Anhydrides as α,β-unsaturated acyl ammonium precursors: Isothiourea-promoted catalytic asymmetric annulation processes

Article abstract of DOI:10.1039/c3sc50199j

The asymmetric annulation of a range of α,β-unsaturated acyl ammonium intermediates, formed from isothiourea HBTM 2.1 and anhydrides with either 1,3-dicarbonyls, β-ketoesters or azaaryl ketones gives either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields (up to 93%) and high enantioselectivity (up to 97% ee).

Full text of DOI:10.1039/c3sc50199j

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Anhydrides as a,b-unsaturated acyl ammonium
precursors: isothiourea-promoted catalytic
Cite this: DOI: 10.1039/c3sc50199j
asymmetric annulation processes†
Emily R. T. Robinson, Charlene Fallan, Carmen Simal, Alexandra M. Z. Slawin
*
and Andrew D. Smith
Received 22nd January 2013
Accepted 1st March 2013
The asymmetric annulation of a range of a,b-unsaturated acyl ammonium intermediates, formed from
isothiourea HBTM 2.1 and anhydrides with either 1,3-dicarbonyls, b-ketoesters or azaaryl ketones gives
either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields
(up to 93%) and high enantioselectivity (up to 97% ee).
DOI: 10.1039/c3sc50199j
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oxidant,14 directly from a,b-unsaturated acyl uorides or enol
Introduction and background
esters,15 or alternatively from a-bromoenones.16 The oxidative
approach from enals has been applied to a range of asymmetric
C–C bond-forming reactions including aza-Claisen,17 Coates-
Claisen,18 cyclopropanation19 and Michael addition processes.20
Given the recognised difficulties in accessing a wide variety
of ynals and enals for such NHC-catalysed approaches and
limitations associated with the scope and generality of such
processes,21 we envisaged a direct strategy to generate an a,b-
unsaturated acyl ammonium species from readily available a,b-
unsaturated carboxylic acids or their anhydrides. Described
herein are our results concerning isothiourea-promoted asym-
metric addition of 1,3-diketones, b-ketoesters and azaaryl
ketones to a,b-unsaturated acyl ammonium intermediates for
the preparation of a range of functionalised esters, stereo-
dened dihydropyranones and dihydropyridones in highly
enantioenriched form (up to 97% ee).
Asymmetric organocatalysis has developed tremendously as a
synthetic strategy within the last decade and a range of meth-
odologies and catalysts have emerged that provide functional-
ised products with high levels of stereocontrol.1 Ideally a given
organocatalyst architecture should be able to participate in a
range of reaction processes and display diverse modes of reac-
tivity, while showing good catalytic efficiency and delivering
products with high levels of enantioselectivity. Within this area,
isothioureas,2 initially employed by Birman and Okamoto as
efficient O-acyl transfer reagents,3 have been utilised in a range
of kinetic resolution,4 asymmetric desymmetrisation,5 C-acyla-
tion and C-carboxylation processes,6 as well as O-silylation
reactions.7 Recent advances have showcased the utility of iso-
thioureas to generate ammonium enolates8 from carboxylic
acids and their applications in aldol-9 and Michael-lactonisa-
tion processes (Fig. 1A).10
Building upon these precedents, this work demonstrates the
previously unexplored ability of isothioureas to generate asym-
metry by promoting the addition of a range of nucleophiles to a
stereodened a,b-unsaturated acyl ammonium species
(Fig. 1B). While Peters and Ye have invoked a,b-unsaturated acyl
ammoniums as precursors to dienolate formation,11 to the best
of our knowledge there are currently no processes that form C–C
bonds directly via such intermediates. Related work in the
literature has shown that NHCs12 can catalytically generate a,b-
unsaturated acyl azolium intermediates through an internal
redox process from alkynals,13 from enals using a stoichiometric
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews,
KY16 9ST, UK. E-mail: ads10@st-andrews.ac.uk
† Electronic supplementary information (ESI) available: All spectroscopic data
and procedures for novel compounds. CCDC 916302. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3sc50199j
Fig. 1 Proposed access to enantioenriched annulation products via an unex-
plored a,b-unsaturated acyl ammonium species.
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of the base showed that EtN(iPr)2, DBU or PS-BEMP (polymer-
Proof of concept and reaction optimisation:
annulations using diketone nucleophiles
supported
2-t-butylimino-2-diethylamino-1,3-dimethylperhy-
dro-1,3,2-diazaphosphorine) could be used in this process,
although DBU gave 6 with reduced enantioselectivity (entry 5).25
The use of PS-BEMP proved optimal, allowing the catalyst
loading of HBTM 2.1 5 to be reduced to 1 mol% without
compromising product enantioselectivity, albeit with reduced
product yields (entry 11). Performing the reaction in THF led to
a reduced yield (entries 4 and 9). While catalytic asymmetric
Michael additions to nitro-olens and enones are well docu-
mented,26 this strategy formally allows the asymmetric Michael
addition of diketones to a,b-unsaturated carboxylic acid deriv-
atives for which there is only limited precedent.27
Initial investigations focused upon generation of an a,b-unsat-
urated acyl ammonium directly from cinnamic acid 1 (Scheme
1A), via in situ activation using 4-methoxybenzoic anhydride
(PMBA) and isothiourea HBTM 2.1 5 (20 mol%).22 Employing
diketone 4 as the nucleophile provided dihydropyranone 2 in
modest 25% isolated yield, albeit with an encouraging 95% ee.
Cinnamic anhydride 3 was next evaluated as an alternative acyl
ammonium precursor,23 giving dihydropyranone 2 in improved
49% yield and 95% ee (Scheme 1B). These initial ndings served
as a benchmark for further optimisation with the aim to lower
catalyst loadings and improve isolated yields.24
Reaction scope and generality
The generality of this process was next probed, initially through
variation of the a,b-unsaturated anhydride component
(Table 2). Using HBTM 2.1 5 (5 mol%) and a number of
symmetrical diketones, this protocol tolerates a range of 2-, 3-,
and 4-substituted b-aryl groups containing either electron-
withdrawing or electron-donating groups, as well as heteroaryl
Table 2 Substrate scope
Scheme 1 Initial proof of concept studies. aIsolated yield of 2; bdetermined by
HPLC analysis.
Further studies showed that in situ ring opening of dihy-
dropyranone 2 with MeOH led to consistently higher isolated
yields of the functionalised ester product 6 (Table 1). Variation
Table 1 Optimisation studies
Entry
HBTM 2.1 (mol%)
Base
Yielda
eeb (%)
1
2
20
10
5
EtN(iPr)2
EtN(iPr)2
EtN(iPr)2
EtN(iPr)2
DBU
PS-BEMP
PS-BEMP
PS-BEMP
PS-BEMP
PS-BEMP
PS-BEMP
77
70
62c
45
86
85
82
83
50
69
62
96
95
—
99
73
95
95
96
83
93
93
3
4d
5
5
20
20
10
5
5
2.5
1
6
7
8
9d
10
11
a
b
c
Isolated yield of 6. Determined by HPLC analysis. Conversion
determined by 1H NMR spectroscopic analysis of the unpuried
reaction mixture. d Reaction conducted in THF.
a
b
c
Isolated yield of 6–21. Determined by HPLC analysis. 10 mol%
catalyst. d Reaction carried out at À78 ꢀC. e Reaction conducted in THF.
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substituents, giving the corresponding functionalised esters in
good yield (up to 86%) and high enantioselectivity (90–97% ee,
6–14). Notable reactivity trends within this series indicate that
anhydrides containing electron decient b-aryl units give
higher product conversion and isolated yields than their elec-
tron rich b-aryl counterparts (product 9). b-Alkyl substituents
within the anhydride are also tolerated (a signicant advantage
over the NHC-catalysed systems that typically exhibit low
enantioselectivity in similar transformations),20b although low
temperatures are necessary to achieve optimal enantiose-
lectivity, resulting in only moderate reaction efficiency and
reduced product yields (15 and 16). Variation of the diketone
functionality was next investigated (Table 2, 17–21). A range of
substituted aryl and heteroaryl diketones participate in this
reaction process, giving functionalised esters 17–21 in
moderate to good yield and high enantioselectivity.28
Scheme 3 Regioselectivity of annulation using unsymmetrical nucleophiles.
aIsolated yield; bdetermined by HPLC analysis.
Table 3 Use of ethyl benzoylacetate as nucleophile
Further investigations probed the stereospecicity of this
asymmetric annulation protocol (Scheme 2). While (E,E)-cin-
namic anhydride 3 gave functionalised ester (S)-6 in 83% yield
and 96% ee (Scheme 2A), (Z,Z)-cinnamic anhydride 22 gave (R)-6
in reduced 41% yield and only 30% ee (Scheme 2B),29 indicating
the necessity of the (E)-conguration for maximum
enantiocontrol.
a
Scheme 2 Stereospecificity of asymmetric annulation process. aIsolated yield of
6; bdetermined by HPLC analysis.
Isolated yield. b Determined by HPLC analysis.
Bode to be ineffective in NHC-catalysis using a,b-unsaturated acyl
azoliums.21 However, in this organocatalysed process, diketone
33 demonstrated favourable reactivity and provided 34 in high
yield and good enantioselectivity (Scheme 4).
Subsequent studies probed the ability of non-symmetric
dicarbonyls to participate in this protocol. Using cinnamic
anhydride 3, 1-phenyl-1,3-dibutanone 23 generated a 70 : 30
mixture of regioisomeric dihydropyranones 24 and 25 in 88%
overall yield and 70% and 61% ee, respectively (Scheme 3A),30
while ethyl benzoylacetate 26 gave dihydropyranone 27 in 60%
isolated yield as a single regioisomer and in 94% ee (Scheme 3B).
The generality of this process was next examined (Table 3),
with b-aryl and b-heteroaryl substituents within the anhydride
tolerated, in all cases giving the corresponding dihydropyranones
27–32 in acceptable yield (46–70%) and high ee (89–96%).31
Having probed the viability of this process, our attention
turned to 1,3-dicarbonyl systems that are not tolerated in related
NHC-catalysed processes. For example, aliphatic cyclic Michael
donors such as 1,3-cyclohexanedione 33 have been reported by
Scheme 4 1,3-Cyclohexanedione as a Michael donor. aIsolated yield; bde-
termined by HPLC analysis.
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Beyond 1,3-dicarbonyls: azaaryl ketones as
nucleophiles
Encouraged by the novel and complementary reactivity of the
isothiourea catalysis, the scope of this asymmetric annulation
was extended beyond the use of 1,3-dicarbonyl nucleophiles.
Gratifyingly, azaaryl ketone 35 proved a competent nucleophile
and displayed improved reactivity compared with simple 1,3-
dicarbonyls. This increased reactivity allows bench grade
solvents in an open ask atmosphere to be employed, PS-BEMP
can be replaced with more cost efficient EtN(iPr)2 and a lower
catalyst loading of 1 mol% could be routinely employed. The
use of this nucleophile led to intriguing regioselectivity. Cycli-
sation occurs preferentially through the benzothiazole nitrogen,
generating dihydropyridone 36a as the major product, in
addition to dihydropyranone 36b as the minor product (88 : 12
regioisomeric ratio). These heterocycles were readily separable
by chromatography, with the major product 36a obtained in
excellent yield and high enantioselectivity (97% ee aer a single
recystallisation, Scheme 5).
Scheme 5 Asymmetric addition of azaaryl ketone 35. aIsolated yield; bde-
termined by HPLC analysis; cdetermined from 1H NMR of unpurified reaction
mixture; dfollowing a single recrystallisation.
Next, the substrate scope with this nucleophile was exam-
ined with respect to the anhydride component (Table 4). The
increased reactivity of the azaaryl ketone 35 provided a wide
range of enantioenriched heterocycles in excellent yields and
enantioselectivities. For example, while anhydrides bearing
electron-rich and aliphatic substituents were modestly tolerated
using diketone 4 (Table 2) in terms of both reactivity and
enantioselectivity, the use of azaaryl ketone 35 with the same
anhydrides leads to enantioenriched products in high yields
under our reaction conditions (Table 4).
Table 4 Anhydride scope with azaaryl ketone 35 as a nucleophile in asymmetric
annulation
Mechanistic investigations
In related NHC-catalysed processes involving a,b-unsaturated
acyl azolium intermediates two potential mechanistic pathways
have been proposed; a Michael addition–lactonisation process
with dicarbonyls, ketene acetals and enamines (favoured by
Studer and Mayr)32 or alternatively an initial 1,2-addition fol-
lowed by a [3,3]-Claisen rearrangement with Kojic acid and
enamine derivatives (favoured by Bode)21 to facilitate the
formation of enantioenriched products. Similarly, in our iso-
thiourea-promoted annulation, related catalytic cycles depicted
in Fig. 2(a) and (b), could potentially be responsible for the
generation of the annulation products with high enantiocon-
trol. Both cycles involve an initial N-acylation of HBTM 2.1 5
with an anhydride to generate the corresponding a,b-unsatu-
rated acyl ammonium 41. The s-cis conformation of ammonium
41 is presumably favoured, with the carbonyl oxygen hypoth-
esised to adopt a syn-conformation with respect to the iso-
thiourea S atom due to a stabilising non-bonding O–S
interaction (no to s*C–S).33 In pathway (a), Michael addition31 of
diketone enolate 42 to the Re face of the a,b-unsaturated acyl
ammonium 41 gives intermediate 43,34 subsequent proton
transfer followed by lactonisation generates the desired dihy-
dropyranone 44, which can be either isolated or subsequently
ring opened with MeOH to generate the ester products 45
in high ee. Alternatively, pathway (b) demonstrates that
a
Isolated yield. b Determined by HPLC analysis. c Determined from 1H
NMR of unpuried reaction mixture.
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Fig. 2 Proposed mechanisms of asymmetric dihydropyranone formation via (a) Michael addition–lactonisation or (b) 1,2-addition, [3,3]-rearrangement.
1,2-addition to the a,b-unsaturated acyl ammonium 42 to
Evidence supporting the intermediacy of an acyl ammonium
generate intermediate 46 followed by a [3,3]-rearrangement and species was next obtained. Treatment of trans-cinnamoyl chlo-
subsequent proton transfer/lactonisation process would lead to ride 51 with HBTM 2.1 5 in CH2Cl2 gave the a,b-unsaturated acyl
the same enantioenriched products.
ammonium salt 52 that was isolated in high yield (Scheme 7).35
To gain insight into the favoured mechanistic pathway, X-ray crystallography conrmed the structure of 52 and
potential intermediates were synthesised and subjected to the provided further support for the syn geometry of the carbonyl
reaction conditions. Interestingly, Lupton has previously shown oxygen and the isothiourea S atom, presumably due to the
that 1,2-addition of NHCs to enol esters such as 47 facilitates previously hypothesised stabilising non-bonding O–S interac-
formation of dihydropyranone 49 in the presence of NHC tion (no to s*C–S).33
catalyst 48, albeit with moderate enantioselectivity (Scheme 6A).
In this regard, 50 was prepared from cinnamoyl chloride and
dicarbonyl 4. This potential [3,3]-rearrangement precursor was
examined under the reaction conditions, resulting in no
conversion into dihydropyranone 2 (Scheme 6B)15a–c aer 24 h at
room temperature. While this result does not rule out either
mechanistic pathway, it indicates that 50 is not a likely inter-
mediate in this process. Additionally the absence of any 1,2-
1
addition products such as 50 in the H NMR of all unpuried
reaction mixtures provides further evidence to support this
view.
Scheme 7 Isolation and representation of the X-ray crystal structure of a,b-
Scheme 6 Probing the mechanism.
unsaturated acyl ammonium salt 52.
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Notes and references
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Scheme 8 a,b-Unsaturated acyl ammonium salt 52 as organocatalyst.
2 For
a comprehensive review of the catalytic uses of
The isolated acyl ammonium salt 52 was next examined as a
precatalyst, employing cinammic anhydride 3 and diketone 4
under our optimised reaction conditions (Scheme 8). The
functionalised ester 6 was isolated in similar yield and enan-
tioselectivity (82% yield, 91% ee) compared with the use of
organocatalyst HBTM 2.1 5 (83% yield, 95% ee) in this process,
consistent with acyl ammonium salt 52 being an intermediate
in this asymmetric annulation.
At this juncture we cannot rule out any plausible mechanistic
pathway that involves an a,b-unsaturated acyl ammonium ion,
although we currently favour a catalytic cycle involving a
Michael addition–lactonisation sequence, described in Fig. 2(a).
Further mechanistic investigations and DFT calculations to
provide insight into the pathway in operation are underway and
will be reported in due course.
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Conclusions
To conclude, HBTM 2.1 5 promotes the asymmetric annula-
tion of a range of nucleophiles including 1,3-diketones,
b-ketoesters and azaaryl ketones to (E,E)-a,b-unsaturated
anhydrides, giving either functionalised esters (upon ring
opening), dihydropyranones, or dihydropyridones in good
yields (up to 86%) and high enantioselectivity (up to 97% ee)
via a postulated a,b-unsaturated acyl ammonium interme-
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We thank the Royal Society for a University Research
Fellowships (ADS), the EPSRC (ER) and the EU (CF and CS) for
funding, as well as European Research Council under the
European Union's Seventh Framework Programme (FP7/
2007–2013) ERC grant agreement nꢀ 279850. We also thank
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11 There is only limited precedent for the potential
intermediacy of a,b-unsaturated acyl ammonium ions in
asymmetric catalysis. For dienolate formation that may
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unsaturated acyl ammonium intermediates have been
asymmetry in these processes showed that HBTM 2.1 was
optimal.
accessed from a,b-unsaturated acid uorides and 23 All a,b-unsaturated anhydrides in this manuscript were
employed in 1,3-dipolar cycloaddition reactions, albeit
with low enantioselectivity, see: (d) S. Pandiancherri,
S. J. Ryan and D. W. Lupton, Org. Biomol. Chem., 2012, 10,
7903–7911.
readily prepared from the corresponding a,b-unsaturated
acid by EDCI-mediated coupling. See ESI† for further
information.
24 The absolute conguration within
2 was proven by
12 For reviews see: (a) D. Enders, O. Niemeier and A. Henseler,
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´
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absence of isothiourea catalyst afforded 75% consumption
of diketone starting material.
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27 The use of a,b-unsaturated acyl phosphonates as ester
equivalents has been demonstrated see: (a) H. Jiang,
to a,b-unsaturated acyl azoliums see: R. C. Samantha,
¨
¨
B. Maji, S. De Sarkar, K. Bergander, R. Frohlich, C. Muck-
Lichtenfeld, H. Mayr and A. Studer, Angew. Chem., Int. Ed.,
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study highlights the similarity of the two potential
mechanistic pathways: E. Lyngvi, J. W. Bode and
F. Schoenebeck, Chem. Sci., 2012, 3, 2346–2350.
~
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guanidines see: (b) Z. Jiang, W. Ye, Y. Yang and
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28 Aliphatic diketones such as 2,4-pentanedione led to 33 Such non-bonded S–O interactions have been widely
products with low levels of enantiocontrol. With cinnamic
anhydride, 2,4-pentanedione in the presence of HBTM 2.1
5 gave the corresponding ester in 64% yield and 37% ee.
See ESI† for details.
recognised; for overviews see: (a) V. I. Minkin and
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K. A. Brameld, B. Kuhn, D. C. Reuter and M. Stahl,
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thiadiazoline derivatives see: (c) Y. Nagao, T. Hirata,
S. Goto, S. Sano, A. Kakehi, K. Iizuka and M. Shiro, J. Am.
Chem. Soc., 1998, 120, 3104–3310. In the context of
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X. Yang, V. B. Birman and K. N. Houk, Org. Lett., 2012, 14,
3288–3291. See also ref. 9b.
29 (Z,Z)-Cinnamic anhydride 22 was prepared by Lindlar
reduction of ethyl 3-phenylpropiolate, ester hydrolysis to
give (Z)-cinnamic acid and subsequent anhydride
formation. For full experimental procedures see ESI.†
30 In situ ring opening by addition of methanol to
dihydropyranones derived from unsymmetrical Michael
donors led to a statistical mixture of diastereoisomers and
so this strategy was not pursued further.
31 Addition of ethyl acetoacetate to cinnamic anhydride 3
afforded the corresponding dihydropyranone in 72% yield, 34 Re face addition to the a,b-unsaturated acyl ammonium is
70% ee; addition of ethyl benzoylacetate to crotonic
anhydride afforded the corresponding hydropyranone in
45% yield, 65% ee. See ESI† for further information.
favoured for b-aryl substituents, with Si face addition
favoured to b-alkyl substituents due to CIP priority
changes.
32 For a mechanistic investigation regarding the preferred 1,4- 35 The acyl ammonium chloride salt 52 was characterised by
addition of diketone enolates and alternative nucleophiles single-crystal X-ray diffraction.†
Chem. Sci.
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