Stereo- and Chemodivergent NHC-Promoted Functionalisation of Arylalkylketenes with Chloral

Article abstract of DOI:10.1002/chem.201503308

Stereo- and chemodivergent enantioselective reaction pathways are observed upon treatment of alkylarylketenes and trichloroacetaldehyde (chloral) with N-heterocyclic carbenes, giving selectively either β-lactones (up to 88:12 dr, up to 94% ee) or α-chloroesters (up to 94% ee). Either 2-arylsubstitution or an α-branched iPr alkyl substituent within the ketene favours the chlorination pathway, allowing chloral to be used as an electrophilic chlorinating reagent in asymmetric catalysis.

Full text of DOI:10.1002/chem.201503308

DOI: 10.1002/chem.201503308
Communication
&
Enantioselective Catalysis
Stereo- and Chemodivergent NHC-Promoted Functionalisation of
Arylalkylketenes with Chloral**
James J. Douglas,[a, d] Gwydion Churchill,[b] Alexandra M. Z. Slawin,[a] David J. Fox,*[c] and
Andrew D. Smith*[a]
ed variation within the alkylarylketene unit is typically tolerat-
Abstract: Stereo- and chemodivergent enantioselective
ed, with 2-substitution of the aryl unit or a-branching in the
reaction pathways are observed upon treatment of alkyl-
alkyl substituent usually leading to either no reaction or mark-
arylketenes and trichloroacetaldehyde (chloral) with N-het-
edly reduced product yields and stereoselectivity.[13,14] In only
erocyclic carbenes, giving selectively either b-lactones (up
a single isolated [2+2] reaction process that employs 2-oxoal-
to 88:12 dr, up to 94% ee) or a-chloroesters (up to
dehydes as the cycloaddition partner is an alkylarylketene
94% ee). Either 2-arylsubstitution or an a-branched iPr
bearing either of these structural features vital for high diaster-
alkyl substituent within the ketene favours the chlorina-
eo- and enantiocontrol.[15] Despite these observations, no ra-
tion pathway, allowing chloral to be used as an electro-
tionale has been reported, nor a systematic study undertaken
philic chlorinating reagent in asymmetric catalysis.
to explore the observed product distributions with variation in
ketene substitution. In this context, we demonstrate herein
that chemo- and stereodivergent reaction pathways are ob-
The ability of N-heterocyclic carbenes (NHCs) to catalyse an
array of organocatalytic reaction sequences is widely recog-
nised,[1] with recent investigations demonstrating their unique
versatility in processes that proceed via reactive acyl anion,[2]
azolium enolate,[3] azolium homoenolate,[4] acyl azolium,[5] or
a,b-unsaturated acyl azolium species.[6] Typically, a-functional-
ised aldehydes,[7] enals,[8] activated esters[9] or recently carbox-
ylic acids[10] can be used as mono-substituted azolium enolate
precursors, with disubstituted azolium enolates generated
using isolable alkylarylketenes. In the latter area, a number of
asymmetric formal [2+2],[11] [3+2][12] and [4+2][13] cycloaddition
reactions have been developed. Within these processes, limit-
served in the NHC-mediated asymmetric functionalisation of al-
kylarylketenes with chloral, generating selectively either b-lac-
tones (up to 88:12 dr, up to 94% ee) or a-chloroesters (up to
94% ee).[16] Notably, 2-arylsubstitution or a-branching within
the alkyl chain of the ketene leads to the chlorination pathway
(Figure 1), demonstrating, to the best of our knowledge, the
[a] Dr. J. J. Douglas, Prof. A. M. Z. Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry
University of St Andrews
North Haugh, St Andrews, Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
Figure 1. Stereo-and chemodivergent functionalization of ketenes with chlo-
ral using NHCs.
Homepage: http://ch-www.st-andrews.ac.uk/staff/ads/group/
[b] Dr. G. Churchill
AstraZeneca, Pharmaceutical Development
Macclesfield, Cheshire, SK10 2NA (UK)
ability of chloral to act as an electrophilic chlorine source in
asymmetric catalysis for the first time.
[c] Dr. D. J. Fox
Department of Chemistry, University of Warwick
Gibbet Hill Road, Coventry, CV7 4AL (UK)
E-mail: d.j.fox@warwick.ac.uk
Initial investigations focused upon the functionalisation of
ethylphenylketene 1 (1.0 eq) with chloral (1.0 eq) using NHC
precatalyst 7 (Scheme 1). KHMDS was required for optimal re-
activity and selectivity,[17] while decreasing the reaction temper-
ature to lower than 08C gave increased enantioselectivity at
the expense of product yield.[18] Following optimization this re-
action process was suitable for preparative scale reactions
(15 mmol of ketene) using 2.5 mol% of precatalyst 7, giving
a 74:26 anti:syn mixture of separable diastereoisomers anti-2
(2.40 g, 94% ee) and syn-3 (0.96 g, 92% ee) in 80% overall
yield. Both anti-2 and syn-3 were crystallized to enantiopuri-
ty,[19] and their relative and absolute configurations unambigu-
[d] Dr. J. J. Douglas
Current Address: Small Molecule Design and Development
Lilly Research Laboratories, Eli Lilly and Company
Indianapolis, IN 46285 (USA)
[**] NHC=N-heterocyclic carbene.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503308.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.KGaA. This
is an open access article under the terms of the Creative CommonsAttribu-
tion License, which permits use, distribution and reprodu.ction in anymedi-
um, provided the original work is properly cited.
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1
Scheme 2. [a] Determined by H NMR spectroscopic analysis of the crude
reaction product. [b] Overall combined isolated yield of separable diastereo-
isomers. [c] Determined by chiral HPLC analysis.
1
Scheme 1. [a] Determined by H NMR spectroscopic analysis of the crude
reaction product. [b] Isolated yield of separable diastereoisomers (drꢀ95:5).
[c] Determined by chiral HPLC analysis.
ously confirmed by single crystal X-ray diffraction, consistent
with high stereocontrol at C(3) imparted by the NHC derived
from precatalyst 7.[20] Remarkably, employing ethyl-1-naphthyl-
ketene 4 with precatalyst 7 and chloral, resulted in a chemodi-
vergent reaction process, giving exclusively the tertiary chlori-
nated vinyl ester 5. Performing this reaction on a 3.5 mmol
scale gave exclusively 5 (1.10 g) in 86% yield and 94% ee. Deri-
vatisation of 5 with (S)-phenylethylamine gave amide 6 as
a single diastereoisomer whose absolute configuration was un-
ambiguously confirmed by single crystal X-ray diffraction.[20] To
the best of our knowledge, this represents a unique example
of chloral acting as an electrophilic chlorinating reagent in
asymmetric catalysis and also a rare chemodivergent NHC-pro-
moted process employing ketenes.
The structural parameters within the ketene that govern the
outcome of these chemodivergent reaction processes were
next examined systematically. 4-Substitution of the aryl unit
with either electron-donating or electron-withdrawing sub-
stituents is tolerated, leading to exclusive b-lactone formation,
in moderate dr (up to 75:25 anti:syn) and good ee (up to
94% ee for the major diastereoisomer) (Scheme 2, 8–11).
Subsequent variation of the alkyl unit within a series of alkyl-
phenylketenes showed that highest diastereoselectivity was
observed with methylphenylketene (15, 95% yield, 88:12 dr,
82% ee). Further variation of the n-alkyl substituent (to give 2,
Et and 13, nBu) gave slightly reduced anti-selectivity with in-
creasing chain length (up to 74:26 dr and 94% ee). iBu Substi-
tution gave 14 with essentially no diastereoselectivity (42:58 dr
anti:syn) with the major syn-diastereoisomer isolated in
84% ee. Interestingly, using the a-branched iso-propylphenyl-
ketene 15 in this protocol gave exclusively a-chloroester 16 in
1
Scheme 3. [a] Determined by H NMR spectroscopic analysis of the crude
reaction product. [b] Isolated yield of separable diastereoisomers. [c] Deter-
mined by chiral HPLC. [d] Isolated yield of partially separable diastereoiso-
mers.
preference to b-lactone formation, giving 16 in 86% yield and
88% ee (Scheme 3). These trends indicate that both diastereo-
selectivity in b-lactone formation, and the dichotomy between
b-lactone formation and a-chlorination pathways, are sensitive
to steric effects of the alkyl ketene substituent.
To further establish the generality of the chlorination path-
way, alternative 2-substituted aryl units within the alkylarylke-
tene were evaluated (Scheme 4). Notably, 1-naphthyl-, 2-tolyl-
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zol-5-ylidene as a model NHC catalyst with methyl-2-methyl-
phenylketene and isopropylphenylketene (Figure 2). Grimme’s
B3LYP-D3(BJ) functional[21] and the 6-31G(d, p) basis set[22] were
used for geometry optimisation and ZPE calculation, with final
energies calculated using the TZVPP basis set.[23] Using these
constraints, transition structures for both the formal [2+2] cy-
cloaddition and a-chlorination reactions from methyl-2-methyl-
phenylketene and iso-propylphenylketene were located
(Figure 2). In accordance with the results of Zhang et al.[24] the
transition states for reactions of the (E)-enolates were signifi-
cantly lower in energy than those of the (Z)-enolates (see SI for
all calculated transition state structures and energies). Using
both of these ketenes, transition states for a-chlorination over
the formal [2+2] cycloaddition process leading to the b-lac-
tones were favoured significantly as observed experimentally.
For b-lactone formation, the transition state leading to the syn-
product was favoured over the anti-.[25] In the calculated transi-
tion states, the forming CÀC bonds in the formal [2+2] cyclo-
addition are significantly shorter (22, 1.88 Š; 23, 1.87 Š) than
the developing CÀCl bonds (24, 2.24 Š; 25, 2.37 Š). This is con-
sistent with the electrophilic chlorine in the SN2-type chlorina-
tion transition state being less sterically demanding than the
sp2-hybridised carbonyl carbon in the formal [2+2] cycloaddi-
tion reaction. With either a 2-substituent within the aromatic
substituent of the alkylarylketene, or a branched iso-propyl
group, the additional steric encumbrance of these substituents
disfavours the formal [2+2] addition, resulting in the chlorina-
tion process being preferred.
Scheme 4. [a] Yield of isolated product. [b] Determined by chiral HPLC
analysis.
or 2-chlorophenyl-substituted alkylarylketenes led to exclusive
formation of the corresponding a-chloroesters 5, 17-21 in
good to excellent yield and enantioselectivities (up to 86%
yield and 94% ee).
Building upon this model, the observed chemodivergent re-
action pathways are proposed to arise from initial NHC addi-
tion to the ketene, with preferential onwards reaction arising
from the (E)-azolium enolate 26. Subsequent stereoselective
formal [2+2] cycloaddition with chloral generates 28, with
elimination of the NHC giving the b-lactone and completing
the catalytic cycle. Alternatively,
The observed change in reactivity from formal [2+2] cyclo-
addition to chlorination with variation in the ketene structure
was also investigated computationally using 1,4-dimethyltria-
the use of chloral as an electro-
philic chlorinating agent results
in the formation of an acyl azoli-
um and enolate ion pair 27 that
combined to give the observed
a-chloroester. Notably, assuming
these mechanistic extremes, ster-
eodivergent reaction pathways
are observed from the (E)-azoli-
um enolate intermediate 26. Re-
face functionalisation of the eno-
late derived from sterically non-
demanding ketenes (such as 1)
leads to the observed b-lactone
configuration. Conversely, Si-face
functionalisation with ketenes
bearing either a 2-substituted
aryl unit or an a-branched iso-
propyl substituent provides the
configuration observed for the
chlorinated esters (Figure 3).
Figure 2. Computed transition states for b-lactone formation and a-chlorination using methyl-2-methylphenyl-
ketene and iso-propylphenylketene.
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the mixture stirred for 15 min. The mixture was then cooled to 08C
in an ice/H2O bath followed by addition of chloral (1.00 mmol). A
08C solution of the requisite ketene (1.00 mmol) in toluene (12 mL)
was subsequently added over 0.5 h. The reaction was stirred for an
additional 3 h at 08C before opening the flask to the air for 0.5 h
and concentration in vacuo. The resulting crude residue with the
stated diastereomeric ratio was purified by flash silica chromatog-
raphy (ether:petrol) to provide either the isolated lactone or chlori-
nated ester.
Acknowledgements
We thank the Royal Society for a URF (ADS), AstraZeneca and
the EPSRC for funding (JD - grant number EP/G501742/1). We
also thank the EPSRC UK National Mass Spectrometry Facility
at Swansea University.
Figure 3. Proposed catalytic cycle.
Keywords: asymmetric catalysis
· chlorination reactions ·
Conclusion
ketenes · lactones · stereodivergent reactions
To conclude, stereo- and chemodivergent asymmetric reaction
pathways are observed upon treatment of alkylarylketenes and
chloral with chiral NHCs, giving selectively either b-lactones
(up to 88:12 dr, up to 94% ee) or a-chloroesters (up to
94% ee), with 2-arylsubstitution or a-branching within the alkyl
chain of the ketene unit leading to the a-chlorination pathway.
Computational studies on a model system have allowed the
structural parameters that lead to selectivity in these reaction
processes to be analysed. Current research from this laboratory
is directed toward developing alternative uses of NHCs and
other Lewis bases in asymmetric catalysis.
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To a flame dried Schlenk flask under an argon atmosphere was
added NHC precatalyst (0.10 mmol), base (0.09 mmol) and toluene
(6 mL) and the mixture stirred for 15 min. The mixture was then
cooled to 08C in an ice/H2O bath followed by addition of a 08C so-
lution of the requisite ketene (1.00 mmol) in toluene (12 mL), im-
mediately followed by chloral (1.00 mmol). Toluene (2 mL) was
added to wash residual reactants into solution and the reaction
was stirred for the stated time at 08C before opening the flask to
the air for 30 min and concentration in vacuo. The resulting crude
residue was purified by flash silica chromatography (ether:petrol)
to provide either the isolated lactone or chlorinated ester as
stated.
General procedure (2): Lactonisation and chlorination at 08C
with dropwise ketene addition
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Communication
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Received: August 20, 2015
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Published online on September 25, 2015
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