Stereoselective Synthesis of Alkylidene Phthalides

Article abstract of DOI:10.1021/acs.orglett.6b01203

The N,O-diacylhydroxylamine derivative 4 has been prepared and its reactivity with nucleophiles investigated. On reaction with lithium enolates of cyclic or acyclic ketones, 4 is converted stereoselectively to the corresponding alkylidene phthalide. The s

Full text of DOI:10.1021/acs.orglett.6b01203

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of Alkylidene Phthalides
Andrei Dragan, D. Heulyn Jones, Alan R. Kennedy, and Nicholas C. O. Tomkinson*
WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral Street,
Glasgow G1 1XL, U.K.
S
* Supporting Information
ABSTRACT: The N,O-diacylhydroxylamine derivative 4 has been prepared and its reactivity with nucleophiles investigated. On
reaction with lithium enolates of cyclic or acyclic ketones, 4 is converted stereoselectively to the corresponding alkylidene
phthalide. The stereochemical outcome of the transformation can be modified by changing the polarity of the reaction medium
and the products isomerized under acidic conditions.
Scheme 1. Phthaloyl Peroxide as an Electrophilic Oxidant
atural products frequently provide the inspiration for
1
Npioneering work in drug discovery and synthesis.
Uncovering new routes to prepare privileged fragments of
biological importance2 is therefore of great interest and delivers a
motivation for methodology development.3 Alkylidene phtha-
lides and their derivatives have a rich chemistry and have received
significant attention from the synthetic community. This is due
to the diverse biological activities associated with the
isobenzofuranone heterocyclic motif, which is present in natural
products such as senkyunolide E and vermistatin. In addition,
this framework has been exploited as a versatile building block in
organic synthesis (Figure 1).4
dihydroxylation.5g A potential reason for the chemistry of 1
lying dormant for such a long period may well reside in the
documented explosive nature of phthaloyl peroxide and the fact
that this compound is reported to be very sensitive to shock.5a
Since phthaloyl peroxides have been shown to be versatile
compounds that have proved challenging to handle, we were
intrigued to discover if their hydroxylamine counterparts would
provide more stable reagents that were reactive with
nucleophiles. In this paper, we describe the preparation of the
N,O-diacylhydroxylamine derivative 48 and show how reaction
with enolate nucleophiles provides a simple stereoselective
method for the preparation of alkylidene phthalides.
Figure 1. Isobenzofuranone skeleton.
Cyclic diacyl peroxides act as electrophilic oxidizing agents of
electron-rich π-systems.5,6 For example, phthaloyl peroxide 1 and
its derivatives are effective in the syn-dihydroxylation of alkenes
and the conversion of aromatic compounds to the corresponding
phenols (Scheme 1). Phthaloyl peroxide 1 was first described as a
monomer by Russell in 1955,7 and its use in alkene oxidation was
thoroughly investigated by Greene in a series of elegant
studies.5a−e Despite this insightful work, exploitation of phthaloyl
peroxide as an oxidant was not revisited until 2011 when Siegel
and co-workers re-examined the use of 1 in alkene syn-
Received: April 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01203
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Letter
Our investigations began by treatment of commercial
phthaloyl chloride with N-Boc-hydroxylamine in the presence
of triethylamine to give 4 in 56% isolated yield after purification
by trituration (see the Supporting Information for full details). In
contrast to phthaloyl peroxide 1, the hydroxylamine derivative 4
proved to be a bench-stable solid that was easy to manipulate and
handle.
Having prepared 4, we examined its reactivity with a series of
nitrogen, sulfur, oxygen, and carbon nucleophiles. While 4
proved less reactive than malonoyl6 and phthaloyl peroxides,5 it
provided an intriguing reactivity with lithium enolates. Treat-
ment of propiophenone 5 with 1 equiv of lithium hexamethyldi-
silazide at −78 °C for 30 min followed by addition of a THF
solution of 4 and allowing the mixture to react at −78 °C for a
further 2 h led to the alkylidene phthalide 6 as a 4:1 mixture of
diastereoisomers, the major isomer of which was isolated in 38%
yield after chromatography (Scheme 2). This represented a novel
reaction outcome, delivering the product in just 52% conversion
(Table 1, entry 3). Allowing the reaction mixture to warm to
room temperature after addition of the electrophile (Table 1,
entry 4) or extending the reaction time to 5 h (Table 1, entry 5)
had no substantial effect on the reaction outcome. Addition of 2
equiv of both base and 4 resulted in complete consumption of
starting material, an excellent yield, and high levels of
stereoselectivity (Table 1, entry 6; 83% yield, 6:1 E/Z).
A potential mechanistic course for the transformation is
outlined in Figure 2. The lithio-enolate 9 derived from
Scheme 2. Preparation of Alkylidene Phthalide
Figure 2. Potential mechanistic course for the formation of 6.
propiophenone could add to either carbonyl group of 4.
Reaction with the O-substituted carbonyl group would lead to
10, which could then deprotonate under the basic reaction
conditions and ring close to give the observed product 6. In
support of this proposal, reaction of 5 under the optimized
conditions gave N-Boc-hydroxylamine 11 in 70% isolated yield.
The alternative bis-electrophiles phthalic anhydride and
phthaloyl chloride were examined under the optimized reaction
conditions (1.0 equiv 7, 2.0 equiv LiHMDS, 2 equiv electrophile,
−78 °C, 1 h). In each case, no clear indication for the presence of
and selective method for the preparation of this class of
heterocycle which has been prepared previously by methods
including the photolysis of epoxybenzoquinones,9 Wittig
reaction of stabilized phosphonium ylides,10 carbonylative
palladium-catalyzed coupling of Baylis−Hillman adducts,11 and
the photolysis of tricarbonyl species.12,13 Intrigued by the dense
functionality introduced through this simple procedure together
with the biological significance of the core structure prepared, we
elected to investigate this reaction further. Selected data from the
optimization of this process are collected in Table 1.
1
the alkylidene phthalide product 8 was observed by H NMR
spectroscopy of the crude reaction mixture, suggesting the
reactivity observed was exclusive to the phthaloyl hydroxylamine
derivative 4.
Having developed a set of optimized conditions for the
reaction of 4′-methylpropiophenone, we went on to examine a
series of alternative substrates within the transformation (Figure
3). Reaction of 4′-, 3′-, and 2′-methylpropiophenone led
selectively to the E-products 8, 12, and 13 in good to excellent
yield (Figure 3, entries 1−3). Along with propiophenone (Figure
3, entry 4; 76%), it also proved possible to successfully introduce
both activating (Figure 3, entry 5; 56%) and deactivating (Figure
3, entry 6; 41%) groups onto the aromatic ring of the
nucleophile. Alternative substitution at the α-position of the
ketone was also tolerated. Benzoin led to the E-product 16 with
the same sense of selectivity as the propiophenone derivatives
(Figure 3, entry 7; 39%). While butyrophenone gave the E-
product 17 in an acceptable yield (Figure 3, entry 8; 40%),
branching of the ketone at the β-position was less well tolerated
(Figure 3, entry 9; 19%). Using 3-pentanone, it was found that
the stereochemical outcome of the transformation could be
manipulated simply by changing the polarity of the reaction
medium (Figure 3, entries 10−12). Using THF as the solvent
delivered the Z-isomer 19 selectively (E:Z 1:6; isolated yield of
the Z-isomer 44%), whereas using HMPA as a cosolvent
delivered both products in a 1:1 ratio, the Z-isomer being isolated
in 43% yield (Figure 3, entry 11). Use of toluene as the reaction
medium again provided the Z-isomer selectively, but the
transformation was significantly less efficient than under the
optimized conditions (Figure 3, entry 12; 28% yield). Cyclic
ketones also proved to be effective substrates within the
transformation, with cyclohexanone delivering the E-product in
Table 1. Reaction Optimization
a
a
entry LiHMDS (equiv) 4 (equiv) time (h)
conv (%)
E/Z
1
2
3
4
5
6
1.0
2.0
3.0
2.0
2.0
2.0
1.0
1.0
1.0
1.0
1.0
2.0
1
1
1
1
5
1
30 (23)
79 (62)
52
5:1
6:1
5:1
b
45
4.5:1
6:1
54
100 (83)
6:1
a
1
Determined by H NMR spectroscopy on crude reaction mixture;
b
isolated yield of major isomer shown in parentheses; Reaction
warmed to room temperature before stirring for 1 h.
Reaction of the lithium enolate derived from 4′-methylpro-
piophenone 7 with 4 (1 equiv) led to the product 8 (23% isolated
yield) as a 5:1 mixture of diastereoisomers (Table 1, entry 1).
Increasing the amount of base present to 2 equiv improved the
amount of product significantly (Table 1, entry 2; 62% yield, 6:1
selectivity). Use of 3 equiv of base had a detrimental effect on the
B
DOI: 10.1021/acs.orglett.6b01203
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Stirring the E-isomer 15 at 25 °C in neat sulfuric acid for 2.5 h
led to isomerization of the double bond (E:Z 1:3), from which
the thermodynamically more stable Z-isomer 23 could be
isolated geometrically pure in 65% yield after purification by SiO2
column chromatography (Scheme 3).15 This provides rapid and
Scheme 3. Isomerization of Alkylidene Benzofuranones
convenient access to both isomeric forms of the alkylidene
phthalide products. Resubmission of geometrically pure 23 to
the isomerization conditions (H2SO4, 2.5 h, 25 °C) led to a
thermodynamic 1:3 mixture of 15 and 23, showing this
isomerization is a fully reversible process.
A series of further transformations of the alkylidene phthalides
was explored (Scheme 4). Treatment of 8 with methylamine
Scheme 4. Further Transformations of Alkylidene Phthalides
Figure 3. Substrate scope. (a) Isolated yield of major isomer. (b) Ratio
1
determined by 400 MHz H NMR spectroscopy of crude reaction
mixture in CDCl3. (c) 23% v/v HMPA used as solvent. (d) Toluene
used as solvent.
63% isolated yield (Figure 3, entry 13) and cyclopentanone
delivering the product 21 in an excellent 80% isolated yield
(Figure 3, entry 14). We were unable to unequivocally determine
the selectivity of these transformations by examination of the
crude reaction mixture by 1H NMR spectroscopy; however, the
major isomer could be isolated from both of these trans-
formations in 63% and 80% yield, respectively, after purification
by SiO2 column chromatography. Esters also proved to be
effective substrates, with ethyl propionate delivering the E-
product 22 with excellent 6.5:1 selectivity and 77% isolated yield
for the major E-isomer (Figure 3, entry 15). Interestingly, under
the optimized conditions, acetophenone gave the product of an
aldol reaction in 93% yield.14
Assignment of the relative stereochemistry of adducts
prepared was based upon comparison of analytical data to
reported literature values.10−13 Unequivocal reinforcement of
these assignments came from X-ray crystallographic analysis of 8,
15, 19, 21, and 23 (see the Supporting Information for full
details).
resulted in cleavage of the newly formed CC to give
dimethylphthalamide 24 in 95% yield. Selective reduction of
the ketone group was achieved by reaction of 8 under Luche
conditions16 to give the alcohol 25 in 66% isolated yield without
compromise in the stereochemical integrity of the double bond.
O-Functionalization of the newly formed alcohol could be
achieved through reaction with both acid anhydrides and acid
chlorides in excellent yields (26 77%; 27 91%). Directed
C
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M.; Picon, S.; Rawling, M. J.; Kariuki, B. M.; Campbell, M.; Tomkinson,
N. C. O. J. Am. Chem. Soc. 2010, 132, 14409. (b) Picon, S.; Rawling, M.;
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T. M.; Rowley, J. H.; Sproules, S.; Tomkinson, N. C. O. Org. Lett. 2015,
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epoxidation of 25 with m-CPBA (1.8 equiv) gave 28 stereo-
selectively (81%),17 the relative stereochemistry of which was
confirmed by single-crystal X-ray crystallographic analysis of 29
(see the Supporting Information for full details). Overall, this
series of transformations shows that each of the distinct
functionalities within the core alkylidene phthalide product can
be manipulated selectively, allowing for effective diversification
of the products.
In summary, the reagent 4 can be prepared in a single step by
reaction of phthaloyl chloride with N-Boc-hydroxylamine 11
under basic reaction conditions. Treatment of enolates derived
from cyclic or acyclic ketones as well as esters with 2 equiv of 4
leads to an alkylidene phthalide product stereoselectivity. The
selectivity observed in the transformation can be altered by
changing the polarity of the reaction medium. Isomerization of
the products also proved possible under acidic conditions
providing a convenient method by which to prepare this
important class of heterocycle. The ability to manipulate the
functional groups in the product suggests that this trans-
formation will be applicable to the preparation of 3-substituted
phthalides which are prevalent in many naturally occurring and
biologically significant molecules.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01203.
Analytical data, experimental procedures, and NMR
spectra for all compounds reported (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: nicholas.tomkinson@strath.ac.uk.
Notes
(8) Compound 4 has been synthesized previously and investigated as a
pro-inhibitor of serine β-lactamases. (a) Zinner, G.; Ruthe, V.; Hitze, M.;
Vollrath, R. Synthesis 1971, 148. (b) Tilvawala, R.; Pratt, R. F.
Biochemistry 2013, 52, 7060.
The authors declare no competing financial interest.
(9) Kato, H.; Tezuka, H.; Yamaguchi, K.; Nowada, K.; Nakamura, Y. J.
Chem. Soc., Perkin Trans. 1 1978, 1, 1029.
ACKNOWLEDGMENTS
■
We thank the University of Strathclyde for financial support and
the EPSRC Mass Spectrometry Service, Swansea, for high-
resolution spectra.
(10) Abell, A. D.; Clark, B. M.; Robinson, W. T. Aust. J. Chem. 1988, 41,
1243.
(11) Coelho, F.; Veronese, D.; Pavam, C. H.; de Paula, V. I.; Buffon, R.
Tetrahedron 2006, 62, 4563.
(12) Mor, S.; Dhawan, S. N.; Kapoor, M.; Kumar, D. Tetrahedron 2007,
63, 594.
(13) For alternative methods for the preparation of this class of
heterocycle, see ref 4.
(14) Allan, J. F.; Henderson, K. W.; Kennedy, A. R. Chem. Commun.
1999, 1325.
(15) Mukhopadhyay, R.; Kundu, N. G. Tetrahedron 2001, 57, 9475.
(16) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(17) Davies, S. G.; Fletcher, A. M.; Thomson, J. E. Org. Biomol. Chem.
2014, 12, 4544.
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Org. Lett. XXXX, XXX, XXX−XXX