NHC-promoted asymmetric β-lactone formation from arylalkylketenes and electron-deficient benzaldehydes or pyridinecarboxaldehydes

Article abstract of DOI:10.1021/jo4003079

A chiral NHC catalyzes the asymmetric formal [2 + 2] cycloaddition of alkylarylketenes with both electron-deficient benzaldehydes and 2- and 4-pyridinecarboxaldehydes to generate stereodefined β-lactones. In the benzaldehyde series, optimal product diastereo- and enantiocontrol is observed using 2-nitrobenzaldehyde (up to 93:7 dr (syn:anti) and 93% ee). Substituted 2- and 4-pyridinecarboxaldehydes are also tolerated in this process, generating the corresponding β-lactones in good yield and enantioselectivity, although the diastereocontrol in these processes is highly dependent upon the aldehyde substitution. These processes are readily scalable, allowing multigram quantities of the β-lactone products to be prepared. Derivatization of these products, either through ring opening into the corresponding stereodefined β-hydroxy and β-amino acid derivatives without loss of stereochemical integrity or via cross-coupling, is demonstrated.

Full text of DOI:10.1021/jo4003079

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Article
NHC-promoted asymmetric beta-lactone formation from arylalkylketenes
and electron-deficient benzaldehydes or pyridinecarboxaldehydes
James Douglas, James E. Taylor, Gwydion Churchill, Alexandra M. Z. Slawin, and Andrew D. Smith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4003079 • Publication Date (Web): 26 Feb 2013
Downloaded from http://pubs.acs.org on February 27, 2013
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NHC-promoted asymmetric β-lactone formation from
arylalkylketenes and electron-deficient benzaldehydes or
pyridinecarboxaldehydes
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a
a
b
a
James Douglas, James E. Taylor, Gwydion Churchill, Alexandra M. Z. Slawin and
a
Andrew D. Smith *
a
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St
Andrews, KY16 9ST, UK
b
AstraZeneca, Process Research and Development, Macclesfield, Cheshire, SK10
2
NA, UK
e-mail: ads10@st-andrews.ac.uk
A
chiral NHC catalyses the asymmetric formal [2+2]ꢀcycloaddition of
alkylarylketenes with both electron deficient benzaldehydes and 2ꢀ and 4ꢀ
pyridinecarboxaldehydes to generate stereodefined βꢀlactones. In the benzaldehyde
series, optimal product diastereoꢀ and enantiocontrol is observed using 2ꢀ
nitrobenzaldehyde (up to 93:7 dr (syn:anti) and 93% ee). Substituted 2ꢀ and 4ꢀ
pyridinecarboxaldehydes are also tolerated in this process, generating the
corresponding βꢀlactones in good yield and enantioselectivity, although the
diastereocontrol in these processes is highly dependent upon the aldehyde substitution.
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These processes are readily scalable, allowing multiꢀgram quantities of the βꢀlactone
products to be prepared. Derivatisation of these products, either through ringꢀopening
into the corresponding stereodefined βꢀhydroxyꢀ and βꢀamino acid derivatives
without loss of stereochemical integrity, or via crossꢀcoupling, is demonstrated.
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Introduction:
The βꢀlactone motif is of widespread interest in chemistry, serving as versatile
1
1b,2
starting materials in complex molecule and building block synthesis, monomers in
3
biodegradable polymer synthesis, as well as being the core structure in a range of
4
natural products with notable pharmacological properties. A number of synthetic
5
methods have been used to prepare these scaffolds in enantioenriched form, ranging
5b
6
from substrate and chiral auxiliary controlled processes to catalytic asymmetric
7
methods. Within the area of asymmetric Lewis base catalysis, a variety of strategies
have been utilised to promote the catalytic asymmetric formation of βꢀlactones from
8
ketenes and aldehydes. Building on the pioneering work of Wynberg using cinchona
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10
11
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alkaloid catalysts, the work of the Nelson, Romo and Calter groups has
expanded this approach, with a range of elegant intraꢀ and intermolecular strategies
developed. Although versatile, typical limitations of the intermolecular process using
cinchona derivatives include the requirement for parent or monoꢀsubstituted ketene(s)
and aliphatic aldehydes for good reactivity. To date, relatively few studies have been
reported that use disubstituted ketenes and benzaldehydes in catalytic asymmetric βꢀ
lactone formation. In this area, Fu has shown that planar chiral 4ꢀ
(pyrrolidino)pyridine (PPY) derivative 1 promotes asymmetric βꢀlactone formation
from symmetrical dialkylketenes and benzaldehydes with high enantioselectivity (up
13
to 91% ee, Scheme 1). Kerrigan has recently shown that BINAPHANE 2 can be
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used to promote asymmetric βꢀlactone formation from alkylarylketenes and 4ꢀ
substituted benzaldehydes, giving preferentially antiꢀβꢀlactones with high diastereoꢀ
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and enantiocontrol (up to 94:6 dr and 92% ee).
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Scheme 1. Previous Lewis base-promoted asymmetric β-lactone formation from disubstituted
ketenes and benzaldehydes
Ye has previously utilized NHCs to promote βꢀlactone formation from
15
alkylarylketenes using trifluoromethylketones (up to >20:1 dr, 99% ee) or activated
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2ꢀoxoꢀaldehydes (up to 20:1 dr, 99% ee, Scheme 2). Notably, the use of ethylꢀ2ꢀ
chloroꢀphenylketene is a necessary substrate constraint for high diastereoselectivity in
the latter process, with 4ꢀchloroꢀbenzaldehyde proving inactive to βꢀlactone formation
in this study. Building upon these precedents and our interest in NHCꢀmediated
17
asymmetric processes, we now report the development of an alternative and scalable
NHCꢀpromoted asymmetric βꢀlactone synthesis from alkylarylketenes and both
benzaldehydes
bearing
electron
withdrawing
substituents
and
pyridinecarboxaldehydes. Furthermore, derivatisation of the βꢀlactone products, either
through ringꢀopening into the corresponding stereodefined βꢀhydroxyꢀ and βꢀamino
acid derivatives, or via crossꢀcoupling, is demonstrated.
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Scheme 2. Previous and proposed asymmetric β-lactone formation from disubstituted ketenes
and aldehydes using NHCs
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Results and Discussion:
Evaluating NHC-promoted β-lactone formation using benzaldehydes
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As NHCs are known to promote benzoin reactions of benzaldehydes as well as
1
9
ketene dimerisation processes, at the outset of our investigations these were
recognised as possible competitive reaction manifolds. NHC precatalyst 3 was chosen
for our studies given its precedent to participate in enantioselective cycloaddition
2
0
processes using ketenes, yet its moderate reactivity in benzoin reactions. Initial
studies employed ethylphenylketene and triazolium precatalyst 3 with a range of
substituted benzaldehydes (Table 1). Whilst benzaldehyde gave no βꢀlactone products
(giving only ketene dimer), promising reactivity was observed with electronꢀdeficient
benzaldehydes utilizing dropwise ketene addition to minimise dimerisation. The
reactions using 4ꢀtrifluoromethylꢀ or 4ꢀnitrobenzaldehyde performed at 0 °C gave
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good yields of βꢀlactone product (5 and 6) with moderate levels of antiꢀ
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diastereoselectivity (entries 2 and 3). Improved enantiocontrol was achieved at the
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detriment of product conversion at −78 °C using 4ꢀnitrobenzaldehyde (entry 4).
Using 2ꢀnitrobenzaldehyde, high synꢀdiastereoselectivity (89:11 syn:anti) was
observed at 0 °C, giving major synꢀdiastereoisomer 7 in 94% ee (entry 5). Further
optimization using 2ꢀnitrobenzaldehyde was achieved through lowering the reaction
temperature, with consistently high levels of diastereoꢀ and enantioselectivity
observed (entries 6 to 7). Interestingly, lowering the reaction temperature below −50
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°C had a detrimental effect on product ee (entry 8), postulated to be due to a
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competitive KHMDSꢀcatalysed racemic pathway at this temperature. The absolute
and relative configuration within 7 was proven through Xꢀray crystallographic
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analysis. Following the promising reactivity and stereoselectivity observed using 2ꢀ
nitrobenzaldehyde, the ability of 2ꢀhalobenzaldehydes to participate in this reaction
process was investigated. 2ꢀFluoroꢀ, 2ꢀchloroꢀ and 2ꢀbromobenzaldehyde all gave the
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corresponding βꢀlactones (8ꢀ10) with poor dr (entries 9ꢀ11), consistent with the 2ꢀ
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nitro substituent being a necessary constraint for optimal diastereoselectivity.
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Table 1. Initial screening of benzaldehydes for NHC-promoted β-lactone synthesis
0
1
2
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6
7
8
9
0
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4
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9
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8
9
0
a
b
c
dr
Major
Yield %
ee %
Entry
Ar
Ph
T / °C
(
syn:anti)
−:−
product
(syn,anti) (syn,anti)
d
1
0
−
−,−
−,−
e
2
4ꢀCF C H
4
0
30:70
27,55
80,38
3
6
f
3
0
40:60
40:60
30,50
7,34
81,14
97,54
4
2
2 6 4
ꢀNO C H
f
4
−78 to rt
f
0
86,−
77,−
83,−
94,−
97,−
93,−
82,−
5
89:11
92:8
6
7
8
−25
−50
−78
2 6 4
ꢀNO C H
93:7
89:11
8
6,−
g
9
2ꢀFC H4
−50
−50
−50
50:50
52:48
56:44
29
36
25
87,69
87,76
95,71
6
g
10
2ꢀClC
6
H
4
4
g
1
1
2ꢀBrC
6
H
a
1
Unless stated, ketene added dropwise as a solution in toluene. dr determined by H NMR analysis of
b
c
the crude reaction mixture. Isolated yield of single diastereoisomer. ee determined by HPLC analysis.
d
e
f
g
Ketene added in a single portion. 1.5 equiv of aldehyde. 1.2 equiv of aldehyde. Isolated yield and ee
of products after ring opening into the corresponding βꢀhydroxy acids and derivatisation.
With 2ꢀnitrobenzaldehyde identified as giving optimum diastereoꢀ and enantiocontrol
in this process, its scope and limitations were explored through variation of the ketene
component (Table 2). Firstly, a series of alkylphenylketenes were reacted under the
optimized conditions. Incorporation of a methyl substituent led to a decrease in dr
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while maintaining high levels of enantioselectivity for both diastereoisomers of
product 11 (entry 1). Ethyl and nꢀbutyl substitution gave βꢀlactones 7 and 12 in high
dr and ee, while iꢀbutyl incorporation leads to high dr but poor ee (entries 2ꢀ4).
Variation of the aryl unit within a series of ethylarylketenes was also investigated,
with the incorporation of both electronꢀwithdrawing and electronꢀdonating
substituents providing βꢀlactones 14ꢀ18 in high dr and ee (entries 5ꢀ9). Further
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substrate variation showed that isoꢀpropylꢀ3ꢀthiopheneketene gave βꢀlactone 19 with
poor dr, although the antiꢀdiastereoisomer was formed in high ee (entry 10). The
NHCꢀcatalysed reaction of either ethylꢀ2ꢀtolylꢀ or ethylꢀ1ꢀnaphthylketene with 2ꢀ
nitrobenzaldehyde gave no βꢀlactone products, returning the aldehyde starting
material (entries 11 and 12). Notably, the observed trend in product
diastereoselectivity using NHCꢀmediated catalysis (reduced dr for methylarylketenes)
is opposite to that observed by Kerrigan using phosphine catalysis (high dr for
14
methylarylketenes, reduced dr for nꢀbutylarylketenes).
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Table 2. Reaction scope and limitations employing 2-nitrobenzaldehyde
a
c
dr
Major
b
ee %
0
1
2
3
4
5
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7
8
9
0
1
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3
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5
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7
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9
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Entry
1
Ar
Ph
R
Yield %
(
syn:anti)
product
(syn,anti)
Me
43:57
93:7
65
90,90
d
2
Ph
Ph
Ph
Et
nꢀBu
iꢀBu
Et
83
74
30
69
79
68
52
75
35
93,−
89, −
d,e
3
94:6
4
5
6
7
8
94:6
<10%,−
85, −
4ꢀFC
6
H
4
93:7
4ꢀClC
6
H
4
4
Et
93:7
86, −
4ꢀBrC
6
H
Et
94:6
92, −
4ꢀMeC
6
H
4
Et
90:10
86:14
45:55
83, −
f
9
4ꢀMeOC
6
H
4
Et
86, −
10
2ꢀthienyl
iꢀPr
58,92
1
1
1
2
2ꢀCH C H
4
1ꢀnaphthyl
Et
Et
−
−
−
−
−
−
−
−
3
6
a
1
Ketene added dropwise as a solution in toluene. dr determined by H NMR analysis of the crude
b
c
reaction mixture. Isolated yield of mixture of diastereoisomers. ee determined by HPLC analysis.
d
e
Isolated yield of single diastereoisomer. ee determined by HPLC analysis via ringꢀoepning with
f
NaN
3
. 1.2 equiv of ketene and 1.0 equiv of aldehyde used.
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Evaluating NHC-promoted β-lactone formation using pyridinecarboxaldehydes
Although the use of 2ꢀnitrobenzaldehyde allows efficient access to a range of βꢀ
lactones in good yield and typically excellent diastereoꢀ and enantiocontrol, the
limited scope of this methodology due to the requirement for a 2ꢀnitro substituent for
reasonable diastereoselectivity reduces its synthetic versatility. To address this, the
ability of heteroaromatic aldehydes to participate in this methodology was
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investigated. Accordingly, furfural and all isomers of pyridinecarboxaldehyde were
identified as possible participants in this protocol. The formation of chiral pyridine
containing compounds is of significance due to their use in both asymmetric
28
29
catalysis and appearance in biologically relevant molecules. Although a number of
30
methods have previously been developed to prepare these motifs, enantiomerically
enriched pyridyl substituted βꢀlactones, to the best of our knowledge, are
3
1
unreported.
While both furfural and 3ꢀpyridinecarboxaldehyde gave the corresponding βꢀlactone
products with unsatisfactory levels of conversion (<10%), 2ꢀ and 4ꢀ
pyridinecarboxaldehyde both proved efficient coupling partners with
ethylphenylketene (Scheme 3). Notably, 2ꢀpyridinecarboxaldehyde preferentially
gave the syn
preferentially gave the anti
differences in syn:anti product distributions previously observed using 2ꢀ and 4ꢀ
ꢀ
diastereoisomer 21 (74:26 syn:anti), while 4ꢀpyridinecarboxaldehyde
ꢀ
diastereoisomer 20 (17:83 syn:anti), consistent with the
32
nitrobenzaldehydes. The absolute and relative configuration within βꢀlactone 21 was
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unambiguously identified via Xꢀray crystallographic analysis, consistent with the
sense of asymmetric induction previously observed using 2ꢀnitrobenzaldehyde.
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Scheme 3. Initial reactivity employing 2- and 4-pyridinecarboxaldehydes
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Subsequent studies probed the generality of this process through variation of the
alkylarylketene and through the effect of substitution within the 2ꢀ
3
3
pyridinecarboxaldehyde (Table 3). Using 2ꢀpyridinecarboxaldehyde, variation of
either the aryl unit within the ketene or the alkyl chain length had little effect upon
reaction stereoselectivity, with syn
ꢀ4). The effect of both electronic and steric perturbation within the 2ꢀpyridyl motif
was next investigated. Using methylphenylketene, 6ꢀbromoꢀ2ꢀ
ꢀβꢀlactones 22ꢀ25 formed in good dr and ee (entries
1
pyridinecarboxaldehyde gave synꢀβꢀlactone 26 (70% combined yield, 80:20 dr
syn:anti, 86% ee syn), while 3ꢀbromoꢀ2ꢀpyridinecarboxaldehyde displayed a reversal
in diastereoselectivity (18:82 syn:anti) and excellent enantioselectivity for the major
anti diastereoisomer 27 (91% ee), albeit with moderate conversion into product
(entries 5 and 6).
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Table 3. NHC-promoted β-lactone formation using 2-pyridinecarboxaldehydes
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11
12
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a
c
dr
Major
product
b
ee %
Entry
1
Ar
Ph
R
Yield %
78
(
syn:anti)
(syn,anti)
Me
77:23
82:18
82:18
80:20
80:20
88,86
d
2
Ph
nꢀBu
Et
62
73
45
70
84,37
79,42
80,−
d
3
4ꢀFC
4ꢀBrC
Ph
6 4
H
4
5
6
H
4
Et
O
O
Me
Ph
Me
N
86,67
Br
2
6
6
Ph
Me
18:82
14
−,91
a
1
Ketene added dropwise as a solution in toluene. dr determined by H NMR analysis of the crude
b
c
d
reaction mixture. Isolated yield of separable diastereoisomers. ee determined by HPLC analysis. 1.1
equiv of ketene and 1.0 equiv of aldehyde used.
The compatibility of a range of 4ꢀpyridinecarboxaldehyde derivatives of increasing
complexity with the methodology was next investigated (Table 4). The use of 3ꢀ
fluoroꢀ4ꢀpyridinecarboxaldehyde resulted in a switch in diastereoselectivity compared
with the parent 4ꢀpyridinecarboxaldehyde, giving moderate diastereocontrol in favour
of synꢀstereoisomer 28 (syn:anti 63:37, entry 1). 4ꢀQuinolinecarboxaldehyde gave
anti βꢀlactone 29 with excellent diastereoselectivity (3:97 syn:anti) and promising
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
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5
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5
5
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5
6
enantioselectivity (82% ee anti) in 57% yield (entry 2). The use of a complex 3,5ꢀ
disubstitutedꢀ4ꢀpyridinecarboxaldehyde gave βꢀlactone 30 with no diastereocontrol,
providing readily separable syn and anti-lactones (50:50 dr) in good yield and
moderate enantioselectivity (70% combined yield, 76% ee syn , 74% ee anti, entry 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 4. NHC-promoted β-lactone formation using 4-pyridinecarboxaldehyde derivatives
a
c
dr
Major
product
b
ee %
Entry
1
Yield %
31
(
syn:anti)
(syn,anti)
63:37
37,64
d
2
3:97
57
70
−,82
d
3
50:50
76,74
a
1
Ketene added dropwise as a solution in toluene. dr determined by H NMR analysis of the crude
b
c
d
reaction mixture. Isolated yield of separable diastereoisomers. ee determined by HPLC analysis. 1.1
equiv of ketene and 1.0 equiv of aldehyde used.
Postulated Reaction Mechanism
While Kerrigan favours Lewis base addition to the aldehyde as the initial step in the
phosphineꢀcatalysed βꢀlactone synthesis from ketenes and benzaldehydes, in this
NHCꢀmediated process, concurrent with the ideas of Ye, we propose initiation
through NHC addition to the ketene (Scheme 4). Addition of in situ generated NHC
3
1 to ketene 32 antiꢀ to the aryl unit generates azolium enolate intermediate 33.
Subsequent concerted but asynchronous formal [2+2] cycloaddition with electron
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deficient benzaldehydes or 2ꢀ and 4ꢀpyridinecarboxaldehydes yields zwitterionic
intermediate 34, with subsequent catalyst regeneration and βꢀlactone formation. The
consistency of configuration at the C(3) position of all the major diastereoisomeric βꢀ
lactone products observed herein is consistent with favourable reaction upon the Reꢀ
face addition of the azolium enolate 33. However, given the obvious subtle interplay
between steric and electronic factors within the aldehyde component that leads to
diastereocontrol in these processes, a full rationale for the differing observed synꢀ or
antiꢀselectivities with change in the aldehyde unit is at best speculative.
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18
19
20
21
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23
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26
27
28
29
30
31
32
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45
46
47
48
49
50
51
52
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54
55
56
57
58
59
60
Scheme 4. Proposed mechanism
Scale up and derivatisation procedures
To demonstrate the synthetic utility of this methodology, this reaction of
ethylphenylkene with 2ꢀnitrobenzaldehyde could be conveniently carried out on a
preparative scale with reduced NHC loadings (2.5 mol%), providing >2.5g of βꢀ
lactone 7 as a single diastereoisomer after purification and in high ee (83% yield, 95%
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2
2
2
2
2
2
2
2
2
2
3
3
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3
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4
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4
4
4
4
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5
5
5
5
5
5
5
6
ee), which could be recrystallised to enantiopurity. Using higher precatalyst 3 loading
of 10 mol%, 2ꢀpyridyl βꢀlactone 21 could also be obtained as a single diastereoisomer
on a >3.5g scale after purification (74% yield, 82:18 dr syn:anti) and in good
enantioselectivity for the major syn βꢀlactone (83% ee).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Scale up of NHC-catalysed reactions with 2-nitrobenzaldehyde and 2-
pyridinecarboxaldehyde
a
b
Combined isolated yield of separable diastereoisomers. ee determined by HPLC analysis.
Functionalisation of βꢀlactones 7 and 21 was subsequently achieved through ring
opening with either azide or hydroxide to give the corresponding α,αꢀdisubstituted βꢀ
aminoꢀ and βꢀhydroxy acid derivatives 36ꢀ39 as single diastereoisomers without loss
1
3,34
of enantiopurity (Scheme 6).
Alternatively, 21 could be treated with benzylamine
to generate βꢀhydroxy acid amide 40 as single diastereoisomer.
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Scheme 6. Derivatisation via ring-opening of β-lactones
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
b
ee determned by HPLC analysis via conversion into NBn, OBn derivative. ee determined by HPLC
c
analysis via conversion into OBn ester. ee determined by HPLC analysis via conversion into Me ester.
Finally, further complexity within the pyridyl substituted βꢀlactone series could be
obtained via palladium cross coupling of βꢀlactone 26 bearing a bromine substituent
3
5
36
(
Scheme 7). Both BuchwaldꢀHartwig and Suzuki couplings of 26 with morpholine
and indole 43 respectively provided highly complex βꢀlactone frameworks 41 and 42
in good yield (66% and 92% yield respectively) and with no erosion of enantiopurity.
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1
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 7. Functionalisation of β-lactones by cross-coupling
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
ee determined by HPLC analysis.
Conclusion: In summary, an efficient and scalable methodology for the
stereocontrolled formation of βꢀlactones catalyzed by chiral NHCs has been
developed. The reaction of a range of disubstituted ketenes with either
2ꢀnitrobenzaldehyde or a variety of 2ꢀ and 4ꢀpyridinecarboxaldehydes proceeds with
generally excellent levels of enantioꢀ and diasteroꢀselectivity. Importantly, this
methodology expands the scope of the formal [2+2] cycloaddition between ketenes
and aldehydes to heteroaromatic aldehydes for the first time, allowing access to
highly functionalised novel structural architectures. Notably, no competing benzoin or
significant formation of ketene dimerisation products were observed under the
reaction conditions, with the βꢀlactones readily transformed into useful synthetic
building blocks. Further studies focusing upon the generation and reaction of azolium
enolates in NHCꢀmediated catalysis are underway, alongside mechanistic and kinetic
investigations to advance our understanding of the reaction dynamics in these systems.
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Experimental
General: All reactions were performed in flame dried glassware using anhydrous
solvents. The required aldehydes where purified by Kugelrohr distillation under
reduced pressure prior to use. All other reagents were obtained from commercial
sources and were used without further purification. Room temperature (rt) refers to
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28
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37
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
0−25 °C, with temperatures between 0 °C and −50 °C obtained using an immersion
1
13
1
cooler. H NMR spectra were acquired at either 300, 400, or 500 MHz, C{ H} NMR
19
1
spectra were acquired at either 75, 100, or 125 MHz, and F{ H} NMR spectra were
acquired at 376 MHz. Chemical shifts are quoted in parts per million (ppm) relative to
the residual solvent peak, coupling constants, J, are quoted in Hertz (Hz). NMR peak
1
1
assignments were confirmed using 2D H COSY and 2D H NOESY where necessary.
Infraꢀred spectra were recorded as thin films on either NaCl plates or KBr discs. Mass
spectrometry (m/z) data were acquired using either electrospray ionisation (ESI),
electron impact (EI), atmostpheric solids analysis probe (ASAP), or nanospray
ionisation (NSI) using a TOF mass analyser. Optical rotations were recorded with a
path length of 1 dm and concentrations, c, are quoted in g/100 mL. All chiral HPLC
traces were compared with an authentic racemic trace prepared using racemic 3.
General procedure for the preparation of ketenes: A flame dried twoꢀneck round
bottom flask separated by a sintered adaptor to a second twoꢀneck round bottom flask
under an argon atmosphere is charged with anhydrous Et
2
O and the appropriate acid
chloride (1 equiv) before being cooled to 0 °C. Et N (1.1 equiv) is added dropwise
3
over 30 min and the reaction stirred overnight at 0 °C. The solution was warmed to rt
and filtered through the sintered adaptor into the second flask and concentrated. The
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
crude oil was transferred via cannula into a flame dried Kugelrohr flask and purified
by distillation.
Ethylphenylketene: Prepared according to the general procedure from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2ꢀphenylbutanoyl chloride (3.00 g, 16.4 mmol) and Et N (2.52 mL, 18.1 mmol) in
3
Et
2
O (45 mL). The crude oil was purified via Kugelrohr distillation 80−90 °C (5
37
mbar) {lit 70 °C (0.5 torr)} to give ethylphenylketene (1.40 g, 60%) as light yellow
1
oil that is stable for up to two months in the freezer under an argon atmosphere. H
NMR (300 MHz, CDCl
3
H 2 3 2 3
) δ 1.24 (3H, t, J 7.4, CH CH ), 2.44 (2H, q, J 7.4, CH CH ),
7
.02−7.10 (3H, m, ArH), 7.28−7.35 (2H, m, ArH).
Methylphenylketene: Prepared according to the general procedure from 2ꢀ
phenylpropanoyl chloride (4.05 g, 24.0 mmol) and Et N (3.34 mL, 24.0 mmol) in
3
Et O (50 mL). The crude oil was purified via Kugelrohr distillation 60−80 °C (5
2
37
mbar) {lit 50 °C, (4 torr)} to give methylphenylketene (1.44 g, 45%) as
1
yellow/orange oil. H NMR (400 MHz, CDCl
3
H 3
) δ 1.92 (3H, s, CH ), 6.93−6.95 (2H,
m, ArH), 6.97−7.01 (1H, m, ArH), 7.21−7.25 (2H, m, ArH).
Butylphenylketene: Prepared according to the general procedure from 2ꢀ
phenylhexanoyl chloride (3.00 g, 14.2 mmol) and Me EtN (1.70 mL, 15.7 mmol) in
Et O (45 mL). The crude oil was purified via Kugelrohr distillation 110−120 °C (5
2
2
1
mbar) to give butylphenylketene (1.26 g, 51%) as yellow/orange oil. H NMR (300
MHz, CDCl ) δ 0.87 (3H, t, J 7.2, nBuH), 1.30−1.53 (4H, m, nBuH), 2.32 (2H, t, J
3
H
7
.4, nBuH ), 6.93−7.01 (3H, m, ArH), 7.19−7.25 (2H, m, ArH).
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Isobutylphenylketene: Prepared according to the general procedure from 4ꢀmethylꢀ2ꢀ
phenylpentanoyl chloride (3.80 g, 18.0 mmol) and Me
2
EtN (2.15 mL, 20.0 mmol) in
Et O (45 mL). The crude oil was purified via Kugelrohr distillation 110−117 °C (5
2
38
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mbar) {lit 37−46 °C, (0.8 torr)} to give isobutylphenylketene (1.75 g, 56%) as
1
yellow/orange oil. H NMR (300 MHz, CDCl
3
) δ
), 2.19 (2H, d, J 7.0, CH
ArH), 7.17−7.25 (2H, m, ArH).
H
0.92 (6H, d, J 6.6, CH(CH
3 2
) ),
1
.66−1.83 (1H, m, CH(CH
3
)
2
2
CH(CH ), 6.95−7.01, (3H, m,
3 2
)
Ethyl-4-flourophenylketene: Prepared according to the general procedure from 2ꢀ(4ꢀ
fluorophenyl)butanoyl chloride (2.70 g, 13.5 mmol) and EtMe N (1.60 mL, 14.8
mmol) in Et O (40 mL). The crude oil was purified via Kugelrohr distillation
04−110 °C (7 mbar) to give ethylꢀ4ꢀflourophenylketene (1.21 g, 55%) as
2
2
1
ꢀ1
1
yellow/orange oil. νmax (thin film)/cm 2100; H NMR (300 MHz, CDCl
(3H, t, J 7.4, CH CH ), 2.33 (2H, q, J 7.4, CH CH ), 6.87−7.97 (4H, m, ArH );
C{ H} NMR (75 MHz CDCl ): δ 12.9, 17.5, 41.1, 116.1 (d, J 21.7), 125.5 (d, J
.6), 128.5 (d, J 3.1), 160.5 (d, J 243.4), 205.7.
3
) δ
H
1.13
2
3
2
3
13
1
3
C
7
Ethyl-4-chlorophenylketene: Prepared according to the general procedure from 2ꢀ(4ꢀ
chlorophenyl)butanoyl chloride (763 mg, 3.51 mmol) and Et N (0.49 mL, 3.51 mmol)
in Et O (20 mL). The crude oil was purified via Kugelrohr distillation 125−135 °C (7
3
2
1
mbar) to give ethylꢀ4ꢀchlorophenylketene (0.37 g, 56%) as yellow/orange oil. H
NMR (300 MHz, CDCl ) δ 1.34 (3H, t, J 7.4, CH CH ), 2.53 (2H, q, J 7.4, CH CH ),
3
H
2
3
2
3
7
.05−7.09 (2H, m, ArH ), 7.37−7.42 (2H, m, ArH ).
Ethyl-4-bromophenylketene: Prepared according to the general procedure from 2ꢀ(4ꢀ
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
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5
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5
5
5
6
2
bromophenyl)butanoyl chloride (5.00 g, 19.1 mmol) and Et MeN (2.30 mL, 21.0
2
mmol) in Et O (45 mL). The crude oil was purified via Kugelrohr distillation 180 °C
(7 mbar) to give ethylꢀ4ꢀbromophenylketene (1.21 g, 28%) as yellow/orange oil. νmax
ꢀ
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(thin film)/cm 2100; H NMR (300 MHz, CDCl
.33 (2H, q, J 7.4, CH CH ), 6.87−7.97 (4H, m, ArH); C{ H} NMR (75 MHz
CDCl ): δ 11.7, 15.9, 40.7, 116.2, 124.4, 130.9, 131.0, 203.2.
3
) δ
H 2 3
1.13 (3H, t, J 7.4, CH CH ),
13
1
2
2
3
3
C
Ethyl-4-tolylketene: Prepared according to the general procedure from 2ꢀ(pꢀ
tolyl)butanoyl chloride (2.16 g, 11.0 mmol) and Et N (1.53 mL, 11.0 mmol) in Et
40 mL). The crude oil was purified via Kugelrohr distillation 110−120 °C (7 mbar)
3
2
O
(
1
9
{lit 68−72 °C, (0.2 torr)} to give ethylꢀ4ꢀtolylketene (0.92 g, 52%) as yellow/orange
1
oil. H NMR (300 MHz, CDCl
3
H 2 3 3
) δ 1.29 (3H, t, J 7.4, CH CH ), 2.40 (3H, s, ArCH ),
2
.50 (2H, q, J 7.4, CH
2
CH
3
), 7.02 (2H, d, J 8.1, ArH), 7.21 (2H, d, J 8.1, ArH).
Ethyl-4-methoxyphenylketene: Prepared according to the general procedure from 2ꢀ(4ꢀ
methoxyphenyl)butanoyl chloride (3.00 g, 14.1 mmol) and Et N (3.93 mL, 28.2
3
2
mmol) in Et O (45 mL). The crude oil was purified via Kugelrohr distillation
140−150 °C (3 mbar) to give ethylꢀ4ꢀmethoxyphenylketene (1.19 g, 48%) as
ꢀ
1
1
yellow/orange oil. νmax (thin film)/cm 2096; H NMR (300 MHz, CDCl
3H, t, J 7.4, CH CH ), 2.41 (2H, q, J 7.4, CH CH ), 3.79 (3H, s, ArCH ), 6.86−6.91
(2H, m, ArH), 6.95−6.99 (2H, m, ArH).
3
H
) δ 1.21
(
2
3
2
3
3
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Isopropyl-3-thionylketene: Prepared according to a literature procedure from 3ꢀ
methylꢀ2ꢀ(thiophenꢀ3ꢀyl)butanoyl chloride (2.27 g, 11.2 mmol, 1 equiv) and Me EtN
5.46 mL, 50.4 mmol, 4.5 equiv) in THF (30 mL) at 0 °C for 10 min then rt for 4.5 h.
The crude oil was purified via Kugelrohr distillation 85−90 °C (3 mbar) {lit
2
(
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
9
1
7
1−73 °C} to give isopropylꢀ3ꢀthionylketene (1.09 g, 59%) as yellow/orange oil. H
NMR (300 MHz, CDCl ) δ 1.25 (6H, d, J 6.7, CH(CH ) ), 2.77 (1H, hep, J 6.7,
3
H
3 2
3 2
CH(CH ) ), 6.79−6.82 (2H, m, ArH), 7.33−7.35 (1H, m, ArH).
General procedure for NHC catalysed [2+2] cycloadditions: To a flame dried
Schlenk flask under an argon atmosphere was added NHC precursor 3 (0.1 equiv),
KHMDS (0.5
M in toluene, 0.09 equiv) and toluene (to give 0.025 M NHC 3) and the
mixture stirred for 15 min. The solution was cooled to −50 °C before the required
aldehyde (1.2 equiv) was added followed by dropwise addition of a solution of the
required ketene (1.0 equiv) in toluene (0.17
M) over 30 min. The solution was stirred
at rt for the time stated before being opened to air and stirred for 30 min. The solution
was concentrated in vacuo and the crude product purified by silica gel
chromatography.
3
-Methyl-4-(2-nitrophenyl)-3-phenyloxetan-2-one 11: Prepared according to the
general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol), KHMDS (0.18 mL,
.09 mmol), methylphenylketene (132 mg, 1.00 mmol) and 2ꢀnitrobenzaldehyde (181
mg, 1.20 mmol) in toluene (10 mL) at −50 °C for 3.5 h. The crude product (dr 43:57
syn:anti) was purified by silica gel chromatography (95:5 petrol:Et O) to give synꢀ11
0
2
(88 mg, 30%) as colourless solid and antiꢀ11 (103 mg, 35% yield) as colourless solid.
20
syn-11: mp 68−70 °C;
[α
]D −61 (c 0.15, CHCl ); Chiral HPLC analysis Chiralpak
3
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ꢀ
1
R R
OJꢀH (5% IPA:hexane, flow rate 1.0 mL min , 220 nm) t major (S,R): 32.0 min, t
ꢀ1
minor (R,S): 36.2 min, 90% ee; νmax (KBr)/cm 2925, 1834 (C=O), 1527, 1341, 1351
1
1
246, 1133, 945, 911, 866, 790, 745, 699; H NMR (400 MHz, CDCl
3
H
) δ 2.20 (3H,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
s, CH
ArHNO
dd, J 8.2, 1.2, ArHNO
), 6.22 (1H, s, CHꢀlactone), 7.00−7.09 (5H, m, ArH), 7.31−7.35 (1H, m,
) 7.55 (1H, td, J 7.5, 1.1, ArHNO ), 7.62 (1H, d, J 7.7, ArHNO ), 7.96 (1H,
); C{ H} NMR (75 MHz, CDCl ) δ 22.4, 67.8, 82.1, 124.9,
3
2
2
2
13
1
2
3
c
126.6, 126.7, 128.0, 128.2, 128.5, 129.2, 132.8, 134.2, 134.4, 146.3, 173.0; HRMS
+
(ASAP) C16
H
14
O
4
N [M+H] requires 284.0917; found 284.0912 (−1.9 ppm). anti-11:
2
D
0
mp 128–130 °C;
[α
]
3
−41 (c 0.3, CHCl ); Chiral HPLC analysis Chiralpak ASꢀH
ꢀ1
R R
(5% IPA:hexane, flow rate 1.0 mL min , 220 nm) t major (S,S): 22.5 min, t minor
ꢀ1
(
R,R): 30.4 min, 90% ee; νmax (KBr)/cm 2982, 1836 (C=O), 1613, 1578, 1526, 1443,
1
1
342, 1125, 1085, 861, 790, 737, 725, 630; H NMR (400 MHz, CDCl
), 6.13 (1H, s, CHꢀlactone), 7.37−7.56 (5H, m, ArH), 7.60−7.64 (1H, m,
ArHNO ), 7.84 (1H, td, J 7.6, 0.9, ArHNO ), 7.95 (1H, d, J 7.8, ArHNO ), 8.25 (1H,
dd, J 8.2, 1.0, ArHNO ); C{ H} NMR (75 MHz, CDCl ) δ 15.5, 65.9, 82.0, 125.5,
3
H
) δ 1.34 (3H,
s, CH
3
2
2
2
13
1
2
3
c
126.1, 128.3, 128.5, 129.1, 129.8, 132.3, 134.9, 137.6, 146.8, 173.0; HRMS (ASAP)
+
C
16
H
14
O
4
N [M+H] requires 284.0904; found 284.0912 (+2.8 ppm).
(
3S,4R)-3-Ethyl-4-(2-nitrophenyl)-3-phenyloxetan-2-one 7: Prepared according to the
general procedure from NHC precursor 3 (28.5 mg, 0.05 mmol), KHMDS (0.09 mL,
.045 mmol), ethylphenylketene (73.1 mg, 0.50 mmol) and 2ꢀnitrobenzaldehyde (91
mg, 0.60 mmol) in toluene (10 mL) at −50 °C for 3.5 h. The crude product (dr 93:7
syn:anti) was purified by silica gel chromatography (95:5 petrol:Et O) to give synꢀ7
157 mg, 83%) as off white solid. mp 58−62 °C [(±) synꢀ7 mp 86 °C];
0
2
2
D
0
(
[α
]
−44 (c
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0.45, CHCl
3
); Chiral HPLC analysis Chiralpak OJꢀH (5% IPA:hexane, flow rate 0.5
ꢀ1
mL min , 220 nm) t major: (S,R) 43.7 min, t minor: (R,S) 51.1 min, 93% ee; ν
R
R
max
ꢀ1
(
KBr)/cm 3094, 1768 (C=O), 1646, 1513, 1452, 1377, 1214, 1124, 971, 883, 851,
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
778, 738; H NMR (400 MHz, CDCl
3
H 2 3
) δ 1.09 (3H, t, J 7.4, CH CH ), 2.51−2.59 (2H,
m, CH
2
CH
3
), 6.19 (1H, s, CHlactone), 6.94−7.02 (5H, m, ArH), 7.20−7.27 (1H, m,
1
3
1
ArHNO
2
2 2
), 7.38−7.48 (2H, m, ArHNO ), 7.90 (1H, dd, J 8.2, 1.2, ArHNO ); C{ H}
NMR (75 MHz, CDCl
3
) δ
c
9.5, 29.4, 73.1, 79.4, 124.8, 126.9, 127.9, 128.3, 128.6,
+
1
29.1, 134.1, 146.6, 172.2; HRMS (EI) C17
98.1078 (+1.4 ppm).
H
16
O
4
N [M+H] requires 298.1074; found
2
(3S,4R)-3-Butyl-4-(2-nitrophenyl)-3-phenyloxetan-2-one 12: Prepared according to
the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol), KHMDS (0.18
mL, 0.09 mmol), butylphenylketene (174 mg, 1.00 mmol) and 2ꢀnitrobenzaldehyde
(181 mg, 1.20 mmol) in toluene (10 mL) at −50 °C for 3.5 h. The crude product (dr
9
2
4:6 syn:anti) was purified by silica gel chromatography (95:5 petrol:Et O) to give
20
synꢀ12 (240 mg, 74%) as off white solid. mp 64−66 °C;
[α
]D −20 (c 0.60, CHCl
3
);
ꢀ1
1
ν
max (KBr)/cm 2958, 1828 (C=O), 1527, 1346, 1117, 918, 790, 744, 701; H NMR
(300 MHz, CDCl ) δ 0.93 (3H, t, J 7.3, nBuCH ), 1.24−1.50 (3H, m, nBuH ),
3
H
3
1
7
7
2
.66−1.81 (1H, m, nBuH ), 2.56 (2H, dd, J 9.3, 7.3, nBuH ), 6.25 (1H, s, CHꢀlactone),
.00−7.09 (5H, m, ArH), 7.28−7.33 (1H, m, ArHNO ), 7.45−7.53 (2H, m, ArHNO ),
); C{ H} NMR (100 MHz, CDCl ) δ 13.9, 22.9,
2
2
13
1
.97 (1H, dd, J 8.2, 1.0, ArHNO
2
3
c
7.0, 36.1, 72.4, 79.7, 124.7, 126.7, 127.8, 128.2, 128.5, 129.0, 132.8, 134.0, 134.1,
+
134.1, 146.5, 172.2; HRMS (ASAP) C19
H
20
O
4
N [M+H] requires 326.1387; found
3
3
26.1381 (−1.8 ppm). synꢀ12 was ring opened with NaN and converted into its
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benzyl ester to allow chiral HPLC analysis: Chiral HPLC analysis Chiralpak ADꢀH
ꢀ1
(
5% IPA:hexane, flow rate 1.0 mL min , 220 nm) t
R R
minor: 4.9 min, t major: 6.4 min,
8
9% ee.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
1
2
3
4
5
6
7
8
9
0
(3S,4R)-3-Isobutyl-4-(2-nitrophenyl)-3-phenyloxetan-2-one 13: Prepared according to
the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol), KHMDS (0.18
mL, 0.09 mmol), isoꢀbutylphenylketene (167 mg, 1.00 mmol) and 2ꢀ
nitrobenzaldehyde (181 mg, 1.20 mmol) in toluene (10 mL) at −50 °C for 6 h. The
crude product (dr 94:6 syn:anti) was purified by silica gel chromatography(95:5
20
petrol:Et
2
O) to give synꢀ13 (95 mg, 30%) as off white solid. mp 78−80 °C;
[α
]D 0.0
(c 0.3, CHCl
3
); Chiral HPLC analysis Chiralpak OJꢀH (5% IPA:hexane, flow rate 1.0
ꢀ1
ꢀ1
mL min , 220 nm) t : 10.6 min, t : 12.3 min, <10% ee; ν (KBr)/cm 2958, 1819
R
R
max
(C=O), 1613, 1582, 1521, 1448, 1341, 1243, 1118, 974, 904, 788, 842, 706, 642, 534;
1
H NMR (300 MHz, CDCl
), 1.90 (1H, hep, J 6.6, iꢀBuH) 2.44 (1H, dd, J 14.6, 6.4, iꢀBuCH
dd, J 14.6, 6.4, iꢀBuCH ), 6.20 (1H, s, CHꢀlactone), 7.00−7.11 (5H, m, ArH),
3
) δ
H
0.82 (3H, d, J 6.7, iꢀBuCH
3
), 1.06 (3H, d, J 6.7, iꢀ
BuCH
3
2
), 2.65 (1H,
2
7
.26−7.34 (1H, m, ArHNO
2
), 7.41−7.46 (2H, m, ArHNO
2
), 7.97 (1H, dt, J 8.1, 0.7,
13
1
ArHNO
2
); C{ H} NMR (100 MHz, CDCl ) δ 23.8, 23.9, 25.4, 45.3, 72.2, 80.1,
3
c
1
24.7, 126.7, 127.7, 128.2, 128.5, 129.0, 132.6, 134.0, 134.3, 146.8, 172.0; HRMS
+
(
20 4
ASAP) C19H O N [M+H] requires 326.1387; found 326.1382 (−1.5 ppm).
(3S,4R)-3-Ethyl-3-(4-fluorophenyl)-4-(2-nitrophenyl)oxetan-2-one
14:
Prepared
according to the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol),
KHMDS (0.18 mL, 0.09 mmol), ethylꢀ4ꢀflourophenylketene (211 mg, 1.20 mmol)
and 2ꢀnitrobenzaldehyde (151 mg, 1.00 mmol) in toluene (10 mL) at −50 °C for 3 h.
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The crude product (dr 93:7 syn:anti) was purified by silica gel chromatography (95:5
20
]D
petrol:Et O) to give synꢀ14 (216 mg, 69%) as colourless solid. mp 102−104 °C;
[α
2
−19 (c 0.85, CHCl
3
); Chiral HPLC analysis Chiralpak ASꢀH (5% IPA:hexane, flow
ꢀ1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rate 1.0 mL min , 220 nm) t minor (R,S): 11.1 min, t major (S,R): 12.3 min, 85% ee;
R
R
ꢀ1
ν
max (KBr)/cm 2971, 1831 (C=O), 1614, 1605, 1522, 1319, 1353, 1310, 1299, 1225,
1
1
167, 1144, 1118, 1017, 949, 894, 859, 816, 787, 745, 682, 654, 609, 536, 506; H
NMR (400 MHz, CDCl
3
) δ
.23 (1H, s, CHꢀlactone), 6.74−7.81 (2H, m, 4ꢀFArH), 7.00−7.07 (2H, m, 4ꢀFArH),
.33−7.38 (1H, m, ArHNO ), 7.53 (2H, dd, J 1.0, 4.9, ArHNO ), 8.00 (1H, d, J 8.1,
H
1.15 (3H, t, J 7.4, CH
2
CH
3
), 2.53−2.68 (2H, m, CH
2 3
CH ),
6
7
2
2
1
9
1
13
1
ArHNO ); F{ H} NMR (376 MHz, CDCl ) δ −114; C{ H} NMR (100 MHz,
2
3
F
CDCl
3
) δ
c
9.5, 29.6, 72.4, 79.5, 115.6 (d, J 21.4), 125.0 128.2, 128.7 (d, J 8.2), 129.4,
1
29.7 (d J 3.1) 132.7, 134.3, 146.6, 162.1 (d, J, 248), 172.0; HRMS (ASAP)
+
C
17
H
15FO
4
N [M+H] requires 316.0980; found 316.0974 (−1.8 ppm).
(
3S,4R)-3-(4-Chlorophenyl)-3-ethyl-4-(2-nitrophenyl)oxetan-2-one 15: Prepared
according to the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol),
KHMDS (0.18 mL, 0.09 mmol), ethylꢀ4ꢀchlorophenylketene (181 mg, 1.00 mmol)
and 2ꢀnitrobenzaldehyde (181 mg, 1.20 mmol) in toluene (10 mL) at −50 °C for 3 h h.
The crude product (dr 93:7 syn:anti) was purified by silica gel chromatography (95:5
2
D
0
petrol:Et
2
O) to give synꢀ15 (262mg, 79%) as off white solid. mp 78−80 °C;
[α
]
−15
(
c 0.5, CHCl ); Chiral HPLC analysis Chiralpak ASꢀH (5% IPA:hexane, flow rate 0.5
3
ꢀ1
mL min , 220 nm) t
R
minor (R,S): 22.5 min, t
R
major (S,R): 24.9 min, 86% ee; νmax
ꢀ1
(KBr)/cm 2975, 1822 (C=O), 1614, 1525, 1497, 1343, 1250, 1130, 1014, 939, 900,
1
8
60, 840, 792, 745, 685; H NMR (300 MHz, CDCl
3
H 2 3
) δ 1.14 (3H, t, J 7.4, CH CH ),
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2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
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5
5
6
2.52−2.67 (2H, m, CH
2
CH
3
), 6.22 (1H, s, CHꢀlactone), 6.97−7.08 (4H, m, 4ꢀClArH),
), 7.50−7.55 (2H, m, ArHNO ), 7.98−8.04 (1H, m,
); C{ H} NMR (100 MHz, CDCl ) δ 9.4, 29.6, 72.4, 79.3, 125.0, 128.2,
7
.33−7.41 (1H, m, ArHNO
2
2
1
3
1
ArHNO
2
3
c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
28.3, 128.9, 129.5, 132.5 (2×C), 134.0, 134.4, 146.7, 171.7; HRMS (ASAP)
+
C H ClO N [M+H] requires 332.0684; found 332.0681 (−0.9 ppm).
17
15
4
(3S,4R)-3-(4-Bromophenyl)-3-ethyl-4-(2-nitrophenyl)oxetan-2-one
16:
Prepared
according to the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol),
KHMDS (0.18 mL, 0.09 mmol), ethylꢀ4ꢀbromophenylketene (225 mg, 1.00 mmol)
and 2ꢀnitrobenzaldehyde (181 mg, 1.20 mmol) in toluene (10 mL) at −50 °C for 3 h.
The crude product (dr 94:6 syn:anti) was purified by silica gel chromatography (95:5
20
]D
petrol:Et
2
O) to give synꢀ16 (257mg, 68%) as pale brown solid. mp 102−104 °C;
[α
−14 (c 0.5, CHCl
3
); Chiral HPLC analysis Chiralpak ASꢀH (5% IPA:hexane, flow
ꢀ1
R R
rate 0.2 mL min , 220 nm) t minor (R,S): 56.8 min, t major (S,R): 61.7 min, 92% ee;
ꢀ1
ν
max (KBr)/cm 2974, 1821 (C=O), 1613, 1526, 1494, 1342, 1249, 1129, 1077, 1011,
1
957, 938, 899, 860, 839, 791, 744, 721, 652, 517; H NMR (300 MHz, CDCl
3
) δ
), 6.22 (1H, s, CHꢀlactone),
.91−6.96 (2H, m, 4ꢀBrArH), 7.19−7.23 (2H, m, 4ꢀBrArH), 7.34−7.41 (1H, m,
H
1
.14 (3H, t, J 7.4, CH
2
CH
3
2 3
), 2.52−2.66 (2H, m, CH CH
6
1
3
1
ArHNO
2
), 7.50−7.55 (2H, m, ArHNO
2
2
), 8.00−8.04 (1H, m, ArHNO ); C{ H} NMR
(100 MHz, CDCl
3
) δ
c
9.4, 29.6, 72.5, 79.3, 122.2, 125.0, 128.2, 128.6, 129.5, 131.8,
+
1
32.5, 133.1, 134.5, 146.7, 171.7; HRMS (ASAP) C17
H15BrO
4
N [M+H] requires
376.0184; found 376.0176 (−0.8 ppm).
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(3S,4R)-3-Ethyl-4-(2-nitrophenyl)-3-(p-tolyl)oxetan-2-one 17: Prepared according to
the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol), KHMDS (0.18
mL, 0.09 mmol), ethylꢀ4ꢀtolylketene (167 mg, 1.00 mmol) and 2ꢀnitrobenzaldehyde
(181 mg, 1.20 mmol) in toluene (10 mL) at −50 °C for 3 h. The crude product (dr
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
90:10 syn:anti) was purified by silica gel chromatography (95:5 petrol:Et
2
O) to give
);
20
synꢀ17 (162 mg, 52%) as off white solid. mp 100−102 °C;
[α
]D −39 (c 0.25, CHCl
3
ꢀ1
Chiral HPLC analysis Chiralpak ADꢀH (5% IPA:hexane, flow rate 1.0 mL min , 220
ꢀ1
nm) t
R
minor (R,S): 9.6 min, t
R
major (S,R): 10.5 min, 83% ee; νmax (KBr)/cm 2975,
1
6
825 (C=O), 1612, 1526, 1341, 1236, 1134, 1104, 951, 937, 890, 858, 837, 742, 722,
1
97, 520; H NMR (300 MHz, CDCl
3
H 2 3
) δ 1.14 (3H, t, J 7.4, CH CH ), 2.14 (3H, s,
ArCH ), 2.52−2.66 (2H, m, CH CH ), 6.23 (1H, s, CHꢀlactone), 6.82−6.93 (4H, m, 4ꢀ
3
2
3
tolylArH), 7.31 (1H, ddd, J 8.5, 6.8, 1.8, ArHNO
2
), 7.47−7.55 (2H, m, ArHNO
2
),
1
3
1
7
.98 (1H, dd, J 8.3, 1.1, ArHNO
2
); C{ H} NMR (75 MHz, CDCl ) δ 9.5, 21.0, 29.5,
3
c
7
2.7, 79.6, 124.8, 126.7, 128.3, 129.1, 129.3, 130.7, 133.0, 134.2, 137.6, 146.5, 172.4;
+
HRMS (ASAP) C18
H
18
O
4
N [M+H] requires 312.1230; found 312.1226 (−1.4 ppm).
(3S,4R)-3-Ethyl-3-(4-methoxyphenyl)-4-(2-nitrophenyl)oxetan-2-one 18: Prepared
according to the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol),
KHMDS (0.18 mL, 0.09 mmol), ethylꢀ4ꢀmethoxyphenylketene (211 mg, 1.20 mmol)
and 2ꢀnitrobenzaldehyde (151 mg, 1.00 mmol) in toluene (10 mL) at −50 °C for 3 h.
The crude product (dr 86:14 syn:anti) was purified by silica gel chromatography
(
90:10 petrol:Et
2
O) to give synꢀ18 (247 mg, 75%) as off white solid. mp 58−64 °C;
−57 (c 0.25, CHCl ); Chiral HPLC analysis Chiralpak ASꢀH (10% IPA:hexane,
flow rate 0.8 mL min , 220 nm) t major (S, R): 18.5 min, t minor (R,S): 20.4 min,
20
[
α
]
3
D
ꢀ1
R
R
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9
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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4
4
4
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5
5
5
5
5
5
5
6
ꢀ
1
86% ee; νmax (KBr)/cm 2974, 1828 (C=O), 1612, 1578, 1527, 1465, 1300, 1254,
1
1
185, 1109, 945, 895, 837, 791, 742, 699, 686 H NMR (300 MHz, CDCl
3
) δ
), 6.21 (1H,
s, CHꢀlactone), 6.57 (2H, d, J 8.9, 4ꢀMeOArH), 6.93 (2H, d, J 8.9, 4ꢀMeOArH), 7.31
H
1.13
(3H, t, J 7.4, CH
2
CH
3
2 3 3
), 2.51−2.64 (2H, m, CH CH ), 3.63 (3H, s, ArOCH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1H, ddd, J 8.6, 6.7, 2.1, ArHNO ), 7.47−7.55 (2H, m , ArHNO ), 7.96 (1H, dd, J 8.3,
2
2
13
1
0
.9, ArHNO
2
); C{ H} NMR (75 MHz, CDCl
3
) δ
c
9.4, 29.4, 55.1, 72.3, 79.7, 113.9,
124.8, 125.7, 128.0, 128.2, 129.0, 133.0, 134.2, 146.4, 158.9, 172.4; HRMS (ASAP)
+
C
18
H
18
O
5
N [M+H] requires 328.1179; found 328.1175 (−1.8 ppm).
3-Isopropyl-4-(2-nitrophenyl)-3-(thiophen-3-yl)oxetan-2-one 19: Prepared according
to the general procedure from NHC precursor 3 (57.0 mg, 0.10 mmol), KHMDS (0.18
mL, 0.09 mmol), isopropylꢀ3ꢀthionylketene (180 mg, 1.00 mmol) and 2ꢀ
nitrobenzaldehyde (181 mg, 1.20 mmol) in toluene (10 mL) at 0 °C to rt over 12 h.
The crude product (dr 45:55 syn:anti) was purified by silica gel chromatography (97:3
petrol:Et
2
O) to give synꢀ19 (73 mg, 23%) as pale brown solid and antiꢀ19 (38 mg,
20
1
2%) as off white solid. syn-19: mp 114 °C;
[α
]D −24 (c 0.15, CHCl
3
); Chiral HPLC
ꢀ1
analysis Chiralpak OJꢀH (2% IPA:hexane, flow rate 0.5 mL min , 220 nm) t major
R
ꢀ1
(S,R): 44.0 min, t
R
minor (R,S): 49.8 min, 58% ee; νmax (KBr)/cm 2978, 1825 (C=O),
1
1
613, 1577, 1522, 1342, 1244, 953, 896, 857, 784, 744, 705, 688, 622; H NMR (300
MHz, CDCl
hep, J 6.8, iꢀPrH), 6.37 (1H, s, CHꢀlactone), 6.56 (1H, dd, J 4.9, 1.5, thiopheneArH),
.97−7.01 (2H, m, thiopheneArH), 7.30−7.38 (1H, m, ArHNO ), 7.50 (2H, d, J 3.9,
ArHNO ), 8.01 (1H, dt, J 8.1, 0.8, ArHNO ); C{ H} NMR (100 MHz, CDCl ) δ
3
) δ
H 3 3
0.96 (3H, d, J 6.8, iꢀPrCH ), 1.45 (3H, d, J 6.8, iꢀPrCH ), 2.87 (1H,
6
2
1
3
1
2
2
3
c
18.4, 19.0, 32.8, 74.5, 76.9, 123.0, 124.7, 125.2, 126.7, 128.3, 129.1, 133.2, 134.2,
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+
135.0, 146.6, 171.2; HRMS (ASAP) C16
H
16
O
4
NS [M+H] requires 318.0795; found
20
3
18.0791 (−1.1 ppm); anti-19: mp 138−142 °C;
[α
]D +40 (c 0.1, CHCl ); Chiral
3
ꢀ1
HPLC analysis Chiralpak OJꢀH (2% IPA:hexane, flow rate 1.0 mL min , 220 nm) t
R
ꢀ1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
major (S,S): 28.8 min, t
minor (R,R): 43.2 min, 92% ee; νmax (KBr)/cm 2974, 1818
R
(
C=O), 1613, 1535, 1469, 1389, 1344, 1261, 1227, 1192, 1143, 1121, 995, 955, 902,
1
8
83, 863, 831, 790, 744, 710, 686, 638; H NMR (300 MHz, CDCl
3
H
) δ 0.41 (3H, d, J
6.7, iꢀPrCH
3
), 0.93 (3H, d, J 6.8, iꢀPrCH ), 2.19 (1H, hep, J 6.7, iꢀPrH) 6.32 (1H, s,
3
CHꢀlactone), 7.40 (1H, dd, J 5.1, 3.0, thiopheneArH), 7.46 (1H, dd, J 5.1, 1.3,
thiopheneArH), 7.61ꢀ7.68 (2H, m, thiopheneArH and ArHNO ), 7.82 (1H, tdd, J 7.9,
2
1
.5, 0.4, ArHNO
2
), 7.93 (1H, dd, J 8.0, 1.3, ArHNO
2
), 8.22 (1H, dd, J 8.2, 1.3,
1
3
1
ArHNO ); C{ H} NMR (100 MHz, CDCl ) δ 16.8, 18.2, 29.3, 71.9, 79.0, 124.4,
2
3
c
1
25.5, 125.6, 128.5, 129.8, 130.1, 131.8, 133.8, 134.2, 148.3, 171.8; HRMS (ASAP)
+
C
16
H
16
O
4
NS [M+H] requires 318.0795; found 318.0788 (−2.1 ppm).
3-Ethyl-3-phenyl-4-(pyridin-4-yl)oxetan-2-one 20: Prepared according to the general
procedure from NHC precursor 3 (57.0 mg, 0.10 mmol), KHMDS (0.18 mL, 0.09
mmol), ethylphenylketene (175 mg, 1.2 mmol) and 4ꢀpyridinecarboxaldehyde (94 ꢀL,
1.0 mmol) in toluene (20 mL) at −50 °C for 2 h. The crude product (dr 17:83,
syn:anti) was purified by silica gel chromatography (50:50 petrol:Et
2
O) to give antiꢀ
2
0 (174 mg, 67%) as colourless solid and synꢀ20 (21 mg, 8% yield) as colourless solid.
2
D
0
1
anti-20: mp 74−82 °C;
[
α
]
+18.0 (c 1.00, CHCl
3
); H NMR (400 MHz, CDCl
), 2.30−2.37 (1H, m, CH CH ), 2.38−2.45 (1H, m,
), 5.51 (1H, s, CH(Ar)), 6.97−6.98 (2H, m, PhHꢀ4, PyHꢀ5), 7.02−7.03 (2H,
3
) δ
H
1
.08 (3H, t, J 7.4, CH
2
CH
3
A
H
B
3
CH CH
H
A B
3
1
3
1
d, J 6.0, PhH), 7.08ꢀ7.15 (3H, m, PhH), 8.41 (1H, d, J 4.9, PyHꢀ6); C{ H} NMR
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