6 (Cq), 56.4
(CH3), 55.7 (CH3), 55.2 (CH3), 48.8 (CH2) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=2938, 1679, 1550,
1453, 1340, 1280, 1176, 1050, 962, 756, 680 cmꢀ1. HRꢀMS (ESI+) m/z calculated for
[C17H18BrO4]+=[M+H]+: 365.0383; found: 365.0378.
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1ꢀ(2ꢀbromoꢀ3,5ꢀdimethoxyphenyl)ꢀ2ꢀ(4ꢀmethoxyphenyl)ethanol (1bt):
To a magnetically stirred solution of the aryl ketone 3 (0.54 mmol) in dry MeOH (10 mL) was
added a NaBH4 (1.08 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It
was then poured into saturated aqueous NH4Cl solution and extracted with ethyl acetate (3 × 15 mL). The
combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude secondary alcohol 1
was purified by column chromatography on silica using petroleum ether/ethyl acetate (85:15) as eluent
and isolated as colorless oil 92% yield (186 mg); [TLC (petroleum ether/ethyl acetate 8:2, Rf(3)=0.50,
1
Rf(1bt)=0.30, UV detection]. H NMR (CDCl3 400 MHz): δ=7.24 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz,
2H), 6.79 (d, J=2.9 Hz, 1H), 6.43 (d, J=2.9 Hz, 1H), 5.28ꢀ5.20 (m, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.80 (s,
13
3H), 3.20ꢀ3.10 (m, 1H), 2.65ꢀ2.55 (m, 1H), 2.11 (br. s, 1H) ppm. C NMR (CDCl3, 100 MHz): δ=160.0
(Cq), 158.4 (Cq), 158.3 (Cq), 145.0 (Cq), 130.4 (CH), 130.3 (Cq), 113.9 (CH), 102.8 (CH), 101.9 (Cq) 98.9
(Cq), 74.3 (CH), 56.3 (CH3), 55.5 (CH3), 55.2 (CH3), 43.1 (CH2) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1):
ν
max=3329, 2930, 1530, 1443, 1350, 1240, 1178, 1050, 945, 750, 676 cmꢀ1. HRꢀMS (ESI+) m/z calculated
for [C17H19BrO4Na]+=[M+Na]+: 389.0359; found: 389.0364.
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[(2ꢀ(2ꢀbromoꢀ5ꢀmethoxyphenyl)butanꢀ2ꢀyl)oxy]trimethylsilane (9)
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To a magnetically stirred solution of the tertiary alcohol 1ai (0.39 mmol) and imidazole (3 mmol) in
dry CH2Cl2 (6 mL) trimethylsilyl chloride (3 mmol) was added at 0 °C. The resulting reaction mixture
was stirred at room temperature for 4 h. The reaction mixture was quenched and extracted with CH2Cl2 (3
× 15 mL). The collected organic layers were dried (Na2SO4) and concentrated under reduced pressure.
Purification of the residue on a silica gel column chromatography (petroleum ether/ethyl acetate 97:03) as
eluent furnished trimethyl silylether 9 in 89% yield (114 mg) as colorless viscous liquid: [TLC (petroleum
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ether/ethyl acetate 9:1, Rf(1ai)=0.40, Rf(9)=0.60, UV detection]. H NMR (CDCl3 400 MHz) δ=7.42 (d,
1H, J=8.3 Hz), 7.33 (d, 1H, J=3.4 Hz), 6.61 (dd, 1H, J=8.3 and 3.4 Hz), 3.78 (s, 3H), 2.55ꢀ2.40 (m, 1H),
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1.85ꢀ1.71 (m, 1H), 1.76 (s, 3H), 0.64 (t, 3H, J=7.3 Hz ), 0.18 (s, 9H) ppm; C NMR (CDCl3, 100 MHz)
δ=158.5 (Cq), 147.1 (Cq), 135.5 (CH), 115.5 (CH), 113.1 (CH), 110.1 (Cq), 79.4 (Cq), 55.2 (CH3), 33.5
(CH2), 28.0 (CH3), 8.5 (CH3), 2.4 (3 × CH3) ppm; IR (MIRꢀATR, 4000–600 cm–1)
νmax=2958, 1568, 1460,
1372, 1249, 1170, 1056, 835, 752, 673 cm–1; HRꢀMS (ESI+) m/z calculated for
[C14H2381BrNaSiO2]+=[M+Na]+ 353.0543, found 353.0540.
3ꢀethylꢀ5ꢀmethoxyisobenzofuranꢀ1(3H)ꢀone (2bg):
This compound was prepared according to the GP and using petroleum ether/ethyl acetate
(85:15) as eluent isolated as brown colored viscous liquid 72% yield (75 mg): [TLC (petroleum
1
ether/ethyl acetate 8:2, Rf(1bg)=0.50, Rf(2bg)=0.40, UV detection]. H NMR (CDCl3 400 MHz): δ=7.76
(d, J=8.3 Hz, 1H), 6.99 (dd, J=1.9 and 8.3 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 5.33 (dd, J=4.4 and 7.3 Hz,
13
1H), 3.87 (s, 3H), 2.00ꢀ2.15 (m, 1H), 1.85ꢀ1.70 (m, 1H), 0.96 (t, J=7.3 Hz, 3H) ppm. C NMR (CDCl3,
100 MHz): δ=170.4 (Cq), 164.6 (Cq), 152.4 (Cq), 127.1 (CH), 118.5 (Cq), 116.2 (CH), 105.8 (CH), 81.5
(Cq), 55.8 (CH3), 27.6 (CH2), 8.7 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=2947, 1750, 1598,
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1465, 1338, 1282, 1190, 1054, 965, 741, 692 cmꢀ1. HRꢀMS (ESI+) m/z calculated for
[C11H13O3]+=[M+H]+: 193.0859; found: 193.0853.
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3ꢀisopropylꢀ5ꢀmethoxyisobenzofuranꢀ1(3H)ꢀone (2bi):
This compound was prepared according to the GP and using petroleum ether/ethyl acetate
(85:15) as eluent isolated as colorless oil 66% yield (68 mg): [TLC (petroleum ether/ethyl acetate 8:2,
1
Rf(1bi)=0.50, Rf(2bi)=0.40, UV detection]. H NMR (CDCl3 400 MHz): δ=7.88 (d, J=7.8 Hz, 1H), 7.65
(dd, J=1.5 and 7.8 Hz, 1H), 7.51 (dd, J=7.3 and 7.3 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 5.36 (d, J=3.9 Hz,
1H), 2.35ꢀ2.20 (m, 1H), 1.11 (d, J=7.3 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H) ppm. 13C NMR (CDCl3, 100
MHz): δ=170.8 (Cq), 148.8 (Cq), 133.8 (CH), 129.0 (CH), 126.7 (Cq), 125.6 (CH), 122.1 (CH), 85.6 (Cq),
32.3 (2C, 2 × CH), 18.6 (CH3), 15.6 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=2941, 1752, 1588,
1460, 1348, 1280, 1191, 1052, 966, 740, 690 cmꢀ1. HRꢀMS (ESI+) m/z calculated for
[C12H14O3Na]+=[M+Na]+: 229.0835; found: 229.0830.
5,6ꢀdimethoxyꢀ3ꢀpropylisobenzofuranꢀ1(3H)ꢀone (2bk):
This compound was prepared according to the GP and using petroleum ether/ethyl acetate
(80:20) as eluent isolated as white colored solid 69% yield (82 mg): mp 82–84 °C; [TLC (petroleum
1
ether/ethyl acetate 7:3, Rf(1bk)=0.40, Rf(2bk)=0.30, UV detection]. H NMR (CDCl3 400 MHz): δ=7.26
(s, 1H), 6.80 (s, 1H), 5.30ꢀ5.43 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 1.90ꢀ2.07 (m, 1H), 1.60ꢀ1.76 (m, 1H),
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1.40ꢀ1.58 (m, 2H), 0.96 (t, J=7.3 Hz, 3H) ppm. C NMR (CDCl3, 100 MHz): δ=171.0 (Cq), 154.7 (Cq),
150.3 (Cq), 144.7 (Cq), 118.0 (Cq), 106.1 (CH), 103.0 (CH), 80.6 (Cq), 56.4 (CH3), 56.3 (CH3), 36.9
(CH2), 18.2 (CH2), 13.8 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=2939, 1749, 1582, 1463, 1345,
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1286, 1181, 1050, 962, 758, 689 cmꢀ1. HRꢀMS (ESI+) m/z calculated for [C13H17O4]+=[M+H]+: 237.1121;
found: 237.1115.
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5,6,7ꢀtrimethoxyꢀ3ꢀpropylisobenzofuranꢀ1(3H)ꢀone (2bl):
This compound was prepared according to the GP and using petroleum ether/ethyl acetate
(75:25) as eluent isolated as colorless oil 67% yield (89 mg): [TLC (petroleum ether/ethyl acetate 6:4,
1
Rf(1bl)=0.50, Rf(2bl)=0.40, UV detection]. H NMR (CDCl3 400 MHz): δ=6.56 (s, 1H), 5.20ꢀ5.30 (m,
1H), 4.11 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 1.88ꢀ2.00 (m 1H), 1.60ꢀ1.75 (m 1H), 1.40ꢀ1.55 (m 2H), 0.95
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(t, J=7.3 Hz, 3H) ppm. C NMR (CDCl3, 100 MHz): δ=168.2 (Cq), 159.5 (Cq), 152.3 (Cq), 148.0 (Cq),
141.6 (Cq), 110.6 (Cq), 99.1 (CH), 79.8 (CH), 62.3 (CH3), 61.4 (CH3), 56.4 (CH3), 37.0 (CH2), 18.2 (CH2),
13.8 (CH3) ppm. IR (MIRꢀATR, 4000–600 cmꢀ1): νmax=2943, 1742, 1578, 1462, 1341, 1282, 1187, 1054,
960, 757, 687 cmꢀ1. HRꢀMS (ESI+) m/z calculated for [C14H18O5Na]+=[M+Na]+: 289.1046; found:
289.1038.
3ꢀcyclohexylꢀ5ꢀmethoxyisobenzofuranꢀ1(3H)ꢀone (2bn):
This compound was prepared according to the GP and using petroleum ether/ethyl
acetate (85:15) as eluent isolated as white colored solid 66% yield (81 mg): mp 200–202 °C; [TLC
1
(petroleum ether/ethyl acetate 8:2, Rf(1bn)=0.50, Rf(2bn)=0.40, UV detection]. H NMR (CDCl3
400 MHz): δ=7.76 (d,
(d,
J
=8.3 Hz, 1H), 6.99 (dd,
J
=2.0 and 8.3 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 5.24
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J
=3.4 Hz, 1H), 3.89 (s, 3H), 1.55ꢀ1.95 (m, 5H), 1.00ꢀ1.40 (m, 6H) ppm. C NMR (CDCl3, 100
MHz): δ=170.6 (Cq), 164.5 (Cq), 151.5 (Cq), 127.1 (CH), 119.0 (Cq), 115.9 (CH), 106.4 (CH), 84.6
(CH), 55.8 (CH3), 42.0 (CH), 29.3 (CH2), 26.2 (CH2), 26.0 (CH2), 25.8 (CH2), 25.6 (CH2) ppm. IR
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(MIRꢀATR, 4000–600 cmꢀ1):
ν
max=2940, 1739, 1568, 1469, 1340, 1282, 1187, 1054, 964, 752, 686
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cmꢀ1. HRꢀMS (ESI+) m/z calculated for [C15H18O3K]+=[M+K]+: 285.0888; found: 285.0882.
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Supporting Information
The Xꢀray crystallographic data (CIF files) for 2bq and 2br and copies of NMR spectra reported. This
material is available free of charge via the Internet at http://pubs.acs.org.
Author Information:
Corresponding author
Fax: +91(40) 2301 6032 Eꢀmail: gvsatya@iith.ac.in
Acknowledgment:
We are grateful to the Department of Science and TechnologyꢀScience and Engineering Research
Board (DSTꢀSERB) [NO.:SB/S1/OCꢀ39/2014], New Delhi, for the financial support. L.M. thanks CSIR,
New Delhi, for the award of research fellowship.
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Li, Z.ꢀH. Curr. Org. Chem. 2007, 11, 833; (d) Mola, A. D.; Palombi, L.; Massa, A. Curr. Org. Chem. 2012,
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