Copper-Mediated, Heterogeneous, Enantioselective Intramolecular Buchner Reactions of α-Diazoketones Using Continuous Flow Processing

Article abstract of DOI:10.1021/acs.joc.8b00147

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper-bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

Full text of DOI:10.1021/acs.joc.8b00147

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Copper mediated, heterogeneous, enantioselective intramolecular
Buchner reactions of #-diazoketones using continuous flow processing
Daniel C Crowley, Denis Lynch, and Anita R. Maguire
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00147 • Publication Date (Web): 15 Mar 2018
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Copper mediated, heterogeneous, enantioselective intramolecular Buchner reactions of
αꢀdiazoketones using continuous flow processing
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*
Daniel C. Crowley†, Denis Lynch† and Anita R. Maguire‡
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†
School of Chemistry, Analytical and Biological Chemistry Research Facility, University
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College Cork, Ireland.
‡
School of Chemistry and School of Pharmacy, Analytical and Biological Chemistry
Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College
Cork, Ireland.
*Eꢀmail: a.maguire@ucc.ie
Abstract
Enantioselective intramolecular Buchner reactions of αꢀdiazoketones can be effected using
heterogeneous copper−bis(oxazoline) catalysts in batch or using continuous flow processing
in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For αꢀ
diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst
was comparable with the standard homogeneous catalyzed process.
Introduction
The intramolecular addition of carbenes to aromatic rings, yielding expanded fused ring
systems, has been investigated over many years.1ꢀ6 The intramolecular Buchner reaction is
typically catalyzed by a transition metal to generate an electrophilic carbenoid, which adds to
the adjacent aryl ring forming a norcaradiene (NCD) product, which exists in tautomeric
equilibrium with a cycloheptatriene (CHT) through reversible electrocyclic ring
opening/closing, as evidenced by time averaged signals in 1H NMR (Scheme 1).7,8
Scheme 1. Intramolecular enantioselective aromatic addition.
Diastereocontrol and enantiocontrol in homogeneous transition metal mediated
intramolecular aromatic additions are well
documented.9ꢀ11 In particular,
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copper−bis(oxazoline) complexes are potent asymmetric catalysts, affording excellent
enantioselectivities.12,13 Heterogeneous catalysis of the reaction is highly desirable to aid
product purification and to enable potential reꢀuse of the catalyst.
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9
In recent years, there has been much interest in designing heterogeneous catalyst systems
with bis(oxazoline) ligands that are easily recoverable and reusable.14ꢀ18 Polymerization of a
suitably functionalised bis(oxazoline) ligand, with crossꢀlinkers (coꢀpolymerization) or by
itself (homopolymerization), to form insoluble polymer bound (IPB) catalysts is one such
method of covalent immobilization.19ꢀ21 These heterogeneous catalyst systems have been
applied to a variety of transformations utilizing carbenoid chemistry, principally for
cyclopropanation, but not for the Buchner reaction to date.22
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The work herein, focuses on covalently immobilized bis(oxazoline) ligands complexed to
copper. During the course of this study, the immobilized copper−bis(oxazoline) was used to
perform heterogeneously catalyzed enantioselective, intramolecular Buchner reactions both
in batch and on continuous flow processing platforms. Flow chemistry is attractive due to its
inherent safety features, such as ease of handling labile and hazardous compounds,23ꢀ26
including the αꢀdiazoketones used in this study. It has recently been applied to performing
homogeneous rhodium catalyzed intermolecular Buchner ring expansions.27 A further feature
of continuous flow processing, of which this work aims to take advantage, is the ability to
employ packed bed reactors for solid phase catalysts.28,29
Results and discussion
Four αꢀdiazoketones (1ꢀ4) previously synthesized within our group were selected for
investigation of intramolecular Buchner reactions on flow. These αꢀdiazoketones differ with
respect to the steric and electronic properties of the substituents on the aromatic ring.30
Substrates 1ꢀ3 have previously afforded relatively stable azulenones 23ꢀ25, amenable to
isolation and determination of enantiopurity,13 while substrate 4 has afforded the highest
reported enantioselectivity to date for this process (95% ee).30 Consequently, these αꢀ
diazoketones were expected to provide an accurate assessment of homogeneous vs.
heterogeneous catalysis and batch conditions vs. continuous flow processing as part of this
work. Use of electron donating methoxy substituents was avoided in this study, as the
azulenones formed are complicated by further dynamic processes,31 while substrates bearing an
αꢀhydrogen are known to generate trienone or tetralone products subsequent to carbenoid insertion
and are also vulnerable to epimerisation,2 and so were not explored during this work. The synthetic
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route to αꢀdiazoketones 1, 2 and 4 began with preparation of their analogous carboxylic acids
5ꢀ7 via Friedel−Crafts alkylation (Table 1).
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Table 1. Synthesis of carboxylic acids (5ꢀ7)
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9
Entry
Acid
R'
H
R''
H
R'''
H
Yield (%)
1
2
3
5
6
7
89
94
92
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H
Cl
H
Me
Me
Me
As this method did not provide exclusively the paraꢀfluoro acid 8, it was synthesized instead
as shown in Scheme 2.32 Ethyl cyanoacetate (9) and acetone were first condensed to form
ethyl 2ꢀcyanoꢀ3ꢀmethylbutꢀ2ꢀenoate (10). This product was then reacted with freshly
prepared 4ꢀfluoromagnesium bromide to form cyanoester 11 which was hydrolyzed to the
corresponding cyanocarboxylic acid 12 and, in turn decarboxylated to 3ꢀmethylꢀ3ꢀ(4ꢀ
fluorophenyl)butanenitrile (13). Finally, this nitrile was hydrolyzed to afford acid 8. While
the synthesis requires five steps, synthetically useful amounts of acid 8 can be readily
accessed by this sequence.
Scheme 2. Synthesis of carboxylic acid 8.
Carboxylic acids 5ꢀ8 were then transformed to the corresponding acyl chlorides with thionyl
chloride (5, 6) or with oxalyl chloride (7, 8). These acyl halides were treated with freshly
prepared diazoethane to afford αꢀdiazoketones 1ꢀ4 (Table 2).
Table 2. Synthesis of αꢀdiazoketones (1ꢀ4)
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Entry Diazo
R'
H
R''
H
R'''
H
Yield (%)
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1
2
3
4
1
2
3
4
83
60
38a
67 a
H
Cl
F
H
H
H
Me
Me
Me
a Isolated yield calculated over two steps from carboxylic acid.
The homogeneous copper catalyst derived from 4ꢀphenyl bis(oxazoline) ligand 14 (Table 3)
has afforded the best enantioselectivities for intramolecular aromatic addition, in comparison
to other commercially available bis(oxazoline) ligands, and accordingly was selected for
immobilization. The suitably functionalized monomer 17 was synthesized using previously
reported methods.33ꢀ36 Following this, Burguete’s methodology for polymerisation and copper
triflate complexation was employed to afford IPB catalyst 19 (Scheme 3).37 The same method
was extended to form IPB catalyst 20 (Scheme 3) by using [Cu(MeCN)4]PF6 in place of
Cu(OTf)2. Thus 19 (TfOꢀ) and 20 (PF6 ) differ in the counterꢀion present – the immobilized
ꢀ
ligand is identical in each case. Atomic absorption spectroscopy (AAS) indicated that the
copper content of 20 is 0.24 mmol/g of catalyst; based on the elemental analysis result for
nitrogen content and assuming all coordination sites of the bis(oxazoline) moieties are
available, the copper content was projected to be 0.16 mmol/g of catalyst. Burguete et al
reported their synthesis of IPB catalyst 19 with a copper content of 0.39 mmol/g.37
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Scheme 3. Synthesis of catalysts 19 and 20
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For the purposes of this work, αꢀdiazoketone 1 was selected as a test substrate for
intramolecular aromatic additions catalyzed heterogeneously with 20 in a batch process
(Table 3). The reaction was monitored by infrared spectroscopy; complete disappearance of
the diazo band (2066 cmꢀ1) was typically seen immediately after addition of the αꢀ
diazoketone was complete. Interestingly, IR monitoring indicates that the heterogeneously
catalyzed reaction proceeds within the same time frame as the homogeneously catalyzed
reaction with no noticeable impact on the rate of the reaction. Notably, the recovered catalyst
changed from its distinctive green colour to dull brown when recovered at the end of the
reaction. However, stirring in tetrahydrofuran returned the catalyst to its initial appearance.
The recovered catalyst, once dry, could then be reꢀused (Table 3, entry 3). The
heterogeneously catalyzed reaction, when conducted in a flask with the immobilized catalyst,
afforded 23 with similar efficiencies and yields (Table 3, entries 2 and 3) to that previously
reported with the related homogeneous catalyst (Table 3, entry 1). Differences in yield
between run 1 and run 2 are associated with losses during chromatography. Examination of
1
the H NMR spectra of the crude products showed that azulenone 23, isolated as a rapidly
equilibrating mixture of tautomeric norcaradiene and cycloheptatriene structures, is the
predominant product 38
.
This equilibration does not impact on the enantioselectivity of the carbenoid
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insertion process as the absolute stereochemistry at Cꢀ8a is fixed during the carbenoid addition and is
retained during the subsequent rapid equilibration between the norcaradiene and cyclohepatriene
structures. The efficiency of the aromatic addition is only marginally reduced relative to the
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homogeneously catalyzed reaction, as evidenced by the ratio of azulenone signals to aromatic
byꢀproduct signals.39
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Table 3 Results for the intramolecular aromatic addition of 1 to form azulenone 23 under batch and flow conditions.
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% eed
Entry
Catalyst
Method Runa Flow rate Efficiency Yield
(%)c
7413
53
65
62
50
55
60
65
41
68
55
33
75
ꢀ
(mL/min)
(%)b
8513
80
1
2
[Cu(MeCN)4]PF6−14 Batch
ꢀ
ꢀ
7813
62
64
61
64
62
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60
55
65
40
32
76
ꢀ
Batch
Batch
Flow
Flow
Flow
Flow
Flow
Flow
Flow
Batche
Flowe
1
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1
1
1
ꢀ
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3
ꢀ
82
4
0.175
0.200
0.250
0.300
0.300
0.300
1.000
ꢀ
78
5
73
6
75
7
78
8
78
9
76
10
11
12
13
14
75
0.060
ꢀ
55
ꢀ
[Cu(MeCN)4]PF6−21 Batch
Batch
1
ꢀ
ꢀ
19
15
16
Batch
Batch
2
3
ꢀ
ꢀ
66
75
55
74
65
66
19
19
a Run refers to use in a single reaction in batch or on flow. b Determined by integration of the aromatic byꢀproduct
signals against those of the azulenone in the 1H NMR spectrum of the crude product. c Purified by column
chromatography. d Determined from chiral shift 1H NMR experiments using (+)ꢀEu(hfc)3. e tBME used as solvent.
Notably, use of heterogeneous IPB catalyst 20 afforded 23 with an enantioselectivity of 62%
ee, reduced from 78% ee with the homogeneous catalyst (Table 3, entries 1 and 2).
Significantly however, when reused under the same conditions, catalyst 20 produced a similar
enantioselectivity (Table 3, entry 3) to its first use. The decreased enantioselection on
immobilization can be rationalized by the altered environment of the bis(oxazoline) ligand in
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the polymer matrix. To explore this further, a bis(oxazoline) ligand 21 with benzyl groups on
the methylene bridge, structurally similar to 20, was prepared. [Cu(MeCN)4]PF6 and ligand
21 were used to homogeneously catalyze the transformation of 1 to azulenone 23. A small
reduction in enantioselectivity (Table 1, entry 13) was noted, albeit to a lesser extent than
with the heterogeneous catalyst, indicating that incorporation of the bis(oxazoline) in the
polymer has a detrimental effect on enantioselectivity.
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Interestingly, the aromatic addition of 1 using catalyst 19 with the triflate counterion did not
yield azulenone 23 (Table 3, entry 14). Unexpectedly, the corresponding tetralone 22 was
isolated, presumably via acid mediated rearrangement of the initially formed azulenone 23,2
due to the presence of either Cu(OTf)2 or triflic acid. It was interesting to note, however, that
when catalyst 19 was recovered and reused under the same conditions, azulenone 23 was
isolated with a yield of 55% and with 65% ee while 22 was not formed (Table 3, entry 15).
When the catalyst was recovered and used for a third time, azulenone 23 was isolated with a
yield of 74% and with 66% ee again without formation of tetralone 22 (Table 3, entry 16). An
unused portion of catalyst 19 was heated to reflux in tetrahydrofuran for 12 hours. When it
was collected by filtration and dried, this material was used to catalyze the formation of
azulenone 23 affording it in a yield of 69% and with 64% ee on its first use, with no evidence
for transformation of 23 to tetralone 22 observed. Heating of catalyst 19 in tetrahydrofuran
appears sufficient to remove any uncoordinated copper(II) triflate or trace quantites of triflic
acid, generating a catalyst which behaves identically to 20 in terms of efficiency and
enantioselectivity produced.
After the initial promising results from the heterogeneous batch reaction, the process was
implemented on a continuous flow platform. A range of experiments were peformed
investigating the optimum flow rate and solvent. The use of tertiary butyl methyl ether
(tBME) was investigated as an alternative solvent as dichloromethane caused the polymeric
t
catalyst to swell leading to high system pressures. While BME ameliorated the problem of
the IPB catalyst (19, 20) swelling, it did not prove to be an efficient solvent with regards to
yield and enantioselectivity in either batch or flow (Table 3, entries 11 and 12) and so
dichloromethane remained the preferred reaction solvent. In our experience, hexane and
acetonitrile are not effective solvents for the Buchner reaction, while use of solvents such as
THF, toluene or xylene was not feasible due to potential competing reactions with the
carbenoid. Ultimately, the increased pressures caused by swelling of the polymer with
dichloromethane were overcome by inclusion of glass wool with the polymer in the column,
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thereby accommodating expansion without increased pressure. Flow rate did not appear to
impact efficiency, yield or enantioselectivity, with comparable results achieved at a flow rate
as high as 1 mL/min (Table 3, entries 4−10). For an optimised reaction, a CH2Cl2 solution
(0.0338 M) of αꢀdiazoketone 1 was pumped through a packed bed reactor loaded with
catalyst 19 (10 mol % copper relative to the portion of diazoketone employed in each run) at
45°C (Table 3, entry 10). After the experiment, tetrahydrofuran was pumped through the
column (at 1 mL/min for 15 min at room temperature) in order to recover the catalyst which
was used in subsequent reactions. The yields and enantioselectivities afforded by the
transformation on flow (Table 3, entry 4) are comparable to the results from the
heterogeneously catalysed batch reaction. One portion of catalyst 20 was utilised and
recovered in eight separate reaction runs. It was used twice in batch and six times on flow.
The catalyst exhibited excellent reusability up to its seventh use, between batch and flow
processes (Table 3, entries 2−8). However, the performance of the catalyst subsequently
dropped, with a lower yield and enantioselectivity recorded for azulenone 23 on run 8 (Table
3, entry 9). Freshly prepared catalyst 20 has a copper content of 0.24 mmol/g of catalyst, as
determined by atomic absorption spectroscopy. The catalyst that was recovered after run 8,
however, had a reduced copper content of 0.19 mmol/g of catalyst, consistent with slow
leaching of the copper over time. The performance of catalyst 20 in comparison with its
copper content is illustrated in Figure 1.
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Figure 1 Comparison of efficiencies and enantioselectivities of heterogeneous aromatic addition with copper content
of catalyst 20
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90
80
70
60
50
40
30
20
10
0
0.25
0.2
0.15
0.1
10
11
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19
20
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Efficiency (%)
ee (%)
Cu (mmol/g)
0.05
0
Run 1 Run 2 Run 3 Run 4 Run 5 Run 6 Run 7 Run 8
Following these results, the substrate scope was expanded to αꢀdiazoketones 2, 3 and 4
(Table 4). Unlike 23, azulenones 24 and 25 were afforded with comparable enantioselectivity
to the analogous homogeneously catalyzed batch reaction, albeit with reduced efficiency
(Table 4, entries 4 and 5). Performing this reaction on flow, with the heterogeneous catalyst
did not have a deleterious effect on enantioselectivity. Notably, azulenones 24, 25 and 26
were afforded with the same enantioselectivity from reactions catalyzed by homogeneous
[Cu(MeCN)4]PF6−14 catalyst or heterogeneous catalyst 20 in either batch or flow (Table 4,
entries 4−10). As the trimethyl substituted azulenone 26 is highly labile, the transformation
was carried out at room temperature and the product was not isolated. Instead, it was
immediately trapped with a dienophile, 4ꢀphenylꢀ1,2,4ꢀtriazolineꢀ3,5ꢀdione (PTAD), to give a
stable cycloadduct 27 whose enantioselectivity was determined by chiral HPLC (Scheme 4).
As with the unsubstituted azulenone 23, there was a decrease in enantioselectivity observed
for the reaction to form 26 (from 95% ee to 83ꢀ85% ee) when catalyzed heterogeneously in
either batch or flow (Table 4, entries 3, 6 and 10). It is interesting to note that the efficiency
of formation of the labile azulenone 26 using the heterogeneous catalyst 20 is notably higher
when conducted in flow than in batch (63 vs 25%, Table 4, entries 6 and 10); this is
rationalised by decreased degradation of the labile azulenone due to removal from the copper
catalyst as it is formed.
Table 4. Comparison of heterogeneously catalyzed aromatic additions on flow and batch with homogeneously
catalyzed aromatic additions in batch.
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Entry Method Diazo R1
ketone
R2
Cl
F
R3 Azulenone
Catalyst
Yield
(%)a
6313
Efficiency
(%)b
% ee
6213
1
2
3
Batch
Batch
Batchc
H
H
[Cu(MeCN)4]PF6
9513
2
3
4
24
−
14
[Cu(MeCN)4]PF6
14
[Cu(MeCN)4]PF6
14
20
H
H
7413
8113
5613
25
−
Me Me Me
ꢀ
ꢀ
9512,30
26
−
4
5
Batch
Batch
Batchc
Flow
H
H
Cl
F
H
H
65
55
ꢀ
ꢀ
65d
52d
85e
64d
57d
56d
83e
2
3
4
2
24
25
26
24
25
25
26
ꢀ
20
20
20
19
20
20
6
Me Me Me
25
70
65
56
63
7
H
H
H
Cl
F
H
H
H
65
52
49
ꢀ
8
Flow
3
9
Flow
Flowc
F
3
4
10
Me Me Me
a Purified by column chromatography. b Determined by integration of the aromatic byꢀproduct signals against those of the
azulenone in the 1H NMR spectrum of the crude product. c Reaction carried out at room temperature. d Determined from
chiral shift 1H NMR experiments using (+)ꢀEu(hfc)3. e Enantioselectivity of PTAD cycloadduct determined by chiral HPLC.
Scheme 4. Synthesis of PTAD cycladduct
The enantioselectivities achieved with the heterogeneous catalyst in both batch and flow for
the four azulenones (23ꢀ26) are compared in Figure 2 with the enantioselectivities previously
reported for the homogeneously catalyzed transformations in batch. Importantly, Figure 2
illustrates that enantioselectivity of the reaction is not affected by the performing the process
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on flow. The reduced enantioselectivity observed for azulenones 23 and 26 appears to be as a
4
5
result of using an immobilized catalyst.
6
7
8
9
Figure 2 Comparison of enantioselectivities of the heterogeneously catalyzed aromatic additions in flow and batch
conditions with the homogeneously catalyzed aromatic additions in batch conditions.
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11
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60
100
90
80
70
60
Homogenenous Batch (% ee)
50
Heterogeneous Batch (% ee)
40
Heterogeneous Flow (% ee)
30
20
10
0
26 (R1, R2, 23 (R2 = H) 24 (R2 = Cl) 25 (R2 = F)
R3 = Me)
In conclusion, enantioselective intramolecular Buchner reactions can be effected using
immobilized copper–bis(oxazoline) catalysts in batch or continuous flow; efficiencies and
reaction rates are comparable to the analogous homogeneous reactions, and, while for some
substrates the enantioselectivity was somewhat decreased, this appears to be solely due to
catalyst immobilization and not affected in any way by use of continuous flow. For αꢀ
diazoketones 2 and 3, the enantioselectivities were comparable to those seen under
homogeneous conditions. Critically, reuse of the heterogeneous catalysts up to 7 times
without deterioration in efficiency and enantioselection has been demonstrated. While
generation of the azulenone in flow does not offer any direct synthetic benefit, in terms of
yield and stereoselectivity, over the batch reaction, one key advantage is that the
enantioselective IPB catalyst can be easily reused in multiple reactions on flow. Furthermore,
in recent years we have demonstrated the safe and efficient generation of diazo compounds in
continuous flow.40,41 Clearly, the potential to couple the synthesis of the diazo precursors
using this methodology with the asymmetric copper catalyzed transformation would enable
use of the synthetic power of αꢀdiazocarbonyl chemistry without handling the hazardous
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precursors at any point. Use of continuous flow processing for reactions of potentially
hazardous reagents such as αꢀdiazoketones offers clear safety advantages, particularly for
scaleꢀup.
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Experimental Section
General Procedures
Solvents were distilled prior to use as follows: dichloromethane was distilled from
phosphorus pentoxide and when used for diazoketone reactions was further distilled from
calcium hydride, ethyl acetate was distilled from potassium carbonate, hexane was distilled
prior to use. Organic phases were dried using anhydrous magnesium sulfate. All commercial
reagents were used without further purification unless otherwise stated.
1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded on a Bruker Avance 300
MHz NMR spectrometer. H (400 MHz) and 13C (100.6 MHz) NMR spectra were recorded
1
on a Bruker Avance 400 MHz NMR spectrometer. All spectra were recorded at 300 K in
deuterated chloroform (CDCl3) unless otherwise stated, using tetramethylsilane (TMS) as
internal standard. Chemical shifts (δH and δC) are reported in parts per million (ppm) relative
1
to TMS and coupling constants are expressed in hertz (Hz). Splitting patterns in H spectra
are designated as s (singlet), bs (broad singlet), d (doublet), bd (broad doublet), t (triplet), bt
(broad triplet), q (quartet), qu (quintet), dd (doublet of doublets), dt (doublet of triplets), dq
(doublet of quartets), ddd (doublet of doublet of doublets), td (triplet of doublets), ddt
(doublet of doublet of triplets), and (m) multiplet. NMR signal assignments were confirmed
with the support of DEPT spectra and correlations detected using COSY, HETCOR, HSQC
and HMBC experiments.
Infrared spectra were measured using a Perkin Elmer FTIR UATR2 spectrometer, or as
potassium bromide discs (for solids) or were recorded as thin films on sodium chloride plates
(for liquids) on a PerkinꢀElmer Paragon 1000 FTꢀIR spectrometer.
Wet flash column chromatography was carried out using Kieselgel silica gel 60, 0.040ꢀ0.063
mm (Merck). Thin layer chromatography (TLC) was carried out on preꢀcoated silica gel
plates (Merck 60 PF254). Visualisation was achieved by UV (254 nm) light absorption.
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Elemental analysis was carried out by Microanalysis Laboratory, National University of
Ireland, Cork, using PerkinꢀElmer 240 and Exeter Analytical CE440 elemental analysers.
Low resolution mass spectra (LRMS) were recorded on a Waters Quattro Micro triple
quadrupole instrument in electrospray ionization (ESI) mode using 50% acetonitrile−water
containing 0.1% formic acid as eluent. High resolution (precise) mass spectra (HRMS) were
recorded on a Waters LCT Premier Tof LCꢀMS instrument in electrospray ionization (ESI)
mode using 50% acetonitrile−water containing 0.1% formic acid as eluent, or on a Kratos
Profile HVꢀ4double focusing high resolution mass spectrometer (EI). Samples were prepared
for either LRMS or HRMS by employing acetonitrile as solvent.
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11
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23
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26
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57
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60
Atomic absorption spectroscopy was performed on an Agilent 240 AA instrument.
Melting points were obtained using a uniꢀmelt Thomas Hoover Capillary melting point
apparatus and are uncorrected. Microwave assisted synthesis was achieved using the CEM
Discover Labmate Synthesiser in conjunction with ChemDriver software (Version 3.5.0) and
the CEM Discover SꢀClass Synthesiser in conjunction with Synergy software. Microwave
temperatures are monitored by a non contact infrared temperature control system. All
continuous processes were performed using a Vapourtec RꢀSeries flow reactor consisting of
four pumps and a glass reactor manifold containing a temperature controlled glass Omnifit®
column. To prepare the reactor for operation, pumps were purged with dichloromethane prior
to use. All reaction tubing, coils, inlets and connections were also purged thoroughly in a
similar manner. Enantiopurity of chiral compounds was determined by chiral stationary phase
high performance liquid chromatography (HPLC) performed on a Chiralcel® ODꢀH column.
HPLC analysis was performed on a Waters alliance 2690 separations module. Chiral
stationary phase HPLC analysis of PTAD adduct 27 was performed using a Chiracel® ODꢀH
column at room temperature with isopropanol:hexane (10:90) as eluent, using a flow rate of
0.5 mL/min and the detector set at λ 229 nm. Samples were prepared at a concentration of
approximately 1 mg/mL in IPA and an injection volume of 25 ꢁL was used. Under these
conditions, (+)ꢀ27 elutes at 19.0 min and (–)ꢀ27 elutes at 21.6 min. All chiral columns were
purchased from Daicel Chemical Industries Limited. Low temperature chiral stationary phase
HPLC analysis was conducted using an IglooꢀCil® column cooler. Optical rotations were
measured at 589 nm in a 10 cm cell on a PerkinꢀElmer 141 polarimeter or on a Rudolph
Autopol V Plus polarimeter; concentrations (c) are expressed in g/100 mL. [α] is the specific
rotation of a compound and is expressed in units of 10−1 deg cm2 g−1.
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Homogeneous catalysis of azulenone formation using a copper−bis(oxazoline) system was
carried out in accordance with literature precedent.12,30
6
7
Synthesis of precursors
8
9
3ꢀMethylꢀ3ꢀphenylbutanoic acid (5) 42
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11
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Benzene (100 mL) was added to a 1 L twoꢀneck flask that was
O
then placed in an ice bath and then charged with dimethylacrylic
OH
acid (5.00 g, 49.9 mmol) while stirring. Aluminium trichloride
(12.50 g, 93.8 mmol) was added very slowly. The ice bath was
removed and the mixture was stirred at room temperature for 48
h. The reaction was quenched by adding it into a 250 mL conical flask containing aq. 10%
HCl (25 mL) and ice (100 g). The yellow organic layer was removed and the aqueous layer
was washed with diethyl ether (2 x 35 mL). The combined organic layers were washed with
20% aq. NaOH (2 x 50 mL). The aqueous layer was then acidified to pH 1 with conc. aq. HCl
and washed with diethyl ether (3 x 40 mL). The organic layers were collected and washed
with brine, dried, filtered and solvent removed under reduced pressure to yield the acid 5 as a
pale yellow solid (5.88 g, 66%). m.p. 54ꢀ56°C (Lit.,42 57ꢀ58°C); νmax/cm−1 (ATR) 2978 br
(OH), 1700 (CO), 1498, 1440, 1409, 1317; δH (400 MHz) 1.47 [6H, s, C(3)C
2.56 [2H, s, C(2) 2], 7.18ꢀ7.37 (5H, m, Ar
). δC{1H}(75.5 MHz) 28.8 [CH3, C(3)
(3)], 48.0 [CH2, (2)H2], 125.4, 126.1, 128.3 {3 x CH, [ (2')H, (6')H,
(4')H]}, 148.0 [C, (1')], 178.0 [C, (1)=O].
H
3, C(4)H3],
H
H
C
H3,
C
C
(4)H3], 37.0 [C,
C
C
C
C
(3')H, (5')H and
C
C
C
C
3ꢀMethylꢀ3ꢀ(4ꢀchlorophenyl)butanoic acid (6) 42
This compound was prepared, using the procedure outlined
for 3ꢀmethylꢀ3ꢀphenylbutanoic acid, from chlorobenzene
(150 mL), dimethylacrylic acid (7.50 g, 74.9 mmol) and
aluminium trichloride (18.75 g, 140.6 mmol) to yield the
acid 6 as a pale yellow solid (14.98 g, 94%). m.p. 64ꢀ66°C
O
OH
Cl
(Lit.,43 66ꢀ67°C); νmax/cm−1 (ATR) 2973 br (OH), 1699 (CO), 1494, 1438, 1321; δH (400
MHz) 1.43 [6H, s, C(3)C 3, C(4) 3], 2.62 [2H, s, C(2) 2], 7.20ꢀ7.35 (4H, m, Ar ).
δC{1H}(75.5 MHz) 28.9 [CH3, C(3)
H3, (4)H3], 36.8 [C, (3)], 47.8 [CH2, (2)H2], 127.0,
H
H
H
H
C
C
C
C
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128.3 {2 x CH, [
C(2')H, C(6')H and C(3')H, C(5')H]}, 131.8 [C, C(1')], 146.4 [C, C(4')Cl],
4
5
177.6 [C, (1)=O].
C
6
7
8
9
3ꢀMethylꢀ3ꢀ(3,4,5ꢀtrimethylphenyl)butanoic acid (7) 44
This compound was prepared, using the procedure outlined
for 3ꢀmethylꢀ3ꢀphenylbutanoic acid, from 1,2,3ꢀ
O
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trimethylbenzene (20 mL, 148.8 mmol), dimethylacrylic
acid (3.11 g, 31.1 mmol) and aluminium trichloride (8.22 g,
61.6 mmol) to yield the acid 7 as a pale brown solid (6.33 g,
92%). m.p 101ꢀ108°C (Lit.,44 112ꢀ113°C); νmax/cm−1 (ATR)
OH
2957 br (OH), 1703 (CO), 1644 1415; δH (300 MHz) 1.43 [6H, s, C(3)C
[3H, s, C(4′)C 3], 2.28 [6H, s, C(3′)C 3, C(5′)C 3], 2.63 [2H, s, C(2)
C(2′) , C(6′) H3], 20.9 [CH3, C(3')
C{1H}(75.5 MHz) 15.0 [CH3, C(4')
28.8 [CH3, C(3) H3, (4)H3], 36.5 [C, (3)], 47.9 [CH2, (2)H2], 124.6 [CH,
(1') or (4')], 136.1 [C, (3'), (5')], 145.0 [C, (1') or (4')], 177.2 [C,
H
3, C(4)
2], 7.00 [2H, s,
H3, C(5') H3],
(2')H,
H3], 2.14
H
H
H
H
H
H].
δ
C
C
C
C
C
C
C
C
C
C
(6')H], 132.8 [C,
(1)].
C
C
C
C
C
C
Ethyl 2ꢀcyanoꢀ3ꢀmethylbutꢀ2ꢀenoate (10) 32
A 500 mL round bottom flask was charged with
β
ꢀalanine (0.14 g,
O
0.15 mmol), ethyl cyanoacetate (9) (31.8 mL, 299 mmol), acetone
(104 mL, 1.41 mol), acetic acid (6 mL) and benzene (70 mL). The
contents of the flask were heated to reflux for 70 h using a
OEt
CN
Dean−Stark trap. Purification by vacuum distillation gave the ester 10 as a white low melting
solid with about 8% percent ethyl cyanoacetate starting material present by 1H NMR analysis.
b.p 115°C at 14 mmHg; νmax/cm−1 (film) 2986, 2227 (CN), 1732 (CO), 1612, 1444, 1371,
1335, 1285, 1086; δH (300 MHz) 1.34 [3H, t,
J 7.12, CH2CH3], 2.31, 2.41 [2 × 3H, 2 × s,
C(3)C 3, C(4)C 3], 4.27 [2H, q, 7.13, C 2CH3].
H
H
J
H
Ethyl cyanoacetate; δH (300 MHz) 3.50 [2H, s, C(2)
were obscured by those of the product ester.
H2]. N.B. Peaks for CH2CH3, CH2CH3
Ethyl 2ꢀcyanoꢀ3ꢀmethylꢀ3ꢀ(4ꢀfluorophenyl)butanoate (11) 32
Ethyl 2ꢀcyanoꢀ3ꢀmethylbutꢀ2ꢀenoate 10 (7.34 g, 47.91
mmol) was added dropwise to 4ꢀfluorophenyl magnesium
bromide [freshly prepared from magnesium (3.50 g, 144.0
O
OEt
CN
F
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mmol), iodine (one crystal) in ether (60 mL), and 1ꢀfluoroꢀ4ꢀiodobenzene (32.04 g, 144.0
mmol) in diethyl ether (60 mL)] at room temperature under nitrogen and the mixture was
heated to reflux for 12 h. The reaction mixture was cooled to room temperature and carefully
poured into aqueous hydrochloric acid (10%, 50 mL). The layers were separated and the
aqueous layer was washed with diethyl ether (40 mL). The combined organic layers were
washed with brine (20 mL), dried, filtered and concentrated under reduced pressure to give
the crude ester as an orange oil. Purification by flash chromatography using ethyl
acetate/hexane (20:80) as eluent gave the ester 11 as a clear oil (7.80 g, 65%). νmax/cm−1
10
11
12
13
14
15
16
17
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19
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(film) 2982, 2248 (CN), 1741 (CO), 1604, 1513, 1236; δH (400 MHz) 1.08 (3H, t,
CH2C 3), 1.62 [6H, s, C(3)C 3, C(4) 3], 3.72 [1H, s, C(2) ], 4.00ꢀ4.09 (2H, m, C
6.99ꢀ7.07, 7.34ꢀ7.40 {2 x 2H, m, [C(2′) , C(6′) and C(3′) , C(5′) ]}.
H3, (4)H3], 40.6 [C,
(3')H, (5')H], 115.6 [C,
(1')], 161.7 [C, d, 1JCF 247,
(1)]; HRMS (ESI−TOF) m/z: [M+NH4]+ Calcd for C14H20N2O2F 267.1509; Found
J
7.1,
H
H
H
H
H2C
H3),
H
H
H
H
δ
C{1H}(75.5 MHz)
(3)], 50.3 [CH,
N], 127.6
(4')], 164.6
13.7 (CH3, CH2
C
H3), 25.8, 27.3 [2 × CH3, C(3)
C
C
C
2
C
(2)H], 62.3 (CH2,
C
H2CH3), 115.1 [CH, d, JCF 21,
[CH, d, 3JCF 8, C(2')H, C(6')H], 139.3 [C, d, 4JCF 3,
C
C
C
C
C
[C,
C
267.1509. m/z (ESI−) 248 [(M−H)−, 19%], 215 (16%), 176 [(M−CH3CH2OCO)−, 22%], 152
(51%), 139 (81%), 127 (19%), 113 (42%), 95 [(CH3C6H4)−, 100%].
2ꢀCyanoꢀ3ꢀmethylꢀ3ꢀ(4ꢀfluorophenyl)butanoic acid (12)
Ethylꢀ2ꢀcyanoꢀ3ꢀmethylꢀ3ꢀ(4ꢀfluorophenyl)butanoate
11
O
(7.36 g, 29.5 mmol) was stirred with sodium hydroxide
pellets (4.72 g, 118.0 mmol) in ethanol (95%, 25 mL) for 12
h. The solution was acidified to pH 2 using aqueous
hydrochloric acid (10%). The aqueous layer was extracted
OH
CN
F
with diethyl ether (3 × 40 mL). The combined organic layers were washed with water (50
mL), brine (50 mL), dried, filtered and concentrated under reduced pressure to give the crude
acid 12 as a yellow oil (3.21 g, 75%). νmax/cm−1 (film) 2980 br (OH), 1728, 1604, 1513; δH
(400 MHz) 1.63, 1.64 [2 × 3H, 2 × s, C(3)C
7.40 {2 x 2H, m, [C(2′) , C(6′) and C(3′)
H
3, C(4) 3], 3.73 [1H, s, C(2)
H
H], 7.01ꢀ7.08, 7.34ꢀ
H
H
H
, C(5′)H]}.
3ꢀMethylꢀ3ꢀ(4ꢀfluorophenyl)butanenitrile (13)
A 100 mL round bottomed flask equipped with a magnetic
stirred bar was charged with 2ꢀcyanoꢀ3ꢀmethylꢀ3ꢀ(4ꢀ
fluorophenyl)butanoic acid 12 (4.91 g, 22.2 mmol). The flask
CN
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was attached to a gas bubbler and subsequently heated in an open vessel microwave reactor
for 30 min at 100 W at 200°C. As 170°C was reached, degassing through the bubbler was
evident. The reaction mixture was cooled to room temperature to give the crude nitrile as a
viscous brown oil. Purification by vacuum distillation gave the nitrile 13 as a yellow oil (2.11
g, 54%). b.p. 110°C at 0.10 mmHg (Lit.45 138ꢀ140°C at 10 mmHg); νmax /cm−1 (film) 2972,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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48
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2250 (CN), 1604, 1513; δH (300 MHz) 1.51 [6H, s, C(3)C
6.99ꢀ7.08, 7.32ꢀ7.37{2 x 2H, 2 x m, [C(3′) , C(5′) ] and [C(2′)
MHz) 28.5 [CH3, C(3) H3, (4)H3], 33.0 [CH2, (2)H2], 36.7 [C,
21.2, (3')H, (5')H], 118.0 [C, (2')H,
(1)], 127.0 [CH, d, 3JCF 8.0,
4JCF 3.3, (1')], 161.5 [C, d, 1JCF 246.0,
(4')].
H3, C(4)H3], 2.59 [2H, s, C(2)H2],
H
H
H
, C(6′)H]}.
δ
C{1H}(75.5
2
C
C
C
C
(3)], 115.4 [CH, d, JCF
C
C
C
C
C(6')H], 141.6 [C, d,
C
C
3ꢀMethylꢀ3ꢀ(4ꢀfluorophenyl)butanoic acid (8) 32,46
A solution of potassium hydroxide (1.57 g, 27.9 mmol) in
ethylene glycol (20 mL) was added to 3ꢀmethylꢀ3ꢀ(4ꢀ
fluorophenyl)butanenitrile 13 (1.55 g, 8.70 mmol) and the
resulting solution was heated under reflux for 12 h. The
solution was then acidified to pH 2 using aqueous
O
OH
F
hydrochloric acid (10%). The aqueous layer was extracted with diethyl ether (3 × 50 mL).
The combined organic layers were washed with aqueous sodium hydroxide (10%, 50 mL),
and then the aqueous layer was acidified to pH 1 with aqueous hydrochloric acid and
extracted with diethyl ether (3 x 50 mL). The combined organic layers were then dried,
filtered and concentrated under reduced pressure to give the pure acid 8 as a viscous, pale
yellow oil (1.01 g, 59%). νmax /cm−1 (film) 2918 br (OH), 1708, 1512, 1232, 833; δH (300
MHz) 1.45 [6H, s, C(3)C
[C(2′) , C(6′) and C(3′)
[C, (3)], 48.1 [CH2, (2)H2], 114.8 [CH, d, JCF 21,
(2')H, C(4')], 177.4 [C, C(1)].
(6')H], 143.6 [C, d, 4JCF 3, (1')], 161.3 [C, 1JCF 244,
H
3, C(4)
H
3], 2.63 [2H, s, C(2)H2], 6.96ꢀ7.01, 7.29ꢀ7.33 {[2 x 2H, m,
H
H
H, C(5′)
H
]}.
δ
C{1H}(75.5 MHz) 29.1 [CH3, C(3)
C
H3,
C
(4)H3], 36.6
2
3
C
C
C
(3')H,
C
(5')H], 127.0 [CH, d, JCF 7,
C
C
C
3ꢀMethylꢀ3ꢀphenylbutanoyl chloride 47
3ꢀMethylꢀ3ꢀphenylbutanoic acid (0.365 g, 2 mmol) and thionyl
chloride (1.17 mL, 16 mmol) were added to a 100 mL round
bottom flask. The reaction was heated to reflux under N2 at
110°C for 3 h. The crude mixture appeared as a brown oil and
O
Cl
was concentrated under reduced pressure. The crude product was purified by bulbꢀtoꢀbulb
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distillation (b.p. 140°C at 0.12 mmHg). The acid chloride was afforded as a clear oil (0.299
4
5
g, 76%). νmax/cm−1 (film) 2971, 1807 (CO), 1497, 1445; δH (400 MHz) 1.48 [6H, s, C(3)CH3
,
6
7
C(4) 3], 3.27 [2H, s, C(2) 2], 7.12ꢀ7.40 (5H, m, Ar ).
H
H
H
8
9
3ꢀMethylꢀ3ꢀ(4ꢀchlorophenyl)butanoyl chloride
10
11
12
13
14
15
16
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This compound was prepared using the procedure outlined
for 3ꢀmethylꢀ3ꢀphenylbutanoyl chloride from 3ꢀmethylꢀ3ꢀ
(4ꢀchlorophenyl)butanoic acid (14.98 g, 70.4 mmol), thionyl
O
Cl
chloride (41.1 mL, 563 mmol) and
(3 drops). The pure acid chloride was afforded as a clear oil
(11.98 g, 62%). b.p. 130°C at 0.6 mmHg; νmax /cm−1 (film) 2971, 1808 (CO), 1596, 1496,
1402; δH (300 MHz) 1.41 [6H, s, C(3)C 3, C(4) 3], 3.27 [2H, s, C(2) 2], 7.21ꢀ7.35 (4H, m,
Ar ).
N,Nꢀdimethylformamide
Cl
H
H
H
H
3ꢀMethylꢀ3ꢀ(3,4,5ꢀtrimethylphenyl)butanoyl chloride
A 100 mL three neck round bottom flask was charged with 3ꢀ
methylꢀ3ꢀ(3,4,5ꢀmethylphenyl)butanoic acid (4.012 g, 18.2
mmol) and diethyl ether (15 mL). The flask was cooled to
0°C in an ice bath and oxalyl chloride (2.0 mL, 23.3 mmol) in
diethyl ether (10 mL) was slowly added to the solution
O
Cl
through an addition funnel. The ice bath was then removed and the flask allowed to reach
room temperature and the reaction mixture was stirred under N2 for 24 h. Following
concentration under reduced pressure, the crude acid chloride was collected as a brown oil
(4.17 g, 96%), which was used immediately without purification. νmax /cm−1 (film) 2968,
1809 (CO), 1599, 1580, 1445, 1386; δH (300 MHz) 1.45 [6H, s, C(3)C 3], 2.14 [3H,
H
3, C(4)H
s, C(4′)C 3], 2.28 [6H, s, C(3′) 3, C(5′) 3], 3.26[2H, s, C(2) 2], 6.91[2H, s, ArH].
H
H
H
H
3ꢀMethylꢀ3ꢀ(4ꢀfluorophenyl)butanoyl chloride
This compound was prepared using the procedure outlined for
3ꢀmethylꢀ3ꢀ(3,4,5ꢀtrimethylphenyl)butanoyl chloride from 3ꢀ
methylꢀ3ꢀ(4ꢀfluorophenyl)butanoic acid (1.40 g, 7.14 mmol)
and oxalyl chloride (2.0 mL, 23.3 mmol) in diethyl ether (30
mL) giving the crude acid chloride as a brown oil (1.47 g,
O
Cl
F
96%), which was used immediately without purification. νmax/cm−1 (film) 2969, 1809 (CO),
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1602, 1513, 1234, 1166, 833; δH (300 MHz) 1.44 [6H, s, C(3)C
H
3, C(4) 3], 3.26 [2H, m,
H
4
5
C(2)H
2], 6.97ꢀ7.08, 7.26ꢀ7.37 {2 x 2H, m, [C(2)
H
, C(6)H
and C(3)H, C(5)H]}.
6
7
Synthesis of αꢀdiazoketones
8
9
Caution: NꢀEthylꢀNꢀnitrosourea is a carcinogen and should be handled with appropriate
10
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care.48
Caution: Diazoethane is both toxic and explosive. All operations should be carried out in a
well ventilated fumehood with adequate shielding. The glassware used for the generation of
diazoethane should have clear glass joints to minimise the risk of explosion. Any items which
come in contact with diazoethane should be washed with aqueous acetic acid before being
removed from the fumehood.
Note: Restricted rotations in the α
ꢀdiazoketones leads to signal broadening in the 1H and 13C
NMR spectra, for example, for the signal associated with the diazocarbon [C(2)=N2].
2ꢀDiazoꢀ5ꢀmethylꢀ5ꢀphenylhexanꢀ3ꢀone (1)
3ꢀMethylꢀ3ꢀphenylbutanoyl chloride (3.94 g, 20.0 mmol) was
dissolved in diethyl ether (200 mL). This solution was added
slowly, over 1 h from an addition funnel, to an ethereal
diazoethane solution [freshly prepared from
NꢀethylꢀNꢀ
nitrosourea (18.2 g, 155 mmol)]49 in a 500 mL round bottom
flask being stirred in a saltꢀice bath under N2, turning the orange solution to yellow. The
resultant solution was then allowed reach room temperature over 3 h while under N2. The
solution was then concentrated under reduced affording the crude product which was purified
by flash chromatography with hexane:ethyl acetate (85:15) as eluent giving diazoketone 1 as
a yellow oil (3.59 g, 83%). νmax/cm−1 (film) 2964, 2061, 1621, 1348, 1266, 1054; δH (300
MHz) 1.47 [6H, s, C(5)C
(5H, m, Ar
). δC{1H}(75.5 MHz) 8.2 [CH ,
(5)], 50.7 [CH2,
148.0 [C, Aromatic
H
3, C(6)
H
3], 1.80 [3H, s, C(1)
(1)H3], 28.5 [CH3,
=N2], 125.5, 126.1, 128.2 [3 x CH, Aromatic
=O]. HRMS (EI) m/z: (MꢀN2)+ Calcd for C13H16O
H
3], 2.69 [2H, s, C(4)
(5) H3, (6)H3], 38.4 [C,
H],
H2], 7.18ꢀ7.37
H
C
C
C
C
3
C
C
(4)H2], 63.8 [C,
], 193.0 [C,
C
C
C
C
188.1202; Found 188.1201. m/z (EI) 188 [(MꢀN2)+ 12%], 173 (28%), 145 (33%), 132 (89%),
119 (100%).
2ꢀDiazoꢀ5ꢀmethylꢀ5ꢀ(4ꢀchlorophenyl)hexanꢀ3ꢀone (2)
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4
5
6
7
8
9
This compound was prepared, using the procedure outlined
for 1, from distilled 3ꢀmethylꢀ3ꢀ(4ꢀchlorophenyl)butanoyl
chloride (11.95 g, 48.50 mmol) in diethyl ether (200 mL)
and an ethereal solution of diazoethane [freshly prepared
O
N2
Cl
from
NꢀethylꢀN
ꢀnitrosourea (45.0 g, 385 mmol)].49 The
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11
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17
18
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29
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crude product was purified by flash chromatography with hexane:ethyl acetate (95:5) as
eluent giving diazoketone 2 a yellow oil (7.30 g, 60%). νmax/cm−1 (film) 2965, 2061, 1621,
1353, 1279, 1011; δH (300 MHz) 1.45 [6H, s, C(5)C
[2H, s, C(4) 2], 7.26ꢀ7.30 [4H, m, Ar
]. δC{1H}(75.5 MHz) 8.1 [CH3,
(5) H3, (6)H3], 38.0 [C, (5)], 50.3 [CH2, (4)H2], 63.6 [C, =N2], 127.0, 128.2 [CH, 2 x
Aromatic H], 131.8, 147.6 [C, 2 x Aromatic ], 192.5 [C,
=O]. HRMS (EI) m/z: (MꢀN2)+.
H
3, C(6)H
3], 1.82 [3H, s, C(1)
H3], 2.68
H
H
C(1)H3], 29.1 [CH3,
C
C
C
C
C
C
C
C
C
Calcd for C H O35Cl 222.0779; Found 222.0811. m/z (EI) 222 (M+ꢀN2).
13 15
2ꢀDiazoꢀ5ꢀmethylꢀ5ꢀ(4ꢀfluorophenyl)hexanꢀ3ꢀone (3)
This compound was prepared, using the procedure outlined
O
for 1, from crude 3ꢀmethylꢀ3ꢀ(4ꢀfluorophenyl)butanoyl
chloride (1.47 g, 7.14 mmol) in diethyl ether (50 mL) and
an ethereal solution of diazoethane [freshly prepared from
N2
F
N
ꢀethylꢀN
ꢀnitrosourea (6.70 g, 57.2 mmol)].49 The crude
product was purified by flash chromatography with hexane:ethyl acetate (95:5) as eluent
giving diazoketone 3 as a yellow oil (0.639 g, 38%). νmax/cm−1 (film) 2967, 2066, 1625; δH
(300 MHz) 1.46 [6H, s, C(5)C
H
3, C(6)
, C(6′)
H3, (6)H3], 38.0 [C,
(3')H,
H
3], 1.81 [3H, s, C(1)
H
3], 2.68 [2H, s, C(4)
H2], 6.96ꢀ
7.02, 7.28ꢀ7.33{2 x 2H, m, [C(2′)
H
H
and C(3′) , C(5′)
H
H
]}.
δ
C{1H}(75.5 MHz) 8.1
[CH3,
C
(1)H3], 28.8 [CH3,
C
(5)
C
C
C
(5)], 50.7 [CH2,
C
(4)H2], 63.7 [C,
(2')H, (6')H],
2
3
C
=N2], 114.8 [CH, d, JCF 20.9,
C
C
(5')H], 127.1 [CH, d, JCF 7.8,
C
C
1
143.6 [C,
C
(1')], 161.2 [C, d, JCF 244.2,
C
(4')], 192.8 [C,
C
(3)]; HRMS (ESI−TOF) m/z:
[(M+H)]+ Calcd for C13H16FN2O 235.1247; Found 235.1240. m/z (ESI+) 235 [(M+H)+,
75%], 207 (54%), 189 (100%), 137 (14%), 123 (48%).
2ꢀDiazoꢀ5ꢀmethylꢀ5ꢀ(3,4,5ꢀtrimethylphenyl)hexanꢀ3ꢀone (4)
This compound was prepared, using the procedure outlined
for 1, from crude 3ꢀmethylꢀ3ꢀ(3,4,5ꢀphenyl)butanoyl
chloride (4.17 g, 17.5 mmol) in diethyl ether (50 mL) and
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an ethereal diazoethane solution [freshly prepared from NꢀethylꢀNꢀnitrosourea (16.50 g, 140.9
4
5
6
7
8
9
mmol)].49 The crude product was purified by flash chromatography with hexane:ethyl acetate
(95:5) as eluent giving diazoketone 4 as a yellow oil (3.13 g, 67%). νmax/cm−1 (film) 2963,
2061, 1712, 1624, 1445, 1346; δH (300 MHz) 1.43 [6H, s, C(5)C
C(1) 3], 2.14 [3H, s, C(4′)C 3], 2.28 [6H, s, C(3′)C 3, C(5′)C 3], 2.68 [2H, s, C(4)C
6.98 [2H, s, C(2′) , C(6′) ]. (1)H3], 15.1 [CH3, (4')CH3],
C{1H}(75.5 MHz) 8.3 [CH3,
20.9 [CH3, C(3') H3, C(5') H3], 28.5 [CH3, (6)H3], 37.9 [C, (5)], 50.7 [CH2,
=N2], 124.7 [CH, (6')H], 132.7 [C, (4')], 136.1 [C, (3'),
(1')], 193.4 [C,
H
3, C(6)H
3], 1.83 [3H, s,
H
H
H
H
H
2],
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11
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14
15
16
17
18
19
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H
H
δ
C
C
C
C
C
(5)C
H3,
C
C
C
C
(4)H2], 63.8 [C,
C
C
(2')H,
C
C
C
(5')], 145.0 [C,
C
C
(1)]; HRMS (ESI−TOF) m/z: [(M+H)]+ Calcd for
C16H23N2O 259.1810; Found 259.1803. m/z (ESI+) 259 [(M+H)+, 46%], 231 (100%), 213
(61%), 147 (27%), 111 (28%), 93 (11%). This ꢀdiazoketone can be stored in a freezer but is
α
labile at room temperature – decomposition has been seen during chromatography and even
during spectroscopic analysis.
Synthesis of azulenones
General procedure for heterogeneously catalyzed reaction in batch
Doubly distilled dichloromethane and catalyst 20 (10 mol%) were added to a flameꢀdried
three neck round bottom flask which was brought to reflux at 40°C under N2. A solution of αꢀ
diazoketone (1 eq) in dichloromethane was added over 20 min to the stirred solution. The
reaction was monitored by IR until the diazo peak was no longer visible. The crude product
was purified by flash chromatography, with hexane:ethyl acetate as eluent, giving azulenone
as a yellow oil. The spectral details were consistent with those described below.
3,8aꢀDihydroꢀ3,3,8aꢀtrimethylazulenꢀ1(2H)ꢀone (23) 12,30
(a) Batch conditions
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Doubly distilled dichloromethane (50 mL)
4
5
6
7
and Rh2(OAc)4 (0.5 mg, 1 mol%) were added
to a flameꢀdried 250 mL three neck round
bottom flask which was brought to reflux at
8
9
40°C under N2. A solution of 1 (0.110 g,
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0.510 mmol) in dichloromethane (50 mL) was added over 20 min to the stirred solution. The
reaction was monitored by IR until the diazo peak was no longer visible. The crude product
was purified by flash chromatography, with hexane:ethyl acetate (85:15) as eluent, giving
azulenone 23 as a yellow oil (0.065 g, 67%). The spectral details were consistent with those
described below.
(b) Continuous flow method
A solution (0.039 M) of diazoketone 1 (0.210 g, 0.971 mmol) in doubly distilled
dichloromethane (25 mL) was prepared. An Omnifit® glass column (150 mm, 6.6 mm
internal diameter) was packed with immobilized catalyst 20 (0.338 g, 10 mol%) along with
glass wool. The solution of 1 (14 mL) was pumped at 1.0 mL/min through the polymer
contained within the column while the column was heated at 45°C. The reaction stream then
passed through a tube (32 cm) and back pressure regulator (8 bar), after which the crude
azulenone was collected as a yellow solution. Tetrahydrofuran was pumped through the
column after the reaction stream in order to recover the polymer, removing the brown
discolouration and returning its original green colour. The crude product was purified by
flash chromatography, with hexane:ethyl acetate (95:05) as eluent, giving azulenone 23 as a
yellow oil (0.072 g, 70%). νmax/cm−1 (film) 3042, 2926, 1747 (CO), 1715 (CO); δH (400
MHz) 0.76 [3H, s, C(8a)C
17.3, one of C(2) 2], 2.28 [1H, B of AB, JAB 17.3, one of C(2)
C(8) ], 6.07ꢀ6.14 [1H, m, C(7) ], 6.23ꢀ6.43 [3H, m, C(4)
C{1H}(75.5 MHz) 11.43 [CH , C(8a)
H3], 28.6, 28.8 [2 x CH3, 2 x C(3)
(2)H2], 84.9 [CH, (8)H], 109.6 [C, (3a)], 119.7, 125.3,
(7)H], 218.5 [C,
=O]. Found HRMS (EI) m/z: [M]+ Calcd
H
3], 1.14, 1.31 [2 × 3H, 2 × s, C(3)(C
H
3)2], 2.20 [1H, A of AB, JAB
2], 4.18 [1H, d, 8.0,
, C(5) , C(6) ].
H3], 38.6 [C,
H
H
J
H
H
H
H
H
δ
C
C
3
C
(8a)], 40.7 [C,
C
(3)], 50.1 [CH2,
(4)H –
C
C
C
126.8, 127.1 [4 x CH,
C
C
C
for C13H16O 188.1187; Found 188.1201. m/z (EI) 188 [(M)+, 22%], 173 (42%), 145 (40%),
132 (100%), 104 (57%).
3,8aꢀDihydroꢀ6ꢀchloroꢀ3,3,8aꢀtrimethylazulenꢀ1(2H)ꢀone (24) 30
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(a) Batch conditions
4
5
6
This compound was prepared,
using the procedure outlined for
23, from diazoketone 2 (0.160 g,
0.64 mmol) in doubly distilled
dichloromethane (50 mL) and
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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33
34
35
36
37
38
39
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43
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46
47
48
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50
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59
60
Rh2(OAc)4 (0. 5 mg, 1 mol%). The crude product was purified by flash chromatography, with
hexane:ethyl acetate (97:3) as eluent, giving azulenone 24 (0.105 g, 70%) as a yellow oil. The
spectral details were consistent with those described below.
(b) Continuous flow method
This compound was prepared, using the procedure outlined for 23, from a solution (8 mL,
0.071 M) of diazoketone 2 (0.445 g, 1.770 mmol) in doubly distilled dichloromethane (25
mL) and immobilized catalyst 20 (0.500 g, 10 mol%). The crude product was purified by
flash chromatography, with hexane:ethyl acetate (97:3) as eluent, giving azulenone 24 as a
yellow oil (0.083 g, 65%). νmax/cm−1 (film) 2963, 2928, 1748 (CO), 1718 (CO); δH (300
MHz) 0.86 [3H, s, C(8a)C
17.3, one of C(2) 2], 2.39 [1H, B of AB, JAB 17.3, one of C(2)
], 6.14 [1H, dd, 8.9, 0.7, C(7) ], 6.23 [1H, d, 8.0, C(4) ], 6.52 [1H, dd,
]. H3], 28.9 [CH3, one of C(3) H3], 29.6 [CH3,
C{1H}(75.5 MHz) 13.6 [CH , C(8a)
(2)], 100.3 [CH, (8)H], 119.1
=O]. HRMS (EI)
H
3], 1.14, 1.33 [2 × 3H, 2 × s, C(3)(C
H
3)2], 2.22 [1H, A of AB, JAB
2], 4.54 [1H, d, 9.0,
8.0, 1.1,
H
H
J
C(8)
H
H
J
H
J
H
J
C(5)
δ
C
C
3
one of C(3)
C
H3], 38.8 [C,
C
(8a)], 44.6 [C,
C
(3)], 50.4 [CH2,
C
C
[
C
H], 125.6 [C,
C
(3)], 127.1, 127.4 [2 x
C
H], 131.6 [C,
C
(6)], 217.2 [C, C
m/z: [M]+ Calcd for C13H15O35Cl 222.0809; Found 222.0811. m/z (EI) 222, 224 [(M)+, 13%,
4%], 207, 209 (28%, 9%), 179, 181 (19%, 6%), 166, 168 (100%, 33%), 138, 140 (62%,
31%).
3,8aꢀDihydroꢀ6ꢀfluoroꢀ3,3,8aꢀtrimethylazulenꢀ1(2H)ꢀone (25) 30
(a) Batch conditions
This compound was prepared,
using the procedure outlined for
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23, from diazoketone 3 (0.093 g, 0.400 mmol) in doubly distilled dichloromethane (50 mL)
and Rh2(OAc)4 (0.5 mg, 1 mol%). The crude product was purified by flash chromatography,
with hexane:ethyl acetate (97:3) as eluent, giving azulenone 25 as a yellow oil (0.060 g,
71%). The spectral details were consistent with those described below.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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(b) Continuous flow method
This compound was prepared, using the procedure outlined for 23, from a solution (14 mL,
0.056 M) of diazoketone 3 (0.330 g, 1.40 mmol) in doubly distilled dichloromethane (25 mL)
and immobilized catalyst 19 (0.350 g, 10 mol%). The crude product was purified by flash
chromatography, with hexane:ethyl acetate (97:3) as eluent, giving azulenone 25 as a yellow
oil (0.089 g, 55%). νmax/cm−1 (film) 2964, 2869, 1750 (CO), 1716 (CO), 1646, 1626; δH (300
MHz) 0.91 [3H, s, C(8a)C
17.3, one of C(2) 2], 2.51 [1H, B of AB, JAB 17.3, one of C(2)
JHF 5.1, C(8) ], 6.03ꢀ6.10 [1H, m, C(7) ], 6.16ꢀ6.25 [2H, m, C(4)
MHz) 15.5 [CH3, C(8a)
H
3], 1.15, 1.37 [2 × 3H, 2 × s, C(3)(C
H
3)2], 2.25 [1H, A of AB, JAB
H
H2], 5.12 [1H, dd, JHH 10.0,
H
H
H
, C(5)
H
].
(3a)], 48.7 [C,
δ
C{1H}(75.5
C
H3], 29.3, 30.9 [2 × CH3, C(3)(
C
H3)2], 38.9 [C,
C
2
C
(8a)], 51.2 [CH2,
C
(2)H2], 111.0 [CH, d, JCF 28,
C
(5)H or
C
(7)H], 115.5ꢀ116.0 (weak)
(5)H or (7)H], 135.3
C(1)]; HRMS (ESI−TOF) m/z:
[CH, m,
C
(8)H], 116.1 [CH, 3JCF 11,
C
(4)H], 117.6 [CH, d, 2JCF 34,
C
C
1
(weak) [C,
C
(3a)], 159.7 [C, d, JCF 242,
C
(6)], 217.7 [C,
[(M+H)]+ Calcd for C13H16FO 207.1185; Found 207.1182. m/z (ESI+) 207 [(M+H)+, 100%],
203 (12%), 109 (4%).
3,8aꢀDihydroꢀ3,3,5,6,7,8aꢀhexamethylazulenꢀ1(2H)ꢀone (26) 30
(a) Batch conditions
Doubly distilled dichloromethane
(50 mL) and Rh2(OAc)4 (0.5 mg, 1
O
mol%) were added to a flameꢀdried
250 mL three neck round bottom
flask. A solution of diazoketone 4
O
(0.202 g, 0.770 mmol) in doubly distilled dichloromethane (50 mL) was added over 20 min to
this solution at room temperature under N2. The reaction was monitored by IR until the diazo
peak was no longer visible. The reaction was concentrated under reduced pressure affording
the crude azulenone. The spectral details were consistent with those described below.
(b) Continuous flow method
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A solution (0.056 M) of diazoketone 4 (0.360 g, 1.40 mmol) in doubly distilled
dichloromethane (25 mL) was prepared. An Omnifit® glass column (150 mm, 6.6 mm
internal diameter) was packed with immobilized catalyst 20 (0.493 g, 10 mol%) along with
glass wool. The solution of 10 (12 mL) was pumped at 0.75 mL/min through the polymer
contained within the column, which was maintained at room temperature. The reaction
stream passed through a tube (32 cm) and back pressure regulator (8 bar) before it was
collected. The solvent was removed using the rotary evaporator giving the crude azulenone
26 as a yellow solution. Tetrahydrofuran was pumped through the column after the reaction
stream in order to recover the polymer, removing the brown discolouration and returning its
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original green colour. H NMR signals and IR bands corresponding to the literature values
were observed for the crude azulenone. νmax/cm−1 (film) 2958ꢀ2866, 1710 s (CO), 1571; δH
(300 MHz) 0.56 [3H, s, C(8a)CH3], 1.02, 1.19 [2 × 3H, 2 × s, C(3)(C
H
3)2], 1.85 [1H, A of
2], 1.86, 1.89 {2 × 3H, 2 × s, C(6)CH3 and one of [C(5)CH3
1.0, one of [C(5)C 3, C(7)C 3]}, 2.08 [1H, B of ABq, AB17.3,
2], 2.47 [1H, s, C(8) ], 5.81 [1H, br s, C(4) ].
ABq,
J
AB 17.2, one of C(2)
H
,
C(7)C
H
3]}, 1.96 {3H, d,
J
H
H
J
one of C(2)
H
H
H
1,2,3b,4ꢀTetrahydroꢀ1,1,3a,4,11,12ꢀhexamethylꢀ7ꢀphenylꢀ4,10ꢀethenoꢀ6H,10Hꢀ
cyclopenta[1,3]cyclopropa[1,2ꢀd][1,2,4]triazolo[1,2ꢀa]pyridazineꢀ3,6,8(3aH,7H)ꢀtrione (27)
Doubly distilled dichloromethane (50 mL) and
Rh2(OAc)4 (0.5 mg, 1 mol%) were added to a flame
dried 250 mL three neck round bottom flask under N2.
A solution of diazoketone 4 (0.202 g, 0.770 mmol) in
doubly distilled dichloromethane (50 mL) was added
over 20 min to the solution at room temperature. The progress of the reaction was monitored
by IR until the diazo peak was no longer visible. The reaction mixture was then cooled to 0
ºC and sublimed 4ꢀphenylꢀ1,2,4ꢀtriazolineꢀ3,5ꢀdione (0.130 g, 0.740 mmol) [freshly prepared
from tꢀbutyl hypochlorite (0.080 g, 0.727 mmol), 4ꢀphenyl urazole (0.130 g, 0.733 mmol) in
acetone (10 mL)]50 was added as a solid in one portion. The reaction mixture was stirred at 0
ºC for 10 min after which the ice bath was removed and the reaction mixture was warmed to
room temperature. The reaction mixture turned from the brickꢀred colour of the dienophile to
a clear solution within minutes of the addition, indicating completion of the reaction. It was
stirred for a further 30 min before concentration of the reaction mixture under reduced
pressure gave the crude adduct as an offꢀwhite solid. Purification by flash chromatography
with hexane:ethyl acetate (97:3) as eluent afforded the adduct 27 as a white solid. m.p. 176ꢀ
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178°C; Anal. Calcd for C24H27N3O3: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.63; H, 7.17;
N, 9.85. νmax/cm−1 (ATR) 2966, 2927, 1757 , 1727, 1699, 1504, 1396; δH (300 MHz) 1.12
6
7
8
9
[3H, s, C(3a)C
1.1, C(4)C 3], 1.84 [3H, d,
2.02 [3H, s, C(12)C 3], 2.13 [1H, B of AB,
7.31ꢀ7.47 [5H, m, Ar ].
C{1H}(100.6 MHz) 7.6 [CH3, C(3a)
C(4) H3, C(11) H3], 21.1 [CH3, C(12) H3], 23.9, 27.1 [2 × CH3, C(1)(
(3b)H], 36.4, 41.0, 43.5 [3 × C, (1), (3a), (10a)], 48.5 [CH2, (2)H2], 57.3 [CH,
(10)H], 66.2 [C, (4)], 125.4, 128.1, 129.0 [3 × CH, Aromatic H], 129.6 [C, Aromatic ],
(11), (12)], 155.4, 156.1 [2 × C, (6), (9)], 211.7 [C, (3)]; HRMS
H
3] 1.24, 1.30 [2 x 3H, 2 x s, C(1)(CH3)2], 1.69 [1H, s, C(3b)
1.1, C(11)C 3], 1.95 [1H, A of AB, 17.8, one of C(2)
17.9, one of C(2) 2], 5.13 [1H, s, C(10)
H
], 1.75 [3H, d,
J
2],
]],
H
J
H
J
H
H
H
J
H
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H
δ
C
H3], 13.3, 16.8 [2 × CH3,
H3)2], 34.5 [CH,
C
C
C
C
C
C
C
C
C
C
C
C
C
130.7, 131.5 [2 × C,
C
C
C
C
C
(ESI−TOF) m/z: [(M+H)]+ Calcd for C24H28N3O3 406.2131; Found 406.2147. m/z (ESI+)
406 [(M+H)+, 100%], 229 (30%), 105 (30%).
(S)ꢀPhenylglycinol (15) 33
Lithium aluminium hydride (7.00 g, 184 mmol) was added to a
NH2
flameꢀdried 250 mL three neck round bottom flask which was
charged with anhydrous tetrahydrofuran (THF) (120 mL) while
under N2. The round bottom flask was then placed in an ice bath and
OH
(S)ꢀphenylglycine (6.20 g, 41.0 mmol) was added while stirring, along with further anhydrous
tetrahydrofuran (60 mL). The mixture was heated to reflux for 48 h. The reaction was
allowed to cool to room temperature and before cooling to 0°C in an ice bath. Water (12 mL)
was added to the reaction very slowly through an addition funnel while stirring vigorously.
Aqueous NaOH (10%, 12 mL) was then added to the reaction mixture dropwise through the
addition funnel followed by a further portion of water (15 mL). The reaction mixture was
stirred at room temperature until a yellow suspension formed. The reaction solution was
collected from the suspension by suction filtration, concentrated under reduced pressure to
remove THF and extracted with dichloromethane (3 x 50 mL). The organic layers were
collected and washed with brine and concentrated under reduced pressure to afford the amino
alcohol 15 as a yellow crystalline solid (5.01 g, 89%). νmax/cmꢀ1 (ATR) 3349ꢀ2400 (OH),
1954, 1882, 1813, 1602, 1494, 1453; δH (400 MHz) 2.30 [3H, br s, N
A of ABX, AB 10.8, AX 8.4, one of C(1) 2 ], 3.73 [1H, dd, B of ABX,
of C(1) 2], 4.04 [1H, dd, X of ABX, JAX 8.3, 4.3, C(2) ], 7.24ꢀ7.38 (5H, m, ArH
H
2, O
H
], 3.55 [1H, dd,
BX 4.3, one
).
J
J
H
J
AB 10.8,
J
H
J
H
BX
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δ
C{1H}(100.6 MHz) 57.4 [CH,
Aromatic H], 142.6 [C, Aromatic
C
HNH2], 68.0 [CH2,
].
CH2OH], 126.5, 127.5, 128.6 [C, 3 x
C
C
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8
9
35
2,2'ꢀMethylenebis[(4S)ꢀ4ꢀphenylꢀ2ꢀoxazoline] (16)
)ꢀPhenylglycinol 15 (2.50 g, 18.0 mmol) was added to a flame
(S
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O
O
dried two neck round bottom flask with dichloromethane (50
mL). Diethyl malonoimidate dihydrochloride (2.11 g, 9.00
mmol) was added to the flask and the solution was stirred at
N
N
Ph
Ph
room temperature under N2 for 72 h. Water (15 mL) was added to the solution which was
washed with dichloromethane (3 x 50 mL). The organic layers were collected and were
concentrated under reduced pressure affording a crude product. The crude product was
purified by flash chromatography on neutral alumina, which was freshly deactivated prior to
use with ammonium hydroxide, with 50:50 hexane:ethyl acetate as eluent. The bis(oxazoline)
16 was collected as a brown oil (1.40 g, 50%) and used without further purification. δH (400
MHz) 3.58 [2H, s, C
2 x one of OC 2), 4.68ꢀ4.72 [2H, dd, B of ABX,
5.29 [2H, overlapping dd, apparent t, X of ABX,
H
2(C=N)2], 4.17ꢀ4.21 [2H, overlapping dd, apparent t, A of ABX,
BX 10.2, AB 8.4, 2 x one of OC 2), 5.24ꢀ
9.0, 2 x C=NC ], 7.25ꢀ7.35 [10H, m, Ar
H2(C=N)2], 69.7 [CH, 2 x C=N H], 75.4 [CH2, 2 x
H2CH], 126.7, 127.6, 128.7 [CH, 6 x Aromatic H] 142.1 [C, 2 x Aromatic ], 163.1 [C,
=N].
J 8.2,
H
J
J
H
J
H
H
].
δ
C{1H}(100.6 MHz) 28.4 [CH2,
C
C
O
C
C
C
2 x
C
2,2'ꢀ[2ꢀ(4ꢀVinylphenyl)ꢀ1ꢀ(4ꢀvinybenzyl)ethylidene]bis[(4S)ꢀ4ꢀphenylꢀ4,5ꢀdihydroꢀ2ꢀoxazole]
(17) 36,37
A solution of 2,2'ꢀmethylenebis[(4S)ꢀ4ꢀphenylꢀ2ꢀ
oxazoline] 16 (2.21 g, 7.20 mmol) in
tetrahydrofuran (10 mL) was added slowly to
stirring sodium hydride (60% dispersion) (2.02 g,
50.4 mmol) in tetrahydrofuran (10 mL). This
mixture was stirred for 1 h under N2. A solution of
4ꢀchloromethylstyrene (4.08 mL, 28.9 mmol) in
O
O
N
N
Ph
Ph
tetrahydrofuran (5 mL) was transferred to an addition funnel and added slowly to the stirring
solution. This mixture was stirred under N2 at room temperature for 24 h, then the reaction
mixture was quenched with water (10 mL) and extracted with dichloromethane (50 mL). The
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aqueous layer was washed with dichloromethane (2 x 20 mL) and the combined organic
layers were dried, filtered and concentrated under reduced pressure. The crude product was
6
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8
9
purified by flash chromatography, with hexane:ethyl acetate (80:20) as eluent, giving the
ꢁꢂ
desired product 17 as a yellow oil (2.64 g, 68%).
[
α
]
−106.54 [
c
0.764, CHCl3]; δH (400
2C(C=N)2], 4.01 [2H,
2], 4.64 [2H, dd, B of ABX, JBX
2], 5.12 [2H, overlapping dd, apparent t, X of ABX, 9.6, 2 x
], 5.25 [2H, d, Jcis 11.1, 2 x one of C=C 2], 5.75 [2H, d, Jtrans 17.5, 2 x one of
2], 6.70 [2H, dd, cis 10.9, trans 17.6, 2 x C =CH2], 6.90ꢀ6.96 [4H, m, Ar ], 7.18ꢀ7.27
[6H, m, Ar ], 7.31ꢀ7.37 [8H, m, Ar ]. H2C(C=N)2],
C{1H}(100.6 MHz) 39.0 [CH2, 2 x
48.0 [C, (CH2)2], 69.7 [CH, 2 x C=N H], 75.1 [CH2, 2 x O H2CH], 113.7 [CH2, 2 x
C= H2], 126.2, 126.9, 127.5, 128.6, 130.9 [CH, 18 x Aromatic H], 136.3, 136.5 [C, 4 x
Aromatic ], 136.6 [CH, 2 x H=CH2], 141.8 [C, 2 x Aromatic ], 167.7 [C, 2 x =N].
ꢀ
MHz) 3.51 [4H, ABq, JAB 14.1, HA δ = 3.53, HB δ = 3.49, 2 x C
overlapping dd, apparent t, A of ABX, 8.6, 2 x one of OC
8.5, AB 10.2, 2 x one of OC
C=NC
C=C
H
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J
H
J
H
J
H
H
H
J
J
H
H
H
H
δ
C
C
C
C
C
C
C
C
C
C
2,2′ꢀ(1ꢀBenzylꢀ2ꢀphenylethylidene)bis[(4S)ꢀ4ꢀphenylꢀ4,5ꢀdihydroꢀ2ꢀoxazole] (21) 36,37
This compound was prepared, using the procedure outlined
for 17, from 2,2'ꢀmethylenebis[(4S)ꢀ4ꢀphenylꢀ2ꢀoxazoline]
16 (1.01 g, 3.26 mmol), sodium hydride (60% dispersion)
(0.91 g, 22.9 mmol) and benzyl chloride (1.65, 13.4 mmol).
The crude product was purified by flash chromatography,
with hexane:ethyl acetate (80:20) as eluent, giving 21 as a
yellow oil (2.64 g, 68%). [α]ꢁꢀꢂ −102.87 [
JAB 14.1, HA δ = 3.53, HB δ = 3.49, 2 x C
A of ABX, 8.6, 2 x one of OC
OC 2], 5.12 [2H, overlapping dd, apparent t, X of ABX,
m, Ar ], 7.13ꢀ7.40 [16H, m, Ar ].
C{1H}(100.6 MHz) 39.3 [CH2,
(CH2)2], 69.7 [CH, 2 x C=N H], 75.0 [CH2, 2 x O H2CH], 126.9, 127.5, 128.3, 128.6,
130.7 [CH, 20 x Aromatic H, 5 signals seen for 6 carbons], 136.8, 141.9 [C, 4 x Aromatic
], 167.9 [C, 2 x =NCH].
c
0.748, CHCl3]; δH (400 MHz) 3.51 [4H, ABq,
H
2C(C=N)2], 4.02 [2H, overlapping dd, apparent t,
J
H
2], 4.62 [2H, dd, B of ABX, JBX 8.5, JAB 10.2, 2 x one of
9.5, 2 x C=NC ], 6.98ꢀ7.13 [4H,
H2C(C=N)2], 48.8 [C,
H
J
H
H
H
δ
C
C
C
C
C
C
C
2,2'ꢀ[2ꢀ(4ꢀVinylphenylꢀ1ꢀ(4ꢀvinybenzyl)ethylidene]bis[(4S)ꢀ4ꢀphenylꢀ4,5ꢀdihydroꢀ2ꢀoxazole]
polymer (18) 37
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