Alkene Dioxygenation with Malonoyl Peroxides: Synthesis of γ-Lactones, Isobenzofuranones, and Tetrahydrofurans

Article abstract of DOI:10.1021/acs.orglett.6b01253

Treatment of homoallylic alcohols or carboxylic acids with malonoyl peroxide 1 provides a stereoselective method for the preparation of tetrahydrofurans, γ-lactones, and isobenzofuranones in 44-82% yield and up to 27:1 trans selectivity. Application of this simple and effective heterocyclization in the synthesis of the antidepressant citalopram is also described.

Full text of DOI:10.1021/acs.orglett.6b01253

Letter
pubs.acs.org/OrgLett
Alkene Dioxygenation with Malonoyl Peroxides: Synthesis of
γ‑Lactones, Isobenzofuranones, and Tetrahydrofurans
Carla Alamillo-Ferrer,† Marianna Karabourniotis-Sotti,† Alan R. Kennedy,† Matthew Campbell,‡
and Nicholas C. O. Tomkinson*,†
†WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral
Street, Glasgow G1 1XL, United Kingdom
‡GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
S
* Supporting Information
ABSTRACT: Treatment of homoallylic alcohols or carboxylic
acids with malonoyl peroxide 1 provides a stereoselective method
for the preparation of tetrahydrofurans, γ-lactones, and isobenzofur-
anones in 44−82% yield and up to 27:1 trans selectivity. Application
of this simple and effective heterocyclization in the synthesis of the
antidepressant citalopram is also described.
Scheme 1. Alkene Dioxygenation with Malonoyl Peroxides
aturated oxygen heterocycles are ubiquitous in nature and
Shave been shown to have profound and diverse biological
activities.1,2 In addition, they have provided molecular
frameworks for the development of multibillion dollar drug
molecules.3 It is therefore not surprising that methods for the
preparation of this class of compound have inspired advances
in synthetic chemistry.
The intramolecular cyclization of unsaturated acids and
unsaturated alcohols provides a powerful and reliable family of
methods for the construction of oxygen heterocycles.
Cyclization can be triggered by transformation of the alkene
into a strongly electrophilic intermediate which is trapped
intramolecularly in a stereospecific manner by an oxygen
nucleophile. The use of iodonium4 and seleniranium5 ions as
the electrophile is well established and has been used
extensively for the formation of cyclic ethers and lactones.
Activation of the alkene with oxygen electrophiles is far less
common. Protonated epoxides can be ring-opened stereo-
selectively with oxygen nucleophiles to furnish cyclic ethers.6
This chemistry has been extended such that under strongly
acidic conditions a one-pot, two-step epoxidation ring-opening
sequence is possible using ammonium persulfate and
trifluoromethanesulfonic acid in acetic acid at 70 °C.7
Elaboration of the products from the Sharpless asymmetric
dihydroxylation is also possible to prepare both ethers and
lactones.8
Malonoyl peroxide 1 is an effective reagent for the metal-
free syn- and anti-dioxygenation of alkenes.9 Reaction of 1
with alkene 2 leads to the dioxonium species 3. In the
presence of water, 3 reacts to deliver the syn-diol 4 after basic
hydrolysis,10,11 whereas conducting the reaction in the
presence of acetic acid leads to the corresponding anti-diol
5 (Scheme 1).12 We were intrigued to discover if an
intermediate such as 7 could be trapped intramolecularly
through introduction of a nucleophile, pendant to the alkene
architecture, to deliver a series of important heterocyclic
structures. Within this paper, we show that oxygen
nucleophiles (6: X = Y = H and X = Y = O) incorporated
within the alkene substrate provide a simple and effective
method to deliver γ-lactones, isobenzofuranones, and
saturated furans stereoselectively through an oxidative
cyclization.
Studies began by investigating the reaction of alkene 9,
which contained a potential carboxylic acid nucleophile, with
malonoyl peroxide 1. A selection of data relevant to the
development of the cyclization is collected in Table 1.
Reaction of 9 with peroxide 1 (1.5 equiv) at 40 °C in dry
dichloromethane gave the γ-lactone 10 with the product from
trans-addition across the alkene predominating (entry 1; 88%
conversion, cis/trans 1:6). Previous investigations with 1 had
Received: May 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01253
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Organic Letters
Letter
a
a
Table 1. Optimization of γ-Lactone Synthesis
Scheme 2. Substrate Scope for γ-Lactone Synthesis
b
b
entry
solvent
additive (equiv) temp (°C) conv (%) cis/trans
1
2
3
4
5
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HFIP
40
40
25
40
25
50
50
25
25
25
25
88
98
1:6
HFIP (1)
HFIP (1)
HFIP (2)
HFIP (2)
HFIP (1)
1:3
57
1:3
97
1:3
61
1:3
100
100
100
92
1:3
c
7
1:13
1:19
1:19
8
HFIP
d
9
HFIP
10
11
EtOH
iPrOH
a
All reactions performed in duplicate with trans-styrylacetic acid (1
b
1
mmol) at 0.5 M concentration for 24 h. Determined by H NMR
spectroscopy on crude reaction mixture. Solvent dried over 3 Å
c
molecular sieves for 24 h prior to use. See the Supporting Information
d
for full details. Reaction conducted for 15 h.
shown that fluorinated alcohols could accelerate reactions with
alkenes.13,14 This proved to be the case with hexafluoro-2-
propanol (HFIP, 1−2 equiv), the reaction proceeding
effectively in the presence of this additive (entries 2−6)
albeit with lower levels of selectivity (cis/trans 1:3).
Conducting the transformation using dry HFIP as the
reaction solvent improved the stereoselectivity of the reaction
significantly, with the product from trans-addition to the
alkene being preferred (entry 7; 100% conversion, cis/trans
1:13). Lowering the reaction temperature to 25 °C improved
this selectivity further (entry 8; 100% conversion, cis/trans
1:19). Conveniently, it was also established that the HFIP did
not require drying prior to use in order to maintain these high
levels of selectivity (entries 8 and 9). Use of the non-
fluorinated alcohols ethanol (entry 10) and 2-propanol (entry
11) resulted in complex mixtures of products, potentially due
to reaction of alcohol and peroxide, suggesting that use of the
less nucleophilic fluorinated alcohols was important within
this transformation.15 Based upon this screening, we adopted
a standard set of conditions for the reaction of alkenes
containing a pendant carboxylic acid functionality of 1.5 equiv
of peroxide at room temperature for 24 h in HFIP as the
reaction solvent (entry 8).
a
Yields quoted are isolated yields of major isomer. All reactions run in
1
duplicate. Stereoselectivities were determined by H NMR spectros-
copy on the crude reaction mixture. Reaction conducted at 50 °C for
24 h. Reaction conducted at 50 °C for 72 h. (Z)-4-Phenylbut-3-
enoic acid used as substrate.
b
c
d
3-enoic acid leading to 20 (entry 9; 58%, cis/trans 5:1).
Confirmation of the relative stereochemistry of the γ-lactone
products came through single-crystal X-ray analysis of
compound 16 where the two newly formed C−O bonds
bore a trans relationship (Figure 1).
Having optimized the process we went on to explore some
of the substrate scope of this simple oxidative cyclization
(Scheme 2). The product from the optimization procedure 10
was prepared in an excellent cis/trans selectivity of 1:19 and
isolated as a single isomer in 69% yield. Substitution of
electron-donating substituents at the 2-, 3-, and 4-positions of
the aromatic ring was tolerated (entries 2−4; 51−70%), where
2- and 4-substitution led to a decrease in the selectivities
observed (cis/trans 1:10). Electron-withdrawing substituents
led to lower reactivity of the alkene. However, simply
warming the reaction to 50 °C provided the products with
acceptable yields and selectivities (entries 5−8). Altering the
stereochemistry of the starting alkene provided access to the
diastereomeric product, with the reaction of (Z)-4-phenylbut-
Figure 1. Single-crystal X-ray structures of 16, 23, and 29.
Given the success of the formally 5-endo-trig oxidative
cyclization triggered by malonoyl peroxide 1, we briefly
examined a formal 5-exo-trig cyclization (Scheme 3).16 Under
the standard reaction conditions developed (HFIP, 50 °C, 24
h) reaction of 2-vinylbenzoic acids 21 gave the corresponding
isobenzofuranones 23−25 in 68−76% isolated yield after
purification by column chromatography, with the structure of
23 confirmed through single-crystal X-ray crystallography
(Figure 1). Although the scope of this transformation was less
well explored, the numerous methods for the preparation of
2-vinylbenzoic acids suggest that this should be an exceedingly
B
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Letter
and 1 under the optimized reaction conditions gave 28 in an
excellent 80% isolated yield (Scheme 4, entry 1). Introduction
of substitution adjacent to the alcohol nucleophile enhanced
reactivity through the Thorpe−Ingold19 effect, providing the
product 29 in 82% isolated yield (entry 2; cis/trans 1:16), the
structure of which was confirmed by crystallography (Figure
1). Introduction of substitution on the aromatic ring in the 4-
(entries 3 and 4), 3- (entries 5 and 6), and 2-position (entries
7 and 8) was well tolerated, with the product being isolated in
good yield and with high levels of stereoselectivity. It is
noteworthy that in each case selectivities for the reaction were
higher than those obtained when using carboxylic acid
nucleophiles (Scheme 2) which is thought to be a reflection
on the rates of cyclization of the two classes of substrate.
Pleasingly, use of a Z-alkene substrate led to the product with
the opposite relative stereochemistry in good yield and
selectivity (entry 9; 67%, cis/trans 5:1).
Scheme 3. Isobenzofuranone Synthesis
useful process for the preparation of this important class of
biologically relevant scaffold.17
Mechanistically, we believe that the reaction is proceeding
as outlined in Figure 2. Nucleophilic attack of the alkene on
Having established that carboxylic acids were suitable
nucleophiles for the preparation of γ-lactones and isobenzo-
furanones, we were intrigued to discover if the method could
also be applied to the synthesis of 3-oxygenated tetrahy-
drofuran rings using homoallylic alcohol substrates. Optimized
conditions for this transformation involved reaction of an
alkene 26 with 1.5 equiv of peroxide 1 at room temperature
in HFIP (Scheme 4).18 Reaction of (E)-4-phenylbut-3-en-1-ol
a
Scheme 4. Cyclic Ether Formation
Figure 2. Proposed mechanistic pathway for the oxidative cyclization.
the weak peroxide bond leads to the zwitterion 38, which
cyclizes to give the dioxonium species 39 as defined for the
dihydroxylation pathway.11 Intramolecular cyclization of the
carboxylic acid forms the γ-lactone ring resulting in the trans
relationship of the two newly formed C−O bonds in the
product 41. This mechanistic pathway is consistent with
previous investigations into the reactivity of malonoyl
peroxide 1 and also accounts for the important observation
that the relative stereochemistry of the product can be altered
by changing the geometry of the starting alkene.
Application of this simple and effective heterocyclization
procedure in the synthesis of the antidepressant citalopram 47
is outlined in Scheme 5.20 The substrate for the key
cyclization 43 was prepared according to the excellent
method of France,21 which proved simple, effective, and
scalable allowing access to gram quantities of material.
Oxidative cyclization of 43 under our standard conditions
followed by hydrolysis of the resulting ester with methylamine
provided 44 (73%, two steps). Functionalization of 44 proved
challenging due to the hindered nature of the primary alcohol.
However, oxidation followed by a Grignard addition and a
hydrolysis/elimination sequence provided the α,β-unsaturated
aldehyde 46 (47%). Organocatalytic conjugate reduction using
a Hantzsch ester followed by reductive amination provided 47
(43%, two steps), which was identical to an authentic sample.
a
Yields quoted are isolated yields. All reactions run in duplicate.
Stereoselectivities were determined by 1H NMR spectroscopy on
crude reaction mixture. Reaction conducted at 50 °C for 20 h. (Z)-4-
Phenylbut-3-en-1-ol used as substrate.
b
c
C
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Scheme 5. Synthesis of Citalopram
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applications of malonoyl peroxides in synthesis.22 The
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01253.
(18) See the Supporting Information for details of this
optimization.
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Drugs Future 1979, 4, 407.
Analytical data, experimental procedures, and NMR
spectra for all compounds reported (PDF)
X-ray crystallogrphic data for 16, 23, and 29 (CIF)
(21) Hewitt, J. F. M.; Williams, L.; Aggarwal, P.; Smith, C. D.;
France, D. J. Chem. Sci. 2013, 4, 3538.
AUTHOR INFORMATION
Corresponding Author
■
(22) For recent examples of the use of malonoyl peroxides see:
(a) Terent’ev, A. O.; Vil, V. A.; Gorlov, E. S.; Nikishin, G. I.;
Pivnitsky, K. K.; Adam, W. J. Org. Chem. 2016, 81, 810. (b) Dragan,
A.; Kubczyk, T. M.; Rowley, J. H.; Sproules, S.; Tomkinson, N. C. O.
Org. Lett. 2015, 17, 2618. (c) Terent’ev, A. O.; Vil, V. A.; Mulina, O.
M.; Pivnitsky, K. K.; Nikishin, G. I. Mendeleev Commun. 2014, 24,
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*E-mail: nicholas.tomkinson@strath.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank EPSRC, GlaxoSmithKline, and CNPq for financial
support and the EPSRC Mass Spectrometry Service, Swansea,
for high-resolution spectra.
D
DOI: 10.1021/acs.orglett.6b01253
Org. Lett. XXXX, XXX, XXX−XXX