Copper-catalysed cyanoalkylative cycloetherification of alkenes to 1,3-dihydroisobenzofurans: development and application to the synthesis of citalopram

Article abstract of DOI:10.1039/c6cc06356j

A copper-catalysed cyanoalkylative cycloetherification of alkenes was developed. Heating a solution of substituted (2-vinylphenyl)methanol in MeCN/MeOH (v/v 7/3) in the presence of a catalytic amount of copper(ii) tetrafluoroborate hydrate [Cu(BF₄)₂·6H₂O], bathophenanthroline, K₃PO₄, BnOH and (tBuO)₂ afforded 1,3-dihydroisobenzofurans (phthalanes) via formation of one C(sp³)-C(sp³) and one C(sp³)-O bonds. A concise synthesis of citalopram, a marketed anti-depressant drug, was accomplished by applying this novel synthetic transformation.

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Communication
Copper-catalysed cyanoalkylative cycloetherification of alkenes to
1,3-dihydroisobenzofurans: development and application to the
synthesis of citalopram
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Tu M. Ha,a Qian Wanga and Jieping Zhu*
A copper-catalysed cyanoalkylative cycloetherification of alkenes
was developed. Heating solution of substituted (2-
vinylphenyl)methanol in MeCN/MeOH (v/v 7/3) in the presence of
catalytic amount of copper (II) tetrafluoroborate hydrate
[Cu(BF4)2 6H2O], bathophenanthroline, K3PO4, BnOH and (tBuO)2
a
a
•
afforded 1,3-dihydroisobenzofurans (phthalanes) via formation of
one C(sp3)-C(sp3) and one C(sp3)-O bonds. A concise synthesis of
citalopram, a marketed anti-depressant drug, was accomplished
by applying this novel synthetic transformation.
1,3-Dihydroisobenzofurans (phthalanes) are present in
number of biologically active natural products1 and
pharmaceuticals such as citalopram ( ) and talopram ( ),
a
1
2
potent selective serotonin reuptake and norepinephrine
transporters inhibitors, respectively.2 As a result, a variety of
synthetic approaches to dihydroisobenzofuran derivatives
have been reported.3 Among them, electrophile-induced
cycloetherification has been extensively investigated.4,5 The
resulting oxa-heterocycle can be further derivatised taking
advantage of the leaving group aptitude of electrophilic group
Scheme
1
Electrophile-induced cycloetherification and
alkylative cycloetherification.
(e.g. El
= halogen, eq 1, Scheme 1). Direct alkylative
bond.8,9 In connection with our ongoing research program
cycloetherification (eq 2) is, on the other hand, far less
studied.6
dealing with copper-catalysed alkylative difunctionalisation of
10-12
alkenes using alkylnitrile as a key reactant,
we report
Important advances have been made during the past few years
in the copper mediated/catalysed difunctionalisation of
unactivated alkenes involving the formation of a C-C and a C-X
bonds.7 Most of the known carbo-oxygenation reactions were
initiated by an intra- or an inter-molecular oxycupration of a C-
C double bond followed by the formation of a C(sp3)-C(sp2)
herein a novel synthesis of 1,3-dihydroisobenzofurans
copper-catalysed reaction of (2-vinylaryl)methanols
4
by a
with
3
alkyl nitriles. The logic of our reaction design is depicted in
Scheme 2. In situ generation of electrophilic cyanoalkyl radical
5
followed by its addition to electron-rich alkene
afford the adduct radical that could be oxidised by a suitable
metal salt to the carbenium ion 7 13
Trapping of the latter by
the pendant hydroxyl group would afford the desired bicyclic
product . Alternatively, radical recombination of with Cu(II)
salt followed by ligand exchange with the tethered hydroxyl
function would provide , which, upon reductive elimination,
would deliver the product
3 would
6
.
4
6
8
4
with concurrent regeneration of
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COMMUNICATION
Journal Name
Cu(I) salt. Overall, the reaction would produce a medicinally used as a co-solvent, we stress that compounds resulting from
relevant heterocycle via formation of a C(sp3)-C(sp3) and a methoxy cyanomethylation of the double bond were not
C(sp3)-O bonds involving formally a (sp3)-H functionalization formed under these conditions.10d
step. The realisation of this unprecedented transformation and
its application to the synthesis of citalopram (
of this communication.
1) is the subject
Table 1 Survey of reaction conditions
entry
Cu salt
Ligand
Solvent
additive
y (%)b
1
2
3
Cu(OTf)2
Bipy
Bipy
Bipy
MeCN
_
_
_
–
–
–
20
24
33
Cu(BF4)2•6H2O
Cu(OTf)2
MeCN
MeCN/MeOH (4/1)
4
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Cu(BF4)2•6H2O
Bipy
MeCN/MeOH (4/1)
MeCN/MeOH (4/1)
MeCN/MeOH (4/1)
MeCN/MeOH (7/3)
MeCN/MeOH (3/2)
MeCN/MeOH (7/3)
MeCN/MeOH (7/3)
MeCN/MeOH (7/3)
MeCN/MeOH (7/3)
37
5
1,10-Phen
Bathophen
Bathophen
Bathophen
Bathophen
Bathophen
Bathophen
Bathophen
47
6
53
7
–
56 c
43
Scheme 2 Synthesis of 1,3-dihydroisobenzofurans by copper-
8
–
catalysed reaction of (2-vinylaryl)methanols with alkylnitriles.
9
BnOHd
62 c
10
11
Ph2CHOHd
PhCH(OH)Med
BnOHd,e
60
We began the survey of reaction conditions using [2-(prop-1-
en-2-yl)phenyl]methanol (3a) as the benchmark substrate.
Using MeCN as solvent, the conversion was generally low and
the best results were obtained using Cu(OTf)2 or
52
12
65 c
a
The reaction was performed in a sealed tube: 3a (0.1 mmol),
Cu(BF4)2·6H2O (0.3 equiv), ligands (0.6 equiv), (tBuO)2 (4.0 equiv), and
K3PO4 (0.25 equiv) in a given solvent (c 0.067 M), 120 °C. b determined
by 1H NMR spectroscopy with CH2Br2 as an internal standard. c Isolated
yield. d 1.2 equiv. e reaction performed at 100 °C.
Cu(BF4)2
presence of K3PO4 (0.25 equiv) and di-tertbutyl peroxide
(tBuO)2, 4.0 equiv] at 120 °C (entries 1-2, Table 1, cf ESI for
•6H2O as catalyst and bipyridine as ligand in the
[
details). Although it has been demonstrated that the copper
salt is mainly responsible for the generation of cyanomethyl
radical 5 10
the presence of tBuO• radical in the reaction
,
mixture could be problematic in the present case. Indeed, the
BDE of benzylic CH of benzyl alcohol (87.5 kcal/mol) is
relatively low and it can therefore easily transfer its hydrogen
With the optimised conditions in hand, the scope of the
copper-catalysed cyanoalkylative cycloetherification of alkenes
was investigated. The results are summarized in Scheme 3. In
to tBuO•
(BDE of tBuO-H: 106.3 kcal/mol).14 Although the BDE
addition to α-methyl, α-hexyl, α-hydroxyethyl and α-
benzyloxyethyl substituted styrenes participated in this
of H-CH2OH (96 kcal/mol) is higher than that of the benzylic
CH, we were pleased to find that by using MeOH as a co-
solvent, the yield of product 4a was increased significantly
(entries 3-4). Using Cu(BF4)2·6H2O (0,3 equiv) as catalyst, the
effect of ligand on the reaction outcome was systematically
examined and bathophenanthroline (0.6 equiv) was found to
be optimum to afford 4a in 53% NMR yield (entries 4-6, see ESI
for complete list of ligand screening). Further varying the
amount of MeOH allowed us to conclude that a mixed solvent
(MeCN/MeOH v/v = 7/3) is optimum to furnish 4a in 56%
isolated yield (entry 7). Intrigued by the role played by
alcoholic solvent, benzyl alcohol, diphenylcarbinol and 1-
phenylethanol (1.2 equiv) were added into the reaction
mixture (entries 9-11). Gratefully, we were able to isolate 4a in
62% yield when BnOH was introduced as an additive (entry 9).
Addition of other substituted benzyl alcohols (p-
NO2C6H4CH2OH, P-ClC6H4 CH2OH, p-MeOC6H4CH2OH), p-cresol
and pinacol afforded 4a in reduced yields (for results, see ESI).
Finally, yield of 4a was slightly increased when the reaction
was performed at 100 °C (entry 12). Although methanol was
reaction to afford the corresponding 1,3-dihydrobenzofurans
4b, 4c and 4d in good yields. α-Aryl substituted styrenes with
electron-donating (Me, MeO) or electron-withdrawing (F, Cl,
Br, NO2) substituents on both aryl rings, regardless of their
positions, participated well in this reaction (4e-4m). While we
expected that substrates with electron-donating substituents
would be transformed to 1,3-dihydroisobenzofurans (example
4f, 4g) in high yields, we were surprised to observe that
substrates with electron-withdrawing groups (NO2, Cl, Br) were
also converted to compounds 4j, 4l, 4m in very good yields.
The presence of halides and nitro group in this bicycles
provided obvious handles for post-functionalizations (vide
supra). Propionitrile, butyronitrile, pentanenitrile and 3-
methoxypropionitrile also took part in the reaction leading to
the corresponding dihydroisobenzofurans 4n-4q as a mixture
of two diastereomers (dr 1/1), although the reactions were
relatively slow and required higher temperature to complete
(110 °C) in these cases. Alkene 3r with a pendant tertiary
benzylic alcohol function afforded 4r in low yield (30%), most
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probably due to the instability of the tertiary alcohol under the methodology, synthesis of
COMMUNICATION
1
featuring the key cyanoalkylative
reaction conditions.15 The secondary benzylic alcohol afforded cycloetherification was undertaken (Scheme 4). Regioselective
a complex reaction mixture under standard conditions.
Heck reaction of triflate 9 with 4-fluorostyrene (10) according
to Zhou17 followed by reduction of the methyl ester furnished
3l. Copper-catalysed reaction of 3l with acetonitrile under our
optimised conditions afforded dihydroisobenzofuran 4l in 71%
yield. The reaction was performed in a gram scale with similar
synthetic efficiency.18 Reduction of the cyano group to primary
amine 11 followed by reductive N,N-dimethylation provided
12. Finally, Rosenmund-von Braun reaction of 12 (CuCN, DMF,
150°C) afforded citalopram (1) in 74% yield.
Scheme 5 Synthetic transformations of dihydroisobenzofuran
4k.
Taking advantage of the aryl bromide function in 4l, a diverse
set of substituents can be introduced to the
Scheme
3
Scope of copper-catalysed cyanoalkylative dihydroisobenzofuran framework. For example, Suzuki-
cycloetherification of alkenes. aReaction conditions: Miyaura cross-coupling of 4l with p-tolylboronic acid afforded
Cu(BF4)2·6H2O (0.3 equiv), bathophenanthroline (0.6 equiv), 13 (eq 1, Scheme 5), while Sonogashira reaction of 4l with
K3PO4 (0.25 equiv), BnOH (1.2 equiv), (tBuO)2 (4.0 equiv), 100 ethynylbenzene provided 14 (eq 2). Applying the sequence of
°C, 18 h. b 110 °C, 22 h, dr = 1/1.
reduction of nitrile and reductive N,N-dimethylation of the
resulting amine to the 1,3-dihydroisobenzofurans shown in
Scheme 3 and 5 would afford a range of citalopram analogues
with structural modification on side chain, aromatic rings and
benzylic positions.
In summary, we developed
a novel synthesis of 1,3-
dihydroisobenzofurans by a copper-catalysed cyanoalkylative
cycloetherification of substituted (2-vinylphenyl)methanol
using alkylnitriles as alkyl donors. One C(sp3)-C(sp3) and one
C(sp3)-O bonds were formed in this domino process. The
synthetic potential of this novel transformation was illustrated
by the development of a concise synthesis of citalopram, a
marketed anti-depressant drug.
Acknowledgements
The Financial supports from EPFL (Switzerland), the Swiss
National Science Foundation (SNSF) and the Swiss National
Centres of Competence in Research (NCCR-Chemical biology)
are gratefully acknowledged.
Scheme 4 Synthesis of citalopram (1).
Citalopram (1), marketed in over 65 countries under different
brand names, was one of the top-selling antidepressant
drugs.16 To illustrate the synthetic potential of our
Notes and references
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