On the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds

Article abstract of DOI:10.1039/c8ob00435h

The scope and limitations are described of reacting unsaturated tosylhydrazones with O₃ followed by Et₃N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ?-unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-?-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Using the ozonolysis-Et₃N strategy, tosylhydrazones from cyclic enones give 2,5- and 2,6-diazoketones with aldehyde or ester functionality at the 1-position; the α-diazoaldehydes prefer the s-trans conformation, with a rotation barrier of 74 kJ mol^-1 at 25 °C determined by NMR. This one-pot ozonolysis/Bamford-Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone, and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydrazone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions.

Full text of DOI:10.1039/c8ob00435h

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On the ozonolysis of unsaturated tosylhydrazones
as a direct approach to diazocarbonyl
compounds†
Cite this: DOI: 10.1039/c8ob00435h
Younes Fegheh-Hassanpour, Faisal Ebrahim, Tanzeel Arif, Herman O. Sintim,
Timothy D. W. Claridge,
Nader T. Amin and David M. Hodgson
*
The scope and limitations are described of reacting unsaturated tosylhydrazones with O3 followed by
Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide
condensation with readily available δ- and ε-unsaturated α-ketoesters, led in the former case to a 2-pyra-
zoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetra-
hydropyridazinol. Using the ozonolysis–Et3N strategy, tosylhydrazones from cyclic enones give 2,5- and
2,6-diazoketones with aldehyde or ester functionality at the 1-position; the α-diazoaldehydes prefer the
s-trans conformation, with a rotation barrier of 74 kJ mol−1 at 25 °C determined by NMR. This one-pot
ozonolysis/Bamford–Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone,
and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydra-
zone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of
particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions.
Received 19th February 2018,
Accepted 20th March 2018
DOI: 10.1039/c8ob00435h
rsc.li/obc
and compatible functional groups would be of value in the
further development of this chemistry.
Introduction
Transition metal-catalysed decomposition of diazo functional-
We were faced with the above issue in the context of our
ity in the presence of a carbonyl group provides one of the best recent asymmetric synthesis of 6,7-dideoxysqualestatin H5
ways of accessing carbonyl ylides for application in 1,3-dipolar (6,7-DDSQ H5, 5, Scheme 2), where cogeneration of keto and
cycloaddition chemistry (Scheme 1).1 The use of cyclic carbo- diazo functionality was achieved through ozonolysis of an
nyl ylides from diazocarbonyl compounds (usually diazo- unsaturated hydrazone 1.2 The resulting diazoketone 2 under-
ketones) is particularly popular, due to the typically efficient went Rh(II)-catalysed tandem cyclic carbonyl ylide formation 3
intramolecular generation of the transient ylide in combi- and cycloaddition with methyl glyoxylate, giving a cycloadduct
nation with the subsequent pericyclic step leading overall to 4 that was eventually converted to the natural product 5
concise construction of complex polycycles. It was therefore through acid-catalysed rearrangement and installation of the
considered that a method to simultaneously reveal the reactive
diazo and ketone functionalities from more readily accessible
Scheme 1 Carbonyl ylide formation-cycloaddition from diazocarbonyl
compounds.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford OX1 3TA, UK. E-mail: david.hodgson@chem.ox.ac.uk
†Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra of all new compounds. NOE and s-E/s-Z NMR study of 41. X-ray
data for compound 35. CCDC 1815202. For ESI and crystallographic data in CIF
Scheme 2 Chemoselective formation of diazoketone 2 leading to 6,7-
DDSQ H5 (5).2
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full side-chain. Herein we report on the development and tertiary alcohol 10, ozonolysis of the silyl ether 11 to the substi-
scope and limitations of the ozonolytic strategy to diazocarbo- tuted α-ketoester 12, and condensation with tosylhydrazide.
nyl compounds.
A 1 : 1 mixture of hydrazone 13 and benzylated isoprenol
1410 (the latter to mimic the alkene present in 1) in CH2Cl2
underwent controlled ozonolysis at −78 °C in the presence of
Sudan red 7B as an end-point indicator.11 Ozonolysis was
halted as soon as the colour of the reaction mixture changed
from red to light pink. Following treatment with Me2S, 1H
NMR analysis of the reaction mixture indicated that alkene 14
was completely oxidised to corresponding ketone 1512 but,
pleasingly, hydrazone 13 survived.13 No evidence of formation
of ketoester 12 was detected by 13C NMR analysis of the crude
reaction mixture (diagnostic α-keto carbon EtO2C-CvO signal
at ∼190 ppm2 absent). Unfortunately, direct transfer of these
promising conditions to unsaturated hydrazone 1 (Scheme 2),
although leading to complete consumption of the alkene func-
tionality did not allow successful isolation of the corres-
ponding keto hydrazone 2 (NNHTs instead of N2); despite
various attempts, partial decomposition on purification by
silica gel chromatography was observed and clean keto hydra-
zone was not obtained. To overcome this problematic step, it
was proposed that if the intermediate ozonide from unsatu-
rated hydrazone 1 was treated with Et3N instead of Me2S, this
should also lead to the desired ketone functionality,14 with the
additional bonus of converting the hydrazone moiety to a
Results and discussion
Prior to embarking on the above total synthesis, studies were
carried out on simpler substrates to assess the viability of the
ozonolytic strategy to diazocarbonyl compounds from unsatu-
rated ketones, successively through condensation reaction
with tosylhydrazide, then ozonolysis3 and finally Bamford–
Stevens4 reaction. It was considered that the diazo functional-
ity should not be generated (from hydrazone) before the
double bond was subjected to ozonolysis since, even assuming
that conditions could be established for the diazo group to
survive alkene ozonolysis unscathed (cf, 11 →12 Scheme 4),
Dauben and co-workers had reported that a structurally related
unsaturated diazo substrate 7, prepared from unsaturated ester
6 by α-formylation and deformylative diazo transfer, under-
went spontaneous intramolecular dipolar cycloaddition to give
a 1-pyrazoline 8 (Scheme 3).5
diazo group4,15 in
a one-pot ozonolysis/Bamford–Stevens
process. Application of this strategy proved successful
(Scheme 2),2 and it was subsequently found that the end-point
indicator could be dispensed with, provided ozonolysis was
halted as soon as the reaction mixture turned blue [diketone 2
(CvN2 replaced by CvO) was observed if ozonolysis was pro-
longed]; however, the scope and limitations of this process
remained to be explored.
Unsaturated tosylhydrazones 24–27 (Scheme 5), lacking the
β-siloxy and β-ester functionality that could be providing
additional steric and/or electronic “protection” of the hydra-
zone to ozonolysis in 1 and 13, were made by tosylhydrazide
condensation with δ- and ε-unsaturated α-ketoesters 20–23.
The latter were readily prepared by addition to diethyl oxalate
of the relevant Grignard reagents available from the corres-
ponding unsaturated bromides 16–19.16
Scheme 3 Formation and instability of diazoalkene 7.5
At the outset of these investigations, the tolerance of hydra-
zone functionality during ozonolysis of an alkene required
clarification, since (like diazo compounds)6 hydrazones are
known to be convertible to ketones through such oxidation
chemistry.7,8 However, rendering the hydrazone electron
deficient, through ester substitution at the hydrazino carbon
and a Ts group on the amino nitrogen, was anticipated to
reduce its reactivity to electrophilic attack by ozone.8 A simpli-
fied hydrazone 13 that retained the key features present in the
target system 1 (Scheme 2), was straightforwardly synthesised
in four steps starting from α-lithiated ethyl diazoacetate9 and
methyl pyruvate (9, Scheme 4), then silylation of the resulting
Scheme 5 Synthesis of unsaturated tosylhydrazones 24–27.
Of the unsaturated tosylhydrazones 24–27, only 24 could be
successfully converted to the corresponding diazocarbonyl
compound 28 though the ozonolysis/Bamford–Stevens
process (Scheme 6). Diazocarbonyl compound 28 has
Scheme 4 Synthesis and tolerance to ozonolysis of hydrazone 13.
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α,β-Unsaturated hydrazones from 3-methylcyclopentenone
(36) and 3-methylcyclohexenone (37) allow access to 1,4- and
1,5-diazoketones 40 and 41 using the ozonolysis–Et3N strategy.
The α-diazo-ε-ketoester 28, made earlier (Scheme 6), was also
accessible via 2-ethoxy-3-methylcyclohexenone (42, prepared
from the epoxide of 3-methylcyclohexenone (37) by α-ring-
opening/β-elimination using NaOEt22) (Scheme 8).23
Scheme 6 Ozonolysis followed by base treatment of unsaturated tosyl-
hydrazones 24 and 25.
previously been prepared by Padwa and co-workers (in
3 steps from α-acetylbutyrolactone), and shown to be a viable
substrate for carbonyl ylide formation – cycloaddition chemistry
(for example with DMAD as the dipolarophile, in 73%
yield).17,18
Surprisingly, following ozonolysis and addition of Et3N,
unsaturated tosylhydrazone 25 was only converted as far as the
keto hydrazone 29, in low yield (20%, Scheme 6). Switching to
DBU19 as a stronger base after ozonolysis of tosylhydrazone 25
led to the 2-pyrazoline 33 (41%). Presumably, DBU does facili-
tate generation of the anticipated diazoketone 30, but under
the reaction conditions the corresponding enol 31 undergoes
cyclisation with the proximal diazo functionality followed by
regioselective tautomerisation from 1-pyrazoline 32.20
Terminal alkene-containing hydrazones 26 and 27
(Scheme 7) were anticipated to lead to diazoaldehydes follow-
ing ozonolysis and base treatment. However, in both cases the
greater reactivity of the aldehyde group, compared to ketone
functionality earlier, led to cyclisation chemistry at the alde-
hyde. With hydrazone 26, only β-ketoester 34 was isolated
(16%), likely arising from intramolecular aldolisation of the
diazoaldehyde followed by 1,2-hydride shift with expulsion of
N2.9c For hydrazone 27, tetrahydropyridazinol 35 was obtained
(64%, structure confirmed by X-ray crystallographic analysis21).
The latter proved recalcitrant to conversion to the corres-
ponding diazoaldehyde, being inert to separate treatment with
Et3N or NaOEt whereas significant decomposition was
observed on exposure to DBU.
Scheme 8 1,4- and 1,5-Diazoketones 40, 41 and 28 from cyclic
enones.
Generation of diazo carbonyl compounds 40, 41 and 28
from the corresponding, α,β-unsaturated hydrazones 38, 39
and 43 indicates that, if the reactions were to proceed
through formation of an ozonide 44, then the Et3N acts as a
reductant; although for the potential ozonides derived from 38
and 39 bridgehead deprotonation might be expected on the
basis of direct analogy with previous studies on simple (cyclo)
alkenes,14 leading to carboxylic acid functionality through
anionic cycloreversion, rather than the aldehyde functionality
observed. However, in these systems, the proximity of the adja-
cent hydrazone functionality, aside from likely dictating
(through stabilisation) carbonyl oxide generation on the proxi-
mal, rather than distal carbon in the first formed molozonide,
could also lead through NH deprotonation to intermediate 45.
The latter, following elimination of Ts−, could undergo
reduction by Et3N (Scheme 9).
Scheme 7 Ozonolysis followed by base treatment of unsaturated tosyl-
hydrazones 26 and 27.
Scheme 9 Proposed pathway to diazocarbonyl compounds 28, 40
and 41.
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The α-diazoaldehydes 40 and 41 display s-cis/trans isomer- chemicals, BDH) in accordance with Still’s method,28 moni-
ism, arising from partial double bond character in the N2C– tored by thin-layer chromatography (TLC) (Merck 60 F254
CHO bond. This phenomenon has been observed for diazo- plates. TLC plates were viewed using ultraviolet light (λmax
)
=
acetaldehyde (the simplest α-diazoaldehyde), α-diazoketones 254/365 nm) and immersion in KMnO4, anisaldehyde or vanil-
and other α-diazo carbonyl compounds.24,25 In solution, lin stains, followed by heating. Except where stated otherwise,
diazoacetaldehyde and monosubstituted α-diazoketones commercially available reagents were used as received. Melting
(RCOCHN2) prefer the Z-form, whereas disubstituted open- points (m.p.s) were obtained using an electrothermal melting
chain α-diazo carbonyl compounds exist exclusively as, or point apparatus to the nearest 1 °C and are uncorrected.
prefer, the E-form. NOE studies on α-diazoaldehyde 41 Infrared spectra were obtained using a PerkinElmer FT-IR
recorded at −40 °C (to eliminate exchange between isomers) spectrometer (Universal ATR Sampling Accessory), with
indicated that the predominant form was E- (analogously for absorption maxima quoted in wavenumbers (cm−1). Peak
40; E- : Z- both ∼85 : 15).13 Stabilisation by weak H-bonding intensities are described as broad (br), weak (w), medium (m)
between β C–H on the (cis-) alkyl chain and the aldehyde may or strong (s). Nuclear magnetic resonance (1H NMR and 13C
contribute to the preference for the E-form.26 For NMR) spectra were recorded on Bruker Avance DPX 200,
α-diazoaldehyde 41, variable temperature 1H NMR studies in AVIIIHD 400, AVII 500, and AVIIIHD 500 spectrometers in
CDCl3 and 1D EXSY analyses were used to obtain exchange CDCl3, referenced to residual CHCl3 singlet at δ 7.27 for 1H
rate constants and hence estimate rotational activation para- NMR spectra, and to the central line of CDCl3 triplet at δ 77.16
meters (ΔH‡ and ΔS‡), from which the activation energy (ΔG‡) for 13C NMR spectra. Chemical shifts are quoted in parts per
barrier to rotation was calculated as 74 kJ mol−1 at 25 °C.13 million (ppm). Coupling constants (J) are measured to the
The latter value lies at the upper end of the range of barriers nearest 0.5 Hertz (Hz). The splittings are quoted as singlet (s),
so far determined for α-diazo carbonyl compounds, and likely doublet (d), triplet (t), quartet (q), or multiplet (m). The 13C
reflects greater electron delocalisation into the aldehyde com- NMR peaks were assigned by standard methods using HSQC.
pared with α-diazo-ketone (and -ester) systems.
X-ray crystallography data were collected with (Rigaku) Oxford
Diffraction SuperNova A diffractometer at 150 K. Low-resolu-
tion mass spectra were obtained using electrospray ionisation
(ESI) or chemical ionisation (CI). High-resolution mass spectra
were obtained by electrospray ionisation (ESI) or chemical ion-
Conclusions
In summary, the scope and limitations of reacting unsaturated isation (CI) using tetraoctylammonium bromide or sodium
tosylhydrazones with O3 followed by Et3N for the direct gene- dodecyl sulfate as the lock mass.
ration of diazocarbonyl systems were examined. Here, the Et3N
4-Ethyl 1-methyl 3-diazo-2-hydroxy-2-methylsuccinate (10).
facilitates two processes: ozonide conversion to keto and/or To a solution of ethyl diazoacetate (571 mg, 5.0 mmol) and
aldehyde functionality,14 and tosylhydrazone to ketone in a methyl pyruvate 9 (510 mg, 5.0 mmol) in THF (10 mL) at
Bamford–Stevens reaction.4,15 The chemistry is viable to −78 °C was added dropwise over 30 min LDA [5.0 mmol,
α-diazo-ε-ketoesters, but an α-diazo-δ-ketoester underwent freshly prepared by adding dropwise n-BuLi (3.35 mL, 1.5 M in
cyclisation to a 2-pyrazoline under the basic reaction con- hexanes, 5.0 mmol) to a solution of freshly distilled i-Pr2NH
ditions following ozonolysis. Terminal alkene hydrazones did (0.73 mL, 5.25 mmol) in THF (5 mL) at 0 °C]. The solution was
not produce diazoaldehydes, as the later proved too reactive in stirred for 3 h at −78 °C and a solution of acetic acid (0.28 mL,
the presence of tethered hydrazone or diazo functionality, 5.0 mmol) in THF (1 mL) at −50 °C was then added dropwise
although the chemistry did provide an interesting route and the reaction mixture allowed to warm to rt. Sat. aq NaCl
to
a
tetrahydropyridazine ring system. Finally, cyclic (20 mL) was added, the organic layer separated and the aq
α,β-unsaturated hydrazones are shown to undergo ozonolytic layer extracted with Et2O (3 × 20 mL). The combined organic
ring-cleavage and Bamford–Stevens reaction to give 2,5- and layers were dried (MgSO4) and evaporated under reduced
2,6-diazoketones with aldehyde or ester functionality at the pressure. The residue was purified by column chromatography
1-position.
(25% Et2O in petrol) to give tertiary alcohol 10 (876 mg, 81%)
as a yellow liquid; Rf 0.29 (25% Et2O in petrol); IR (film, νmax
cm−1) 3488 m, 2950 m, 2075 s, 1750 s and 1719 s; 1H NMR
(200 MHz; CDCl3) δ 4.30–4.10 (3H, m, CH2CH3 and OH), 3.83
(3H, s, CO2Me), 1.60 (3H, d, J 0.5, CH3), 1.28 (3H, t, J 7.0,
OCH2CH3); 13C NMR (50 MHz; CDCl3) δ 174.5 (CO2Me), 166.0
Experimental
General information
All reactions requiring anhydrous conditions were carried out (CO2Et), 71.8 (HOCCO2Me), 64.3 (CN2), 61.6 (CH2CH3),
under an atmosphere of argon in flame-dried glassware. 53.8 (CO2Me), 24.0 (CH2CH3), 14.7 (CH3); HRMS (CI) m/z
+
Tetrahydrofuran (THF), dichloromethane (DCM), ether (Et2O) (M + NH4 ), found 234.1087, C8H16O5N3 requires 234.1090.
and ethyl acetate (EtOAc) were obtained from Grubbs’ drying
4-Ethyl 1-methyl 2-((tert-butyldimethylsilyl)oxy)-3-diazo-2-
stills.27 MeOH was dried over 4 Å MS for at least 24 h. Petrol methylsuccinate (11). To a solution of 2,6-lutidine (1.4 mL,
(petroleum ether) 30–40 °C was used in flash column chrom- 12 mmol) in CH2Cl2 (10 mL) was added TBSOTf (1.4 mL,
atography. The latter was carried out using silica gel (VWR 6.0 mmol) dropwise at 0 °C. After 30 min, a solution of tertiary
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alcohol 10 (865 mg, 4.0 mmol) in CH2Cl2 (5 mL) was added through the reaction mixture. Then Me2S (0.82 mL,
dropwise and the mixture warmed to rt and stirred for 48 h. 5.91 mmol) was added and the reaction mixture was warmed
Brine (20 mL) was then added and the aq layer extracted with to rt. After stirring for 12 h, the solution was concentrated
CH2Cl2 (3 × 20 mL). The combined organic layers were dried under reduced pressure to give a mixture of 13 and ketone
(MgSO4) and evaporated under reduced pressure. The residue 1512 as a colourless oil.13
was purified by column chromatography (5% Et2O in petrol) to
General procedure A for the formation of hydrazones
give silyl ether 11 (876 mg, 93%) as a colourless oil; Rf 0.30
(5% Et2O in petrol); IR (film, νmax cm−1); 3496 m 2956 m, (i) Mg turnings (50.6 mmol) were flame-dried under vacuum
1
2930 m, 2078 s, 1742 s; H NMR (200 MHz; CDCl3) δ 4.20 (1H, for 15 min and then allowed to cool to rt under argon. A
q, J 7.0, 1 H of CH2CH3), 4.19 (1H, q, J 7.0, 1H of CH2CH3), mixture of THF/Et2O (0.88 mL mmol−1, 1 : 1) was added, fol-
3.76 (3H, s, CO2Me), 1.68 (3H, s, CH3), 1.26 (3H, t, J 7.0, lowed by dropwise addition of bromoalkene (16.9 mmol). The
OCH2CH3), 0.88 (9H, s, Si(CH3)2C(CH3)3), 0.12 (3H, s, mixture was stirred for 15 min and then transferred dropwise
Si(CH3)2C(CH3)3), 0.10 (3H, s, Si(CH3)2C(CH3)3); 13C NMR to a solution of diethyl oxalate (11.3 mmol) in THF/Et2O
(50 MHz; CDCl3)
δ
172.5 (CO2Me), 171.0 (CO2Et), 73.5 (0.88 mL mmol−1, 1 : 1) at −78 °C. After 2 h at −78 °C, the reac-
(TBSOCCO2Me), 60.9 (CH2CH3), 52.8 (CO2Me), 25.9 tion was quenched with sat. aq NH4Cl (15 mL) and extracted
(Si(CH3)2C(CH3)3), 25.7 (Si(CH3)2C(CH3)3), 18.4 (CH2CH3), 14.6 with EtOAc (3 × 50 mL). The combined organic layers were
(TBSOCCH3), −3.07 (Si(CH3)2C(CH3)3), −3.63 (Si(CH3)2C dried (MgSO4), filtered, and evaporated under reduced
(CH3)3) [CN2 not observed]; HRMS m/z (M + Na+), found pressure to give α-ketoester as colourless oil, which was used
353.1508, C14H26N2NaO5Si requires 353.1509.
in the next step without further purification. (ii) A mixture of
4-Ethyl 1-methyl
(Z)-2-((tert-butyldimethylsilyl)oxy)-2- crude α-ketoester (11.2 mmol) and TsNHNH2 (13.4 mmol) in
methyl-3-(2-tosylhydrazineylidene)succinate (13). A solution of MeOH (1.3 mL mmol−1 of α-ketoester) was heated to 45 °C
silyl ether 11 (660 mg, 2.0 mmol) in CH2Cl2 (40 mL) was overnight. The mixture was then cooled to rt, concentrated
cooled to −15 °C. A stream of O3 in oxygen was bubbled under reduced pressure and purified by column chromato-
through the solution. After 1 h, ozone treatment was termi- graphy to give the hydrazone.
nated (monitored by the disappearance of IR stretch at
General procedure B for ozonolysis/Bamford–Stevens process
2078 cm−1). The excess O3 was removed by bubbling N2
through the reaction mixture and warmed to rt. The residue A solution of hydrazone (1.48 mmol) in CH2Cl2 (115 mL
was concentrated under reduced pressure to give α-ketoester mmol−1) was cooled to −78 °C. A stream of O3 in oxygen was
12 which was used directly in the next step. A solution of bubbled through the solution. Ozone treatment was termi-
α-ketoester 12 and TsNHNH2 (540 mg, 2.9 mmol) in THF/ nated when the colour of the reaction mixture changed from
EtOH (6 mL, 1 : 1) was heated to reflux. After 24 h, the residue colourless to light blue. The excess O3 was removed by bub-
was concentrated under reduced pressure and purified by bling N2 through the reaction mixture. After 10 min, Et3N
column chromatography (50% Et2O in petrol) to give Z29- (5.91 mmol) was added and the reaction mixture was warmed
hydrazone 13 (478 mg, 75% from 11) as a colourless oil; to rt. After stirring for 3 h, the reaction mixture was passed
Rf 0.52 (50% Et2O in petrol); IR (film, νmax cm−1); 2924 s, through a pad of silica, evaporated under reduced pressure
1767 s, 1460 m; 1H NMR (200 MHz; CDCl3) δ 11.58 (1H, s, and purified by column chromatography to give the diazo-
NH), 7.83 (2H, d, J 8.0, 2xArCH), 7.31 (2H, d, J 8.0, 2xArCH), carbonyl compound.
4.33–4.07 (2H, m, CH2CH3), 3.66 (3H, s, CO2Me), 2.42 (3H, s,
Ethyl 6-methyl-2-oxohept-6-enoate (20) and ethyl (Z)-6-
ArMe), 1.52 (3H, s, TBSOCCH3), 1.25 (3H, t, J 7.0, CH2CH3), methyl-2-(2-tosylhydrazineylidene)hept-6-enoate (24). Following
0.75 (9H, s, Si(CH3)2C(CH3)3), 0.03 (3H, s, Si(CH3)2C(CH3)3) the general procedure A(i) using Mg turnings (206 mg,
and −0.18 (3H, s, Si(CH3)2C(CH3)3); 13C NMR (50 MHz; CDCl3) 8.46 mmol), 5-bromo-2-methylpent-1-ene 1630 (600 mg,
δ 173.5 (CO2Me), 161.3 (CO2Et), 144.4 (ArC), 138.0 (ArC), 135.3 3.68 mmol) and diethyl oxalate (0.40 mL, 2.94 mmol) to give
(CvN), 129.9 (ArCH), 127.9 (ArCH), 77.6 (TBSOCCH3), ethyl 6-methyl-2-oxohept-6-enoate (20) (542 mg, 63%) as col-
62.0 (CH2CH3), 52.2 (CO2Me), 25.4 (Si(CH3)2C(CH3)3), 24.1 ourless oil; Rf 0.79 (20% Et2O in petrol); IR (film, νmax cm−1
)
(Si(CH3)2C(CH3)3), 21.6 (ArMe), 18.0 (CH2CH3), 13.7 2930 w, 1726 s, 1447 w, 1254 s, 1084 s, 1045 s; 1H NMR
(TBSOCCH3), −2.9 (Si(CH3)2C(CH3)3) and −3.3 (Si(CH3)2C (500 MHz; CDCl3) δ 4.75 (1H, s, 1H of H2CvC), 4.69 (1H, s, 1H
(CH3)3); HRMS m/z (M + H+), found 487.1944. C21H35N2O7SSi of H2CvC), 4.32 (2H, q, J 7.0, CH2CH3), 2.84 (2H, t, J 7.0,
requires 487.1934.
CH2CvO), 2.07 (2H, t, J 7.0, CH2CvCH2), 1.80 (2H, q, J 7.5,
CH2CH2CH2CvO), 1.71 (3H, s, CH3CvC), 1.37 (3H, t, J 7.0,
CH2CH3); 13C NMR (125 MHz; CDCl3) δ 194.7 (CvOCO2Et),
Model study for selective ozonolysis
A solution of hydrazone 13 (137 mg, 0.29 mmol), benzylated 161.3 (CvOCO2Et), 144.7 (CH3CvC), 111.1 (CvCH2), 62.5
isoprenol 1410 (51 mg, 0.29 mmol) and Sudan red 7B11 (1 mg) (CH2CH3), 38.6 (CH2CvO), 36.9 (CH2CvCH2), 22.2
in CH2Cl2 (20 mL) was cooled to −78 °C. A stream of O3 (CH3CvCH2), 20.8 (CH2CH2CH2CvO), 14.1 (CH2CH3); HRMS
in oxygen was bubbled through the solution. Ozone m/z (M + Na+), found 185.1174, C10H17O3 requires 185.1172.
treatment was terminated when the colour of the reaction Following the general procedure A(ii) using 6-methyl-2-
turned light pink. The excess O3 was removed by bubbling N2 oxohept-6-enoate (20) (38.0 mg, 0.206 mmol) and TsNHNH2
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(46.0 mg, 0.248 mmol) gave Z29-hydrazone 24 (37.8 mg, 66%) J 7.0, CH2CH3), 2.48–2.40 (5H, m, CH3Ar and CH2CHvCH2),
as colourless oil; Rf 0.67 (20% Et2O in petrol); IR (film, νmax 1.96 (2H, q, 7.0, CH2CH2CvN), 1.58 (2H, q, 7.5,
J
J
1
cm−1) 3672 w, 3235 w, 1721 s, 1430 s, 1204 s, 1113 s; H NMR CH2CH2CvN), 1.32 (3H, t, J 7.0, CH2CH3); 13C NMR (125 MHz;
(500 MHz; CDCl3) δ 11.79 (1H, s, NH), 7.83 (2H, d, J 8.0, CDCl3) δ 162.2 (CO2Et), 144.3 (ArCMe), 139.1 (ArC), 138.2
2xArCH), 7.30 (2H, d, J 8.0, 2xArCH), 4.70 (1H, s, 1H of (H2CvCH), 135.8 (CvN), 129.7 (ArCH), 128.0 (ArCH),
H2CvC), 4.61 (1H, s, 1H of H2CvC), 4.26 (2H, d, J 7.0, 115.0 (H2CvCH), 62.0 (CH2CH3), 32.9 (CH2CHvCH2), 32.5
CH2CH3), 2.42 (5H, m, ArCH3 and CH2CvCH2), 1.92 (2H, t, (CH2CH2CvN), 25.8 (CH2CH2CvN), 21.7 (ArCH3), 14.1
J 7.0, CH2CH2CvN), 1.66 (3H, s, CH3CvCH2), 1.61 (2H, t, (CH2CH3); HRMS m/z (M + Na+), found 339.1374, C16H23N2O4S
J 7.0, CH2CH2CvN), 1.32 (3H, t, J 7.0, CH2CH3); 13C NMR requires 339.1373.
(125 MHz; CDCl3) δ 162.3 (CO2Et), 145.2 (CvCH2), 144.3
Ethyl (E)-2-(2-tosylhydrazineylidene)hex-5-enoate (27). Following
(ArCMe), 139.1 (ArC), 135.7 (CvN), 129.7 (ArCH), 128.0 the general procedure A using Mg turnings (1.23 g, 50.6 mmol),
(ArCH), 110.3 (CvCH2), 62.0 (CH2CH3), 36.9 (CH2CvCH2), 4-bromobut-1-ene 19 (1.0 mL, 5.88 mmol) and diethyl oxalate
32.7 (CH2CH2CvN), 24.5 (CH2CvN), 22.4 (CH3CvCH2), 21.7 (0.53 mL, 3.92 mmol). A mixture of crude α-ketoester 23
(ArCH3), 14.1 (CH2CH3); HRMS m/z (M + Na+), found 375.1350, (612 mg, 3.92 mmol) and TsNHNH2 (876 mg, 4.70 mmol) gave
C17H24N2NaO4S requires 375.1349.
Ethyl 5-methyl-2-oxohex-5-enoate (21) and ethyl (Z)-5- unknown trace impurity by NMR) as a white solid; Rf 0.35
methyl-2-(2-tosylhydrazineylidene)hex-5-enoate (25). Following (30% EtOAc in petrol); m.p. 80–82 °C; IR (film, νmax cm−1
E-hydrazone 27 (903 mg, ∼71%, over 2 steps, containing
)
the general procedure A(i) using Mg turnings (376 mg, 3211 w, 3076 w, 1715 m, 1641 m, 1372 w, 1187 s, 1056 s;
15.48 mmol), 4-bromo-2-methylbut-1-ene 17 (1.00 g, 1H NMR (500 MHz; CDCl3) δ 8.79 (1H, s, NH), 7.86 (2H, d,
6.71 mmol) and diethyl oxalate (0.70 mL, 5.16 mmol) to give J 8.0, 2xArCH), 7.32 (2H, d, J 8.0, 2xArCH), 5.71–5.59 (1H, m,
α-ketoester 2131 (324 mg, 37%) as colourless oil; Rf 0.72 (20% H2CvCH), 4.93 (1H, d, J 17.0, 1 H of H2CvCH), 4.86 (1H, d,
Et2O in petrol); 1H NMR (500 MHz; CDCl3) δ 4.77 (1H, s, 1H of J 10.0, 1H of H2CvCH), 4.23 (2H, q, J 7.0, CH2CH3),
H3CCvCH2), 4.70 (1H, s, 1H of H3CCvCH2), 4.33 (2H, q, J 7.0, 2.54 (2H, t, J 7.5, CH2CvN), 2.43 (3H, s, CH3Ar), 2.16
CH2CH3), 3.00 (2H, t, J 7.0, CH2CvO), 2.35 (2H, t, J 7.0, (2H, q, J 7.5, CH2CH2CvN), 1.31 (3H, t, J 7.0, CH2CH3);
CH2CH2vO), 1.75 (3H, s, CH3), 1.38 (3H, t, J 7.0, CH2CH3); 13
C
13C NMR (125 MHz; CDCl3) δ 163.7 (CO2Et), 146.8 (ArCMe),
NMR (125 MHz; CDCl3) δ 194.1 (CvO), 161.1 (CO2Et), 143.6 144.7 (ArC), 136.0 (H2CvCH), 134.9 (CvN), 129.7 (ArCH),
(CvCH2), 110.8 (CvCH2), 62.5 (CH2CH3), 37.6 (CH2CvCH2), 128.1 (ArCH), 116.7 (H2CvCH), 61.8 (CH2CH3), 29.4
30.8 (CH2CvO), 22.7 (CH3), 14.1 (CH2CH3). Following the (CH2CH2CvN), 25.5 (CH2CH2CvN), 21.7 (ArCH3), 14.2
general procedure A(ii) using ethyl 5-methyl-2-oxohex-5-enoate (CH2CH3); HRMS m/z (M + H+) found 325.1216, C15H21N2O4S
(21) (320 mg, 1.88 mmol) and TsNHNH2 (420 mg, 2.26 mmol) requires 325.1217.
gave Z29-hydrazone 25 (537 mg, 84%) as a white solid; Rf 0.43
(20% EtOAc in petrol); m.p. 42–44 °C; IR (film, νmax cm−1
Ethyl 2-diazo-6-oxoheptanoate (28). Following the general
procedure B using hydrazone 24 (25 mg, 0.071 mmol), CH2Cl2
)
3210 w, 2930 w, 1693 m, 1371 s, 1296 s, 1186 s, 1170 s, 1084 s; (5 mL) and Et3N (40 µL, 0.30 mmol) gave diazocarbonyl 2817
1H NMR (500 MHz; CDCl3) δ 11.8 (1H, s, NH), 7.83 (2H, d, (8 mg, 57%) as a yellow oil; Rf 0.43 (30% Et2O in petrol); IR
J 8.0, 2xArCH), 7.31 (2H, d, J 8.0, 2xArCH), 4.60 (1H, s, 1H (film, νmax cm−1) 2081 s, 1686 s, 1371 m, 1158 m; 1H NMR
of H3CCvCH2), 4.54 (1H, s, 1H of H3CCvCH2), 4.27 (2H, (500 MHz; CDCl3) δ 4.22 (2H, q, J 7.0, CH2CH3), 2.51 (2H, t,
q, J 7.0, CH2CH3), 2.58 (2H, t, J 7.0, CH2CvN), 2.43 (3H, J 7.0, CH2CvO), 2.33 (2H, t, J 7.5, CH2CN2), 2.16 (3H, s,
s, CH3Ar), 2.18 (2H, t, J 7.0, CH2CH2CvN), 1.65 (3H, s, CH3CvO), 1.80 (2H, quint, J 7.0, J 7.0, CH2CH2CN2), 1.28 (3H,
CH3CvCH2), 1.33 (3H, t, J 7, CH2CH3); 13C NMR (125 MHz; t, J 7.0, CH2CH3); 13C NMR (125 MHz; CDCl3) δ 208.1
CDCl3) δ 162.2 (CO2Et), 144.5 (CvCH2), 144.3 (ArCMe), (CH3CvO), 167.7 (CO2Et), 61.0 (CH2CH3), 42.3 (CH2CvO),
138.7 (ArC), 135.8 (CvN), 129.7 (ArCH), 128.0 (ArCH), 30.2 (CH3CvO), 22.8 (CH2CN2), 21.9 (CH2CH2CN2), 14.7
110.9 (CvCH2), 62.0 (CH2CH3), 34.8 (CH2CvCH2), 31.5 (CH2CH3) [CN2 not observed]; HRMS [M
(CH2CvN), 22.4 (CH3CvCH2), 21.7 (ArCH3), 14.1 (CH2CH3); 221.0896, C9H14N2NaO3 requires 221.0897.
+
Na]+ found
HRMS m/z (M + Na+), found 339.1374, C16H23O4N2S requires
Ethyl (Z)-5-oxo-2-(2-tosylhydrazineylidene)hexanoate (29).
Following the general procedure using hydrazone 25
(26). (180 mg, 0.53 mmol), CH2Cl2 (65 mL) and Et3N (0.30 mL,
339.1373.
Ethyl
B
(Z)-2-(2-tosylhydrazineylidene)hept-6-enoate
Following the general procedure A using Mg turnings (1.23 g, 2.13 mmol) gave keto hydrazone 29 (36 mg, 20%) as a yellow
50.6 mmol), 5-bromopent-1-ene 18 (2.0 mL, 16.9 mmol) and oil; Rf 0.46 (40% EtOAc in petrol); IR (film, νmax cm−1) 2924 w,
diethyl oxalate (1.53 mL, 11.3 mmol). A mixture of crude 1714 s, 1693 m, 1370 s, 1277 s, 1167 s, 1085 s; 1H NMR
α-ketoester 22 (1.90 g, 11.2 mmol) and TsNHNH2 (2.50 g, (500 MHz; CDCl3) δ 7.75 (2H, d, J 8.0, 2xArCH), 7.31 (2H, d,
13.4 mmol) gave Z29-hydrazone 26 (3.04 g, 80% over 2 steps) as J 8.0, 2xArCH), 4.25 (2H, q, J 7.0, CH2CH3), 2.72 (2H, t, J 7.0,
a white solid; Rf 0.44 (20% Et2O in petrol); m.p. 69–71 °C; IR CH2CvO), 2.65 (2H, q, J 7.5, CH2CvN), 2.42 (3H, s, CH3Ar),
(film, νmax cm−1) 3213 br, 2980 br, 1715 m, 1641 m, 1166 s, 2.14 (CH3CvO), 1.31 (3H, t, J 7.0, CH2CH3); 13C NMR
1065 s; 1H NMR (500 MHz; CDCl3) δ 11.79 (1H, s, NH), 7.83 (125 MHz; CDCl3) δ 207.3 (CvO), 162.0 (CO2Et), 144.4
(2H, d, J 8.0, 2xArCH), 7.31 (2H, d, J 8.0, 2xArCH), 5.78–5.68 (ArCMe), 137.1 (ArC), 135.8 (CvN), 129.8 (ArCH), 127.8
(1H, m, H2CvCH), 4.99–4.92 (2H, m, H2CvCH), 4.26 (2H, q, (ArCH), 62.2 (CH2CH3), 38.7 (CH2CvO), 30.3 (CH3CvO), 26.7
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(CH2CvN), 21.7 (ArCH3), 14.1 (CH2CH3); HRMS m/z (M + Na+), CDCl3) δ 169.0 (HCvCCH3), 160.8 (CvN), 144.0 (ArC), 135.7
found 341.1162, C15H21O5N2S requires 341.1165. (ArC), 129.7 (ArCH), 128.1 (ArCH), 126.7 (HCvCCH3), 34.9
Ethyl 3-acetyl-4,5-dihydro-1H-pyrazole-5-carboxylate (33). (CH2CCH3), 26.6 (CH2CN), 21.7 (ArCCH3), 18.1 (HCCCH3);
Following the general procedure
using hydrazone 25 HRMS m/z (M + H+) found 265.1004, C13H17N2O2S requires
B
(100 mg, 0.30 mmol), CH2Cl2 (36 mL) and DBU (0.18 mL, 265.1005; discernible data for E-isomer: 1H NMR (500 MHz;
1.18 mmol) gave 2-pyrazoline 33 (22.4 mg, 41%) as a clear oil; CDCl3) δ 6.22 (1H, s, CH3CvCH), 2.59 (2H, m, CH2CvN), 1.96
Rf 0.54 (40% EtOAc in petrol); IR (film, νmax cm−1) 3338 br, (3H, s, CHCCH3); 13C NMR (125 MHz; CDCl3) δ 169.8
2983 w, 1735 s, 1662 s, 1346 m, 1207 s, 1095 s; 1H NMR (HCvCCH3), 166.5 (CvN), 143.9 (ArC), 129.6 (ArCH), 128.1
(500 MHz; CDCl3) δ 6.75 (1H, s, NH), 4.44 (1H, dd, J 5.0, J 12.5, (ArCH), 119.7 (HCvCCH3), 34.1 (CH2CCH3), 30.3 (CH2CN),
CHCO2Et), 4.22 (2H, q, J 7.0, CH2CH3), 3.26 (1H, dd, J 5.0, 21.8 (ArCCH3), 18.8 (HCCCH3).
J 17.5, 1 H of CH2), 3.10 (1H, dd, J 12.5, J 17.5, 1H of CH2),
4-Methyl-N′-(3-methylcyclohex-2-en-1-ylidene)benzenesulfono-
2.42 (3H, s, CH3CvO), 1.30 (3H, t, J 7.0, CH2CH3); 13C NMR hydrazide (39). Following the general procedure A(ii) using
(125 MHz; CDCl3) δ 194.3 (CvO), 171.9 (CO2Et), 150.7 (CvN), 3-methylcyclohex-2-en-1-one (37) (2.0 mL, 17.6 mmol) and
62.2 (CH2CH3), 61.7 (CHCO2Et), 33.4 (CH2), 25.7 (CH3CvO), TsNHNH2 (4.27 g, 22.9 mmol) in MeOH (15 mL) gave a
14.2 (CH2CH3); HRMS m/z (M
+
H+), found 185.0922, mixture of E-/Z- hydrazone 39 (4.38 g, 89%, 60 : 40 E : Z as
1
C8H13O3N2 requires 185.0921.
determined by H NMR NH signals) as a white solid; Rf 0.35
Ethyl 2-oxocyclopentane-1-carboxylate (34). Following the (30% EtOAc in petrol); data as lit.33
general procedure 2 using hydrazone 26 (500 mg, 1.48 mmol),
2-Diazo-5-oxohexanal (40). Following the general procedure
CH2Cl2 (170 mL) and Et3N (0.82 mL, 5.91 mmol) gave B using hydrazone 38 (1.00 g, 3.78 mmol) in CH2Cl2 (420 mL)
β-ketoester 3432 (37 mg, 16%) as a colourless oil; Rf 0.54 (30% and Et3N (2.1 mL, 15.2 mmol) to give s-E/s-Z-diazoaldehyde 40
EtOAc in petrol); 1H NMR (500 MHz; CDCl3) δ 4.19 (2H, q, (338 mg, 64%, 86 : 14 E : Z, as determined by 1H NMR CHO
J 7.0, CH2CH3), 3.14 (1H, t, J 9.5, CHCO2Et) 2.33–2.27 (4H, m, signal and NOE studies) as a yellow oil; Rf 0.38 (50% EtOAc in
CHCH2 and CHCH2CH2), 2.17–2.10 (1H, m, CH2CO), 1.89–1.83 petrol); IR (film, νmax cm−1) 2927 w, 2087 s, 1712 s, 1615 s,
(1H, m, CH2CO), 1.28 (3H, t, J 7.0, CH2CH3); 13C NMR 1280 w, 1146 s; 1H NMR (500 MHz; CDCl3) δ 9.47 (1H, s, CHO),
(125 MHz; CDCl3)
(CH2CH3), 54.9 (CHCO2Et), 38.2 (CHCH2), 27.5 (CHCH2CH2), (3H, s, CH3); 13C NMR (125 MHz; CDCl3) δ 207.7 (CvOCH3),
21.1 (CH2CvO), 14.3 (CH2CH3). 182.9 (CHO), 71.2 (CN2), 41.0 (CH2CvO), 29.9 (CH3), 16.4
Ethyl
δ 212.6 (CvO), 169.5 (CO2Et), 61.5 2.75 (2H, t, J 6.0, CH2CvO), 2.54 (2H, t, J 6.0, CH2CN2), 2.16
6-hydroxy-1-tosyl-1,4,5,6-tetrahydropyridazine-3-car- (CH2CN2); HRMS m/z (M − H+), found 139.0510, C6H7N2O2
boxylate (35). Following the general procedure B using hydra- requires 139.0513; discernible data for Z-diazoaldehyde: 1H
zone 27 (500 mg, 1.54 mmol), CH2Cl2 (170 mL) and Et3N NMR (500 MHz; CDCl3) δ 9.23 (1H, s, CHO), 2.67 (2H, t, J 6.0,
(0.86 mL, 6.17 mmol) gave tetrahydropyridazinol 35 (322 mg, CH2CvO), 2.19 (3H, s, CH3); 13C NMR (125 MHz; CDCl3)
64%) as a yellow solid; Rf 0.58 (50% EtOAc in petrol); δ 206.6 (CvOCH3), 185.5 (CHO), 42.9 (CH2CvO), 30.1 (CH3),
m.p. 122–125 °C; IR (film, νmax cm−1) 3478 br, 2981 w, 1713 w, 17.2 (CH2CHN2).
1298 w, 1167 s, 1064 s, 726 s, 666 s; 1H NMR (500 MHz; CDCl3)
2-Diazo-6-oxoheptanal (41). Following the general procedure
δ 7.88 (2H, d, J 8.0, ArCH), 7.30 (2H, d, J 8.0, ArCH), 5.87 (1H, B using hydrazone 39 (500 mg, 1.80 mmol) in CH2Cl2 (200 mL)
s, CHOH), 4.26 (2H, q, J 8.0, CH2CH3), 3.81 (1H, s, OH), 2.68 and Et3N (1.00 mL, 7.2 mmol) to give s-E/s-Z-diazoaldehyde 41
1
(1H, dd, J 5.0, J 18.5, 1H of CH2CvN), 2.41 (3H, s, ArCH3), (172 mg, 63%, 84 : 16 s-E : s-Z, as determined by H NMR CHO
2.38–2.29 (1H, m, 1H of CH2CvN), 2.14 (1H, m, 1H of signal and NOE studies) as a yellow oil; Rf 0.39 (50% EtOAc in
CH2CH2CvN), 1.57 (1H, m, 1H of CH2CH2CvN), 1.34 (3H, petrol); IR (film, νmax cm−1) 2936 w, 2084 s, 1712 s, 1629 s,
t, J 7.0, CH2CH3); 13C NMR (125 MHz; CDCl3) δ 163.4 1167 s; 1H NMR (500 MHz; CDCl3) δ 9.56 (1H, s, CHO), 2.50
(CO2Et), 144.6 (ArCMe), 142.7 (ArC), 135.2 (CvN), 129.6 (2H, t, J 7.0, CH2CvO), 2.35 (2H, t, J 7.5, CH2CN2), 2.14 (3H, s,
(ArCH), 128.2 (ArCH), 73.4 (CHOH), 61.6 (CH2CH3), 24.0 CH3), 1.79 (2H, p, J 7.0, J 7.0, CH2CH2CN2); 13C NMR
(CH2CH2CvN), 21.7 (ArCH3), 16.3 (CH2CvN), 14.2 (CH2CH3); (125 MHz; CDCl3) δ 207.9 (CvOCH3), 182.8 (CHO), 70.7 (CN2),
HRMS m/z (M + H+), found 327.1009, C14H19N2O5S requires 42.2 (CH2CvO), 30.2 (CH3), 21.3 (CH2CH2CN2), 20.6
327.1009.
(CH2CN2); HRMS m/z (M + H+), found 155.0814, C7H11N2O2
4-Methyl-N′-(3-methylcyclopent-2-en-1-ylidene)benzenesulfo- requires 155.0815; discernible data for Z-diazoaldehyde: 1H
nohydrazide (38). Following the general procedure A(ii) using NMR (500 MHz; CDCl3) δ 9.19 (1H, s, CHO), 2.54 (2H, t, J 7.0,
3-methylcyclopent-2-en-1-one (36) (2.0 mL, 20.4 mmol) and CH2CvO), 2.46 (2H, t, J 7.5, CH2CHN2), 2.17 (3H, s, CH3), 1.84
TsNHNH2 (4.94 g, 26.5 mmol) gave an E-/Z- mixture of hydra- (2H, t, J 7.0, CH2CH2CHN2); 13C NMR (125 MHz; CDCl3)
zone 38 (4.20 g, 78%, 14 : 86 E : Z as determined by 1H NMR δ 207.4 (CvOCH3), 185.4 (CHO), 41.7 (CH2CvO), 30.2 (CH3),
NH signals) as a white solid; Rf 0.51 (30% EtOAc in petrol); 22.8 (CH2CH2CHN2), 22.3 (CH2CHN2).
m.p. 149–151 °C; IR (film, νmax cm−1) 3212 w, 2914 w, 1625 w,
2-Ethoxy-3-methylcyclohex-2-en-1-one (42). To a solution of
1
1330 s, 1163 s, 1092 s; H NMR (500 MHz; CDCl3) δ 7.86 (2H, H2O2 (9.86 mL, 116 mmol, 30%) in MeOH (35 mL) at 0 °C was
d, J 8.0, 2xArCH), 7.53 (1H, s, NH), 7.30 (2H, d, J 8.0, 2xArCH), added 3-methylcyclohex-2-en-1-one (37) (4.0 mL, 35.3 mmol)
5.91 (1H, s, CH3CvCH), 2.43 (7H, d, J 16.0, ArCH3 and followed by dropwise aq NaOH (2.9 mL, 17.6 mmol, 6 M)
CH2CH2CvN), 1.91 (3H, s, CHCCH3); 13C NMR (125 MHz; maintaining the temperature below 5 °C. After 45 min, the
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mixture was poured onto ice (5 g) and extracted with CH2Cl2
(3 × 15 mL), dried (MgSO4), concentrated under reduced
pressure to give the corresponding epoxide22 (5.80 g) which
was used directly in the next step. The crude epoxide (5.80 g,
46.0 mmol) in EtOH (5 mL) was added to a refluxing solution
of Na (1.50 g, 69.0 mmol) in EtOH (20 mL). After 5 min, the
mixture was cooled to 0 °C and poured onto ice (5 g), extracted
with CH2Cl2 (3 × 15 mL), washed with brine (15 mL), dried
(MgSO4), concentrated under reduced pressure and purified by
column chromatography (20% EtOAc in petrol) to give
α-ethoxyenone 42 (1.38 g, 25% from 37) as colourless oil; Rf 0.4
(20% EtOAc in petrol); IR (film, νmax cm−1) 3441 br, 2930 m,
1673 s, 1432 w, 1196 w, 730 w; 1H NMR (500 MHz; CDCl3)
δ 3.78 (2H, q, J 7.0, CH2CH3), 2.38 (2H, t, J 7.0, CH2CvO), 2.33
(2H, t, J 7.0, CH2CCH3), 1.87 (5H, m, CH2CH2CCH3 and CCH3),
1.22 (3H, t, J 7.0, CH2CH3); 13C NMR (125 MHz; CDCl3) δ 194.9
(CvO), 148.1 (CvCCH3), 146.1 (CvCCH3), 67.6 (CH2CH3),
38.7 (CH2CvO), 31.4 (CH2CCH3), 22.2 (CH2CH2CCH3), 17.8
(CCH3), 15.5 (CH2CH3); HRMS m/z (M+) found 155.10667,
C9H14O2 requires 155.10666.
Notes and references
1 D. M. Hodgson, A. H. Labande and S. Muthusamy, Org.
React., 2013, 80, 133.
2 Y. Fegheh-Hassanpour, T. Arif, H. O. Sintim, H. A. Al-Mamari
and D. M. Hodgson, Org. Lett., 2017, 19, 3540.
3 For a recent review on alkene ozonolysis, see: T. J. Fisher
and P. H. Dussault, Tetrahedron, 2017, 73, 4233.
4 M. Regitz and G. Maas, Diazo Compounds: Properties and
Synthesis, Academic Press, London, 1986, p. 257.
5 W. G. Dauben, R. T. Hendricks, M. J. Luzzio and H. P. Ng,
Tetrahedron Lett., 1990, 31, 6969.
6 A. Ursini, R. Pellicciari, B. Tamburini, R. Carlesso and
G. Gaviraghi, Synthesis, 1992, 363.
7 D. Enders, L. Wortmann and R. Peters, Acc. Chem. Res.,
2000, 33, 157.
8 R. E. Erickson, P. J. Andrulis Jr., J. C. Collins, M. L. Lungle
and G. D. Mercer, J. Org. Chem., 1969, 34, 2961.
9 (a) U. Schöllkopf and H. Frasnelli, Angew. Chem., Int. Ed.
Engl., 1970, 9, 301; (b) U. Schöllkopf, B. Bánhidai,
H. Frasnelli, R. Meyer and H. Beckhaus, Liebigs Ann. Chem.,
1974, 1767; (c) N. R. Candeias, R. Paterna and P. M. P. Gois,
Chem. Rev., 2016, 116, 2937.
(E)-N′-(2-Ethoxy-3-methylcyclohex-2-en-1-ylidene)-4-methyl-
benzenesulfonohydrazide (43). Following the general pro-
cedure A(ii) using 2-ethoxy-3-methylcyclohex-2-en-1-one (42)
(1.32 g, 8.51 mmol) and TsNHNH2 (1.90 g, 10.2 mmol) gave 10 P. A. Cleary and K. A. Woerpel, Org. Lett., 2005, 7, 5531.
E-hydrazone 43 (2.57 g, 94%) as a white solid; Rf 0.48 (40% 11 T. Veysoglu, L. A. Mitscher and J. K. Swayze, Synthesis,
EtOAc in petrol); m.p. 115–117 °C IR (film, νmax cm−1) 3211 w,
1980, 807.
2929 w, 1639 w, 1402 m, 1162 s; 1H NMR (500 MHz; CDCl3) 12 P. H. Dussault, I. Q. Lee, H.-J. Lee, R. J. Lee, J. Niu,
δ 7.95 (1H, s, NH), 7.87 (2H, d, J 8.0, 2xArCH), 7.28 (2H, d,
J 8.0, 2xArCH), 3.68 (2H, q, J 7.0, CH2CH3), 2.39 (3H, s,
J. A. Schultz and U. R. Zope, J. Org. Chem., 2000, 65,
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CvCCH3), 2.33 (2H, t, J 7.5, CH2CN), 2.11 (2H, t, J 7.0, 13 See ESI† for details.
CH2CCH3), 1.77 (3H, s, ArCH3), 1.68 (2H, pent. J 7.0, J 7.0, 14 Y.-S. Hon, S.-W. Lin, L. Lu and Y.-J. Chen, Tetrahedron,
CH2CH2CN), 1.23 (3H, t, J 7.0, CH2CH3); 13C NMR (125 MHz;
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δ 150.7 (CvN), 145.1 (CvCOEt) 143.9 (ArC), 15 (a) H. O. House and C. J. Blankley, J. Org. Chem., 1968, 33,
CDCl3)
135.6 (ArC), 133.4 (CvCCH3), 129.5 (ArCH), 128.3 (ArCH),
67.4 (CH2CH3), 30.1 (CH2CCH3), 25.1 (CH2CN), 21.7
53; (b) C. J. Blankley, F. J. Sauter and H. O. House, Org.
Synth., 1973, V, 258.
(ArCCH3), 20.8 (CH2CH2CN), 17.5 (CvCCH3), 15.6 (CH2CH3); 16 (a) L. M. Weinstock, R. B. Currie and A. V. Lovell, Synth.
HRMS m/z (M + H+) found 323.14236, C16H23N2O3S requires
323.14239.
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Ethyl 2-diazo-6-oxoheptanoate (28). Following the general
procedure B using hydrazone 43 (1.0 g, 3.10 mmol), CH2Cl2 17 A. Padwa, Z. J. Zhang and L. J. Zhi, Org. Chem., 2000, 65,
(350 mL) and Et3N (1.73 mL, 12.4 mmol) gave diazoester 28 5223.
(348 mg, 57%) as yellow oil; Rf 0.43 (30% Et2O in petrol); data 18 Diazocarbonyl compound 28 and structurally-related sub-
identical to that reported above.
strates also undergo chiral Lewis acid-catalysed cyclisation/
1,2-shift in the enantioselective formation of α-substituted
cyclic β-ketoesters, see: W. Li, F. Tan, X. Hao, G. Wang,
Y. Tang, X. Liu, L. Lin and X. Feng, Angew. Chem., Int. Ed.,
2015, 54, 1608. See also ref. 9c.
Conflicts of interest
There are no conflicts of interest to declare.
19 H. Xu, W. Zhang, D. Shu, J. B. Werness and W. Tang,
Angew. Chem., Int. Ed., 2008, 47, 8933.
20 (a) Q.-X. Wu, H.-J. Li, H.-S. Wang, Z.-G. Zhang, C.-C. Wang
and Y.-C. Wu, Synlett, 2015, 243; (b) T. A. Yangirov,
G. R. Zubairova, R. M. Sultanova, R. Z. Biglova,
V. A. Dokichev and Yu. V. Tomilov, Russ. J. Org. Chem.,
2012, 48, 924.
Acknowledgements
We thank the EPSRC, the Higher Education Commission of
Pakistan and the University of Oxford for studentship support
(to Y. F.-H., T. A., H. O. S., respectively) and Steven Mansfield 21 CCDC 1815202 (35)† contains the supplementary crystallo-
(Oxford) for crystal structure determination.
graphic data for this paper.
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