Synthesis of 2-Alkylideneisochromans by Cyclocarbonylative Sonogashira Reactions

Article abstract of DOI:10.1002/ejoc.201402979

In this study we used a tandem carbonylative Sonogashira reaction/cyclisation process to construct alkylidene-functionalized isochromans in high yields with complete stereoselectivity (only Z isomers were formed). The reaction was performed in the absence

Full text of DOI:10.1002/ejoc.201402979

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402979
Synthesis of 2-Alkylideneisochromans by Cyclocarbonylative Sonogashira
Reactions
Laura Antonella Aronica,*[a] Luca Giannotti,[b] Stefano Giuntini,[a] and
Anna Maria Caporusso[a]
Keywords: Synthetic methods / Cross-coupling / Carbonylation / Cyclization / Oxygen heterocycles
In this study we used a tandem carbonylative Sonogashira
reaction/cyclisation process to construct alkylidene-function-
alized isochromans in high yields with complete stereoselec-
tivity (only Z isomers were formed). The reaction was per-
formed in the absence of a CuI co-catalyst with a small
amount of PdCl2(PPh3)2 (0.2–0.5 mol-%), and aryl iodides
bearing both electron-donating and electron-withdrawing
substituents were successfully employed.
triflate[17] have also been shown to be effective. A different
approach was reported by Florio[18] et al. and is based on
the sequence of lithiation/acid-catalyzed cyclization of N-
alkyl-(o-tolyl)aziridines. Later on, the same group described
the preparation of polysubstituted isochromans by means
of a one-pot procedure based on the addition of ortho-lith-
iated aryloxiranes to enaminones.[19] Ramana and co-
workers[20,21] reported the application of [2+2+2] alkyne–
diyne cyclotrimerization to the preparation of enantiopure
isochromans catalyzed by a rhodium species. Function-
alized diynes were also used in a Heck carbopalladation/
cyclization sequence[22] for the synthesis of highly substi-
tuted isochromans. Finally, palladium catalysts have been
employed in cyclization reactions[23–26] of benzyl and homo-
benzyl alcohols derivatives.
Introduction
Isochromans (Figure 1) are an important class of mo-
lecules in medicinal chemistry because of their biological
properties. Indeed, some of them exhibit hypotensive,[1] an-
titumor,[2] antibacterial,[3] and antioxidant[4] activities and
plant grow-regulating potential.[5] Some others are neuro-
kinin-1-receptor antagonists[6] or have a specific effect on
the dopaminergic system.[7] Moreover, isochromans can be
precursors for the synthesis of isochromanones,[8] tetra-
hydrobenzazepines,[9] and benzodiazepine-4-ones,[10] all of
which are important building blocks in organic chemistry.
Recently, a few examples of the synthesis of heterocyclic
derivatives such as isoquinolones, isoindolinones,[27] flav-
ones, chromones,[28] and benzofurans[29] based on palla-
dium-catalyzed Sonogashira reactions were described. In
particular, 2-iodophenols and 2-iodoaniline were treated
with terminal acetylenes under a carbon monoxide atmo-
sphere to generate acetylenic ketones that underwent cycli-
zation to afford the heterocyclic derivatives depicted in
Scheme 1.
Figure 1. Isochroman structure.
Several excellent methods for the formation of the iso-
chroman skeleton are described in the literature. Many of
them are based on the oxa-Pictet–Spengler reaction,[11–15]
which consists of the condensation of a β-arylethanol deriv-
ative with a carbonyl compound to form a hemiacetal; this
intermediate undergoes cyclization to give the isochroman
ring. The reaction is often promoted by acid catalysts such
as H2SO4, HCl, p-toluenesulfonic acid, acetic acid, oleic
acid, AlCl3, TiCl4, and ZnCl2, but zeolites[16] and bismuth
[a] Dipartimento di Chimica e Chimica Industriale, University of
Pisa,
Scheme 1. Sonogashira reaction for the synthesis of heterocyclic
compounds.
Via Risorgimento 35, 56123 Pisa, Italy
E-mail: laura.antonella.aronica@unipi.it
http://www.dcci.unipi.it
[b] Dipartimento di Biotecnologie, Chimica e Farmacia,
Via Aldo Moro 2, 53100 Siena, Italy
Intrigued by this data and prompted by our recent results
on the Sonogashira carbonylative reaction,[30] we decided
to investigate the possibility to apply a carbonylative Sono-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402979.
6858
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Synthesis of 2-Alkylideneisochromans
gashira reaction/cyclization sequence to the synthesis of
isochromans. Indeed, starting from a suitable substrate, this
tandem
process
afforded
2-alkylideneisochromans
(Scheme 2), the preparation of which is seldom reported.[31]
Scheme 4. Preliminary carbonylative reaction between 2-(2-ethyn-
ylphenyl)ethanol and iodobenzene.
Scheme 2. Possible synthesis of isochroman through cyclocarb-
onylative Sonogashira reaction.
Results and Discussion
2-(2-Ethynylphenyl)ethanol (1) was chosen as a model
substrate and was prepared according to the method de-
scribed in Scheme 3. 2-Iodophenylacetic acid (2) was easily
reduced to corresponding benzyl alcohol 3 in high yield Figure 2. Isochroman structure.
(89%) by means of NaBH4/BF3·OEt2.[32] The acetylenic
moiety was then introduced with a cross-coupling Sonoga-
Notably, according to Baldwin’s rules,[34] only six-mem-
bered ring 6a was generated during the cyclization process
(6-exo-dig), whereas no trace amounts of the possible tetra-
hydrobenzoxepine derivative were detected. In addition to
isochroman derivative 6a, a small amount (5% purified
yield) of 3-[2-(2-phenoxyethyl)phenyl]-1-phenyl-2-yn-1-one
(7a) was isolated (Figure 3).
shira reaction with trimethysilylacetylene to yield desired
product 4 (88%).[33] Finally, the trimethylsilyl group was
smoothly removed by treatment of 4 with an excess amount
of tetrabutylammonium fluoride (TBAF, 90%).[33]
Scheme 3. Synthetic sequence for the preparation of 2-(2-ethyn-
ylphenyl)ethanol (1).
Figure 3. Structure of 3-[2-(2-phenoxyethyl)phenyl]-1-phenyl-2-yn-
1-one.
A preliminary cyclocarbonylative Sonogashira reaction
was performed by treating 1 with iodobenzene in triethyl-
A plausible mechanism for the formation of both prod-
amine chosen as both the solvent and the base at 100 °C ucts 6a and 7a is described in Scheme 5. It involves, first,
for 24 h with PdCl2(PPh3)2 (0.2 mol-%) and under an atmo- the Sonogashira carbonylative reaction between iodo-
sphere of CO (2.0 MPa, Scheme 4). To our delight, analysis benzene (5a) and ethynyl alcohol 1, which should form 3-[2-
of the crude mixture by NMR spectroscopy indicated the (2-hydroxyethyl)phenyl]-1-phenylprop-2-yn-1-one (8) as the
complete conversion of the reagents and the formation of intermediate of both derivatives. At this point, Pd0 insertion
2-(isochroman-1-ylidene)-1-phenylethanone (6a) as the into the O–H bond would generate palladium hydride spe-
principal product, which was isolated in a chemically pure cie I, which can undergo two different transformations.
form (column chromatography) in high yield (89%). The Hydropalladation to the triple bond (Scheme 5, II) followed
configuration of the double bond of the olefinic moiety was by reductive elimination could afford isochroman 6a with
then determined by analysis of the results obtained with a regeneration of the palladium catalyst. On the other hand,
NOESY (nuclear Overhauser effect spectroscopy) experi- the presence of ether 7a can be explained with a direct in-
ment. Relevant NOE effects were detected between vinylic sertion of palladium into the C–I bond of iodobenzene
Ha and aromatic Hb and Hc, as shown in Figure 2, which (Scheme 5, III) with subsequent reductive elimination of
thus indicated the exclusive formation of the Z isomer of Pd0. As a matter of fact, a few examples of the arylation of
isochroman 6a with two conjugated double bonds in an benzylic or homobenzylic alcohols catalyzed by transition-
s-cis geometry.
metal-based species have been described.[35]
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L. A. Aronica, L. Giannotti, S. Giuntini, A. M. Caporusso
SHORT COMMUNICATION
with respect to the iodoarenes (2.5 mmol vs. 2 mmol) and
in the presence of a slightly higher amount of the catalyst
(0.5 instead of 0.2 mol-%), ether byproducts 7b and 7c com-
pletely disappeared and improved yields (87–89% vs. 73–
75%) of isochromans 6b and 6c were obtained (Table 1, en-
tries 4 and 5).
Table 1. Cyclocarbonylative reaction of 2-(2-ethynylphenyl)ethanol
and aryl iodides.[a]
Entry
5
Ar
(Z)-6
Yield[b]
[%]
7
Yield[b]
[%]
1
2
3
a
b
c
b
c
d
e
f
Ph
a
b
c
b
c
d
e
f
89
75
73
87
89
81
75
80
83
72
68
a
b
c
5
7
8
–
–
–
–
–
–
–
–
1-naphthyl
2-MeC6H4
1-naphthyl
2-MeC6H4
4-MeC6H4
2-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-NCC6H4
2-NCC6H4
4[c]
5[c]
6
–
–
–
–
–
–
–
–
7
8
9
10
11
g
h
i
g
h
i
Scheme 5. Hypothetical mechanism for the formation of iso-
chroman 6 and ether 7.
[a] Reactions were performed with 1 (2 mmol), 5 (2 mmol), Et3N
(5 mL), and PdCl2(PPh3)3 (0.004 mmol) at 100 °C for 24 h under
an atmosphere of CO (2.0 MPa). [b] Yield of isolated product after
purification by silica gel column chromatography. [c] Reaction was
performed with 1 (2.5 mmol) and PdCl2(PPh3)2 (0.5 mol-%).
Moreover, the carbonylation of the triple bond was
found to be fundamental for the cyclization process. Indeed,
if a reaction between ethynyl alcohol 1 and iodobenzene
(5a) was performed in the absence of carbon monoxide,
only 2-[2-(phenylethynyl)phenyl]ethanol (9) was formed
(56% purified yield, Scheme 6).
Moreover, upon performing the reaction with 2-iodo-
benzonitrile (5i), that is, in the presence of a strong electron-
withdrawing group in the ortho position, a small amount
(16%, Figure 4) of 2-{[2-(2-hydroxyethyl)phenyl]ethynyl}-
benzonitrile (10) was isolated.
Scheme 6. Sonogashira reaction between 2-(2-ethynylphenyl)eth-
anol and iodobenzene.
The cyclocarbonylative Sonogashira reaction was then
extended to several aryl iodides 5 possessing electron-do-
nating and electron-withdrawing substituents in the ortho
and para positions. As described in Table 1, quantitative
conversion of the reagents was detected in all experiments.
The reactions generated isochroman derivatives 6a–i in
Figure 4. Byproduct of the Sonogashira cyclocarbonylation of 2-
iodobenzonitrile.
This result can be explained with a competitive noncarb-
good to excellent yields (68–89%) with complete stereose- onylative Sonogashira reaction that determined the forma-
lectivity towards the formation of the Z isomer, regardless tion of direct coupling product 10. According to the results
of the stereoelectronic features of employed aryl iodides 5. previously observed in the noncarbonylative experiment
A small decrease in the chemoselectivity was observed if the (Scheme 6), 10 did not cyclize because of the absence of the
steric requirements of 5 increased, such as in the cases of CO moiety.
α-naphthyl and o-tolyl derivatives (Table 1, entries 2 and 3).
Finally, upon testing 4-iodonitrobenzene in the cyclo-
However, upon performing the reactions between 1 and aryl carbonylative reaction, an unexpected result was obtained.
iodides 5b and 5c with a small excess amount of alcohol 1 Indeed, the reaction afforded (Z)-1-(4-aminophenyl)-2-
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Synthesis of 2-Alkylideneisochromans
(isochroman-1-ylidene)
(Scheme 7, path I). The structure of this product was con-
firmed by means of a cyclocarbonylative reaction per-
ethanone
(11)
exclusively
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Conclusions
We developed a new approach for the synthesis of alkyl-
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Experimental Section
Typical Procedure for the Synthesis of (Z)-2-(Isochroman-1-ylidene)-
1-phenyletanone (6a): A Pyrex Schlenk tube was charged with 2-
(2-ethynylphenyl)ethanol (0.292 g, 2 mmol), iodobenzene (0.22 mL,
2 mmol), and Et3N (5 mL). This solution was introduced by a steel
siphon into the autoclave, previously charged with PdCl2(PPh3)2
(2.91 mg, 0.004 mmol) and placed under vacuum (13.3 Pa). The re-
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400 mesh, CHCl3) to yield 6a (0.446 g, 1.78 mmol, 89%) and
3-[2-(2-phenoxyethyl)phenyl]-1-phenyl-2-yn-1-one (7a; 0.034 g,
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SHORT COMMUNICATION
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Received: July 23, 2014
Published Online: September 24, 2014
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