Preparation of (2E,4E)-2-(2-benzyloxyethyl)-5-(3-methoxy-4-chlorophenyl) penta-2,4-dienal as a key intermediate in the synthesis of strobilurin B

Article abstract of DOI:10.1007/s11172-012-0215-2

(2E,4E)-2-(2-Benzyloxyethyl)-5-(4-chloro-3-methoxyphenyl)penta-2,4-dienal was obtained by the condensation of 4-benzyloxybutanal N-tert-butylimine with 4-chloro-3-methoxycinnamic aldehyde with ≥98% configurational purity and 40% yield. When 4-benzyloxy-2-triethylsilylbutanal imine was used, a 7: 3 mixture of the target (2E,4E)-dienal with its (2Z,4E)-isomer was obtained in 60% yield; the latter quantitatively isomerized to the thermodynamically preferable target (2E,4E)-dienal.

Full text of DOI:10.1007/s11172-012-0215-2

Russian Chemical Bulletin, International Edition, Vol. 61, No. 8, pp. 1616—1621, August, 2012
1616
Preparation of (2E,4E)ꢀ2ꢀ(2ꢀbenzyloxyethyl)ꢀ5ꢀ(3ꢀmethoxyꢀ
4ꢀchlorophenyl)pentaꢀ2,4ꢀdienal as a key intermediate
in the synthesis of strobilurin B
V. A. Popovsky, A. V. Stepanov, and N. Ya. Grigorieva
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: ves@ioc.ac.ru
(2E,4E)ꢀ2ꢀ(2ꢀBenzyloxyethyl)ꢀ5ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenyl)pentaꢀ2,4ꢀdienal was obꢀ
tained by the condensation of 4ꢀbenzyloxybutanal Nꢀtertꢀbutylimine with 4ꢀchloroꢀ3ꢀmethoxꢀ
ycinnamic aldehyde with 98% configurational purity and 40% yield. When 4ꢀbenzyloxyꢀ2ꢀ
triethylsilylbutanal imine was used, a 7 : 3 mixture of the target (2E,4E)ꢀdienal with its (2Z,4E)ꢀ
isomer was obtained in 60% yield; the latter quantitatively isomerized to the thermodynamicalꢀ
ly preferable target (2E,4E)ꢀdienal.
Key words: strobilurins, aldol condensation, stereocontrolled synthesis, aldimines, arylꢀ
enals, dienals.
Earlier, we have shown1 that the thermodynamic prefꢀ
erence of 2,5ꢀdisubstituted 2E,4Eꢀdienals (1) (with reꢀ
spect to their 2Z,4Eꢀisomers (1´)) opens a highly stereoꢀ
selective approach to the construction of antibiotics of
strobilurin series.2,3 In fact, starting from dienals 1a,b
(Scheme 1), a sixꢀstep sequence of stereospecific reacꢀ
tions was developed, which allowed one to obtain arylꢀ
diene esters 2a,b4 in high yields and stereochemical purity
98%. Since the latter are known as synthetic precursors
of simplest strobilurins A (3a) and X (3b) and their transꢀ
formation to 3a,b is described in the literature,5 the prepaꢀ
ration of esters 2a,b formally means the synthesis of the
strobilurins named.
In the present work, we describe the synthesis of dienal
1c, a key intermediate in the total synthesis of more comꢀ
plicated strobilurin B (3c). The present work starts a seꢀ
ries of studies on the generality of the developed approach
to the synthesis of strobilurin antibiotics, as well as the
influence of substitution in the aromatic ring on the reacꢀ
tivity and stereochemistry of transformations of aryldiene
compounds used in the previously mentioned sequence of
transformations of dienals 1 to compounds 2 (see Ref. 4).
The choice of strobilurin 3c as the object of study of versaꢀ
tility of the approach developed for the construction of
strobilurin antibiotics has been reasoned also by the fact
that the synthesis of strobilurin B by one of the methods
Scheme 1
R1 = R2 = H (a); R1 = H, R2 = OMe (b); R1 = OMe, R2 = Cl (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1599—1604, August, 2012.
1066ꢀ5285/12/6108ꢀ1616 © 2012 Springer Science+Business Media, Inc.

Strobilurin B
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1617
Scheme 2
R = H (6), Me (7)
Reagents and conditions: i. (MeO)2SO2/acetone; ii. KMnO4/H2O—Py, 50 C, 8 h; iii. LiAlH4/THF; iv. PCC/CH2Cl2; v. CH(OEt)3/
EtOH, HClO4; vi. CH2=CHOC2H5/Et2O, BF3•Et2O; vii. NaOAc•3 H2O/AcOH, 90 C.
described earlier for the synthesis of strobilurin A (3a)
failed6.
than 2% of its (2Z,4E)ꢀisomer (1´c) (1H NMR data are
given below).
According to the methodology developed for the conꢀ
struction of strobilurins, we planed to obtain dienal 1c by
the condensation of benzyloxybutanal Nꢀtertꢀbutylimine
(4a)7 with the earlier undescribed 4ꢀchloroꢀ3ꢀmethoxyꢀ
cinnamic aldehyde (5). The latter was synthesized in four
steps (Scheme 2) starting from commercially available
6ꢀchloroꢀmꢀcresol (6). Its methylation and oxidation of
the obtained methoxy derivative 7 with KMnO4 in aqueꢀ
ous pyridine using the modified by us procedure8 gave rise
to acid 8, which was routinely converted through the step
of the corresponding alcohol to the substituted benzaldeꢀ
hyde 9. The transformation of 9 to the cinnamic aldehyde
derivative 5 was performed by a twoꢀstep Nazarov—Makin
method9 through the preparation of diethyl acetal 10. The
compound BF3•Et2O has proved the optimum catalyst of
the first step of this process (the reaction of acetal 10 with
ethyl vinyl ether). In this case, ethoxy acetal 11 was obtainꢀ
ed in 85% yield (the yield of the undesirable telomer 12,
according to the 1H NMR data, did not exceed 5%). Treatꢀ
ment of ethoxy acetal 11 with the equimolar amount of
NaOAc•3H2O in AcOH gave enal 5 in total 60% yield
in two steps.
Note that 1H NMR spectroscopy showed, together
with the starting aldehyde 5 and aldehyde 14 formed
by hydrolysis of excessive imine 4a, the presence of
4ꢀchloroꢀ3ꢀmethoxycinnamic alcohol (15) (~15%, see
below) among the other components of the reaction
mixture. This allowed us to suggest that aldehyde 5
was involved not only in the condensation with the deproꢀ
tonated imine 4a, but also in the parallel Cannizzaro
reaction.
The efficiency of the condensation failed to be imꢀ
proved either when imine 4a was replaced with its
Nꢀcyclohexyl analog (4b) (Scheme 3, method B) or when
the reaction was carried out in the presence of HMPA
(Scheme 3, method C). Moreover, in the latter case, the
total yield of dienals 1c and 1´c was decreased to 27%
(however, their ratio remaining the same), whereas the
yield of alcohol 15 increased to 30%.
Alcohol 15 has not been described earlier. Its structure
unambiguosly was confirmed by an alternative synthesis,
namely by the reduction of aldehyde 5 with NaBH4
(98% yield).
The condensation of aldehyde 5 with deprotonated aldꢀ
imine 4a under conditions used earlier in the condensaꢀ
tion of 4a with cinnamic and 4ꢀmethoxycinnamic aldeꢀ
hydes7 (Scheme 3, method A), leads, after acidic hydrꢀ
olysis of the initial reaction product, imine 13, to the
target dienal 1c in 40% yield, which contained no more

1618
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
Popovsky et al.
Scheme 3
R = But (A, C, D); cycloꢀC6H11 (B)
Methods: A, B: i—iii; C: i, iv, ii, iii; D: i, vii, viii.
Reagents and conditions:
i: LDA/THF—C6H14, –15 С, –15 С0 С, 0 С, 40 min;
ii. 5/THF, –80 С, 1 ч, –80 С0 С, 3.5 h;
iii. H3O+;
v. Et3SiCl, –80 С, 30 min,–80 С0С, 4 h;
vi. H2O;
vii. 5, –80 С, 1.5 h, –80 С –20 С, 2.5 h;
viii. CHCl3, 100 С (sealed tube), 1 h.
iv. HMPA, –80 С, 30 min;
The Peterson condensation of aldehyde 5 with Et3Si
derivative (16) of aldimine 4a obtained by the silylation of
the latter turned out to be more efficient (Scheme 3, methꢀ
od D). In this case, after acidic hydrolysis of the initial
reaction products, a mixture of stereoisomeric dienals 1c
and 1´c was obtained in ~70% yield in the ratio 7 : 3,
whereas the content of alcohol 15 did not exceed 2%.
Isomeric dienals 1c and 1´c were isolated in the indiꢀ
vidual states by chromatography in 60% total yield, their
structures were unambiguosly confirmed by a combinaꢀ
tion of physicochemical methods, primarily, by high resoꢀ
lution mass spectrometry (HRMS) and 1H NMR spectroꢀ
scopy using the NOE procedure. Thus, two oneꢀproton
doublet signals at  6.95 and 7.09 were found in the region
The presence of the NOE (14%) between the proton with
the doublet of doublets signal at  7.70 in the H NMR
1
spectrum of dienal 1´c and the proton of the formyl group
indicate the Zꢀconfiguration of the C(2)=C(3) bond,
which also is confirmed by the presence of the NOE (7.5%)
between the proton with the doublet signal at  7.12 and
the protons of the allyl CH2 group.
Heating of the solution of 2Z,4Eꢀdienal 1´c in chloroꢀ
form in a sealed tube (100 C, 1 h) virtually quantitatively
gives the target 2E,4Eꢀisomer (1c). It is interesting to note
that these conditions are much milder than those reꢀ
quired for the transformation of aliphatic Zꢀenals to their
Eꢀisomers.10
In conclusion, the work performed resulted in the prepꢀ
aration of 2E,4Eꢀdienal 1c in 60% yield and configuraꢀ
tional purity 98%, which contain an aryldiene system of
the C=C bond in the configuration necessary for the conꢀ
struction of strobilurin B.
1
for the resonance of the olefin protons in the H NMR
spectrum of dienal 1c, as well as a oneꢀproton doublet of
doublets signal at  7.31. In this case, the proton with the
signal at  7.09 showed the NOE (33.9%) with the proton
of the formyl group, whereas the proton with the doublet
of doublets signal gave the NOE (5%) with the protons of
the allyl CH2 group. These data allow us to, first, assign
the doublet at  7.09 to HC(3), and, second, make a conꢀ
clusion on the (E)ꢀconfiguration of the C(2)=C(3) bond.
Experimental
UV spectra were recorded on a Uꢀ1900 Spectrophotometer
instrument in ethanol solution, IR spectra were recorded on
a Specord Mꢀ80 spectrometer for neat samples or (for alcohols)
in CHCl3 solution. 1H and 13C NMR spectra of solutions in
CDCl3 were recorded on a Bruker ACꢀ200 spectrometer relative
to the signals of the solvent ( 7.27 and 77.0, respectively). The
signals for the vinyl protons in the 1H NMR spectra were asꢀ
1
The second doublet signal in the H NMR spectrum of
dienal 1c ( 6.95) was assigned, respectively, to HC(5). Its
spinꢀspin coupling constant with HC(4) (16.2 Hz) indiꢀ
cates the Eꢀconfiguration of the C(4)=C(5) bond. The
structure of 2Z,4Eꢀdienal 1´c was confirmed similarly.

Strobilurin B
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1619
signed based on the NOEꢀexperiment. The signals in the
13C NMR spectra of isomeric compounds 1c and 1´c were asꢀ
signed with allowance for the calculated spectra obtained using
the MestReNova 6.0.2 program (Mestrelab research S.I.,
www.mestrelab.com, 2009) and the spectral data for the relative
compounds.11 The numeration of atoms for some compounds in
Schemes 2 and 3 is given so that to make convenient description
of their NMR spectra and not always corresponds to the IUPAC
nomenclature requirements. High resolution mass spectra
(HRMS) were measured on a micrOTOF II (Bruker Daltonics)
instrument using electrospray ionization (ESI), the scanning
range from m/z 50 to 3000, positive ions (capillary voltage 4500 V).
The samples were injected using a syringe. The solvent acetoꢀ
nitrile, the solution flow speed 3 m min–1. The interface temꢀ
perature 180 C, the sprayer gas nitrogen (4.0 L min–1). Melting
points were measured on a Kofler heating stage and were not
corrected. Column chromatography was performed on Silicagel
60 (0.04—0.06 mm, Fluka). The solvents were purified using the
following methods: diethyl ether and THF were kept over KOH,
with subsequent distillation over Na and LiAlH4, then, they were
refluxed with Naꢀketyl benzophenone until a blue color was
persistent and distilled directly into the reaction vessel; hexane
was distilled over Na; MeOBut was purified by distillation.
A solution of LDA was prepared directly in the reactor from
equivalent amount of diisopropylamine and 1.3—1.5 M hexane
solution of BuLi. Experiments with the use of BuLi and LDA
were carried out under argon, using a glassware which was dried
at 160 C during 12 h and cooled in the flow of argon. The
standard treatment of the organic extracts included their neutraꢀ
lization, drying with Na2SO4, and concentration in vacuo on
a rotary evaporator. The reactants NaBH4, HC(OEt)3, and 6ꢀchloꢀ
roꢀmꢀcresol (Fluka) were used without additional purification.
4ꢀChloroꢀ3ꢀmethoxybenzaldehyde (9) was obtained (see
Scheme 2) as described earlier8 as colorless crystals with
m.p. 53—54 C. It was shown that transformation of comꢀ
pound 7 to acid 8 at 50 C reached completion within 8 h, rather
than within 24 h as it was reported in the work.8 Physicochemiꢀ
cal characteristics of compounds 7—9 correspond to the literaꢀ
ture data.8
4ꢀChloroꢀ3ꢀmethoxycinnamic aldehyde (5). Step 1. The comꢀ
pound BF3•Et2O (0.1 mL) was added to acetal 10 (5.2 g,
21.3 mmol) (Ar) at room temperature. The orange solution obꢀ
tained was cooled to 0 C, followed by addition of a solution of
ethyl vinyl ether (1.5 g, 20.8 mmol) in Et2O (8 mL) over 10 min.
The reaction mixture was heated to reflux, which was continued
for 3 h, then the mixture was cooled to obtain, after the standard
treatment, crude 3ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenyl)ꢀ3ꢀethoxyproꢀ
panal diethyl acetal (11) (6.6 g) as colorless liquid (which, acꢀ
cording to the 1H NMR data, contained 85% of the major comꢀ
pound). The acetal was used in subsequent step without addiꢀ
tional purification.
Step 2. A solution of ethoxy acetal 11 (7.2 g, 22.75 mmol)
and AcONa•3 H2O (3.1 g, 22.8 mmol) in glacial acetic acid
(20 mL) was stirred at 90 C for 4 h, then the mixture was poured
into cold water and extracted with MeOBut. After the standard
treatment of the extract, a mixture of crystalline reaction prodꢀ
ucts (4.7 g) was obtained, with the content of the target aldehyde
being about 85% (NMR data). Recrystallization from MeOBut
gave pure aldehyde 5 (3.5 g, 78%), m.p. 92—94 C. Found (%):
C, 61.08; H, 4.80; Cl, 18.12. C10H9ClO2. Calculated (%):
C, 61.08; H, 4.61; Cl, 18.03. HRMS, m/z; found: 219.0191;
calculated for C10H9ClO2: [M + Na]+, 219.0183. UV (max/nm
()): 320 (15600), 292 (26600). IR, /cm–1: 3314, 3105, 3013,
2990, 2946, 2851, 2766, 2244, 1873, 1676, 1624, 1592, 1572,
1483, 1474, 1417, 1401, 1316, 1300, 1288, 1269, 1239, 1195,
1176, 1129, 1063, 1029, 1015, 985, 871, 850, 795, 744, 692,
615, 596. 1H NMR, : 3.95 (s, 3 H, H3CO); 6.69 (dd, 1 H,
HC(2), J1 = 15.9 Hz, J2 = 7.6 Hz); 7.09 (s, 1 H, HC(2´));
7.11 (d, 1 H, HC(6´), J = 8.1 Hz); 7.42 (d, 1 H, HC(5´),
J = 8.1 Hz); 7.43 (d, 1 H, HC(3), J = 15.9 Hz); 9.71 (d, 1 H,
HC(1), J = 7.6 Hz). 13C NMR, : 56.17 (OMe); 110.94
(C(2´)); 121.78 (C(6´)); 125.90 (C(4´)); 128.99 (C(2)); 130.77
(C(5´)); 133.85 (C(1´)); 151.29 (C(3)); 155.45 (C(3´)); 193.18
(C(1)).
4ꢀBenzyloxybutanal Nꢀtertꢀbutylimine (4a) was obtained as
described earlier7 in 94% yield. Physicochemical characteristics
of compound 4a correspond to the literature data.7
4ꢀBenzyloxybutanal Nꢀcyclohexylimine (4b) was obtained
similarly to imine 4a from 4ꢀbenzyloxybutanal (4.5 g, 25 mmol)
and cyclohexylamine (2.8 g, 28 mmol), The yield was 95%.
1H NMR, : 1.00—2.00 (m, 6 CH2); 2.30 (m, 2 H, H2C(2)); 2.88
(m, 1 H, HC(1´)); 3.50 (t, 2 H, H2C(4), J = 6 Hz); 4.50 (s, 2 H,
H2CPh); 7.30 (m, 5 H, Ph); 7.67 (t, 1 H, HC=N, J = 6 Hz). The
thermally unstable imine 4b was dried until the weight was conꢀ
stant at 20 C and the pressure of 2 Torr and was used in subseꢀ
quent reactions without additional purification.
4ꢀBenzyloxyꢀ2ꢀtriethylsilylbutanal Nꢀtertꢀbutylimine (16).
A solution of imine 4a (1.87 g, 8 mmol) in THF (15 mL) was
added to a stirred solution of LDA (9 mmol) in THF (15 mL)
and hexane (4.5 mL) at –20 C over 40 min, the reaction mixꢀ
ture was heated to –5 C and stirred at this temperature for
30 min. A light orange solution obtained was cooled to –80 C,
followed by addition of a solution of Et3SiCl (1.27 g, 8.45 mmol)
in THF (15 mL) over 15 min Then, the mixture was stirred for
30 min at –80 C, warmed up to 0 C over 4 h, and quenched
with cold water. The aqueous layer was separated and extracted
with MeOBut. After the standard treatment of the combined
organic extracts and drying of the residue in vacuo (2 Torr) until
the weight was constant, imine 16 (2.6 g, 94%) was obtained,
which was used in the next step without additional purification.
4ꢀChloroꢀ3ꢀmethoxybenzaldehyde diethyl acetal (10). A 60%
solution of HClO4 (0.3 mL) was added to a solution of aldehyde 9
(10.5 g, 61.6 mmol) and ethyl orthoformate (11 g, 74.3 mmol) in
anhydrous ethanol (100 mL) (Ar) with stirring, the reaction mixꢀ
ture was stirred for 5.5 h at room temperature, followed by addiꢀ
tion of a 10% solution of NaOH in MeOH (2.5 mL), ethanol was
evaporated in vacuo after 15 min. The residue was dissolved in
MeOBut (100 mL) and after standard treatment an oily liquid
(14.6 g) was obtained, which was fractionally distilled in vacuo to
obtain acetal 10 (12.6 g, 84%), b.p. 106—110 C (1 Torr). Found
(%): C, 58.94; H, 7.15; Cl, 14.50. C12H17ClO3. Calculated (%):
C, 58.90; H, 7.00; Cl, 14.49. HRMS, m/z: found: 267.0763;
calculated for C12H17ClO3: [M + Na]+, 267.0758. IR, /cm–1
:
2976, 2932, 2880, 1588, 1584, 1560, 1488, 1464, 1400, 1372,
1352, 1344, 1332, 1296,1268, 1256, 1172, 1112, 1096, 1064, 1032,
864, 828, 784. 1H NMR, : 1.25 (t, 6 H, 2 CH2CH3, J = 7.1 Hz);
3.58 (m, 4 H, 2 OCH2); 3.95 (s, 3 H, H3CO); 5.46 (s, 1 H,
OCHO); 7.00 (dd, 1 H, HC(6), J1 = 8.1 Hz, J2 = 1.6 Hz); 7.08
(d, 1 H, HC(2), J = 1.6 Hz); 7.34 (d, 1 H, HC(5), J = 8.1 Hz).
13C NMR, : 15.13 (CH3CH2); 56.04 (OMe); 61.10 (OCH2);
100.90 (OCHO); 110.30 (C(2)); 119.60 (C(6)); 122.30 (C(4));
129.70 (C(5)); 139.30 (C(1)); 154.90 (C(3)).

1620
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
Popovsky et al.
Physicochemical characteristics of imine 16 correspond to the
literature data.12
135.98 (C(1)); 138.31 (Ph); 139.25 (C(2)); 140.52 (C(5)); 150.21
(C(3)); 155.25 (C(3)); 194.25 (C(1)).
(2E,4E)ꢀ2ꢀ(2ꢀBenzyloxyethyl)ꢀ5ꢀ(4ꢀchloroꢀ3ꢀmethoxyꢀ
phenyl)pentaꢀ2,4ꢀdienal (1c). A. A solution of imine 4a (1.8 g,
7.7 mmol) in THF (20 mL) was added to a solution of LDA
(9.3 mmol) in THF (24 mL) and hexane (5.5 mL) at –15 C over
1.5 h. The reaction mixture was warmed up to 0 C and stirred
for 40 min at this temperature. Then, the dark orange solution
obtained was cooled to –80 C, followed by addition of a soluꢀ
tion of aldehyde 5 (0.9 g, 4.58 mmol) in THF (20 mL) and
stirring for 30 min at –80 C. Then, the reaction mixture was
warmed up to 0 C over 3.5 h and kept at 4—5 C for 13 h. The
solution obtained was added to a mixture of 3% aq. HCl (100 mL)
and MeOBut (50 mL), stirred for 1 h, the layers were separated.
The aqueous layer sequentially was extracted with MeOBut
(3×30 mL) and chloroform (2×30 mL). After the standard treatꢀ
ment of the combined ethereal extracts, a mixture of reaction
products (1.7 g) was obtained, which contained dienal 1c (with
impurities of isomer 1´c 2%) and cinnamic alcohol derivative
15 in the ratio of 2 : 1, as well as 8—10% of the starting cinnamic
aldehyde 5 and 18% of aldehyde 14 (1H NMR data). Flashꢀ
chromatography of this mixture on SiO2 (40 g) using a gradient
elution from light petroleum to MeOBut yielded dienal 1c (0.7 g)
containing 2% of isomer 1´c and about 10% of aldehyde 5, as
well as alcohol 15 (0.3 g) (see below). The standard treatment of
the chloroform extract gave a mixture of reaction products (0.9 g),
which according to the 1H NMR data contained 65% of comꢀ
pound 13, the Nꢀtertꢀbutylimine of dienal 1c. 1H NMR, , of
compound 13: 1.22 (s, 9 H, But); 2.99 (t, 2 H, H2C(1´),
J = 6.8 Hz); 3.65 (t, 2 H, H2C(2´), J = 6.8 Hz); 3.90 (s, 3 H,
MeO); 4.55 (s, 2 H, CH2Ph); 6.58 (d, 1 H, HC(3), J = 11.2 Hz);
6.67 (d, 1 H, HC(5), J = 15.6 Hz); 6.97 (s, 1 H, HC(2)); 7.60
(m, 8 H, Ar + HC(4)); 7.85 (s, 1 H, HC(1)). The mixture was
dissolved in acetone (17 mL), followed by addition of a solution
of H2SO4 (0.1 mL) in water (5 mL) and reflux for 4.5 h. Then,
the mixture was cooled, neutralized with NaHCO3, acetone was
evaporated in vacuo, and the residue was diluted with water. The
aqueous solution was extracted with MeOBut (3×20 mL), the
combined extracts subsequently were subjected to the standard
treatment, the mixture of reaction products was chromatoꢀ
graphed on SiO2 as described above to obtain dienal 1c (0.3 g),
in which the content of both dienal 1´c and aldehyde 5 did not
exceed 2%. A repeated chromatography of the combined fracꢀ
tions of dienal 1c isolated from the ethereal and chloroform
extracts on SiO2 using elution with benzene allowed us to obtain
dienal 1c (0.65 g, 40%), which did not contain aldehyde 5. Dieꢀ
nal 1c, b.p. (decomp.) 160 C (a bath, 0.065 Torr). HRMS,
m/z: found 379.1063; calculated for C21H21ClO3: [M + Na]+,
379.1071. UV (max/nm ()): 338 (18600), 218 (11800). IR,
/cm–1: 3326, 3086, 3063, 3031, 2964, 2931, 2857, 2718, 1673,
1620, 1588, 1570, 1491, 1455, 1414, 1372, 1298, 1257, 1197,
1184, 1098, 1062, 1030, 1004, 968, 870, 806, 739, 698. 1H NMR,
: 2.81 (t, 2 H, H2C(1´), J = 6.5 Hz); 3.60 (t, 2 H, H2C(2´),
J = 6.5 Hz); 3.88 (s, 3 H, H3CO); 4.50 (s, 2 H, H2CPh); 6.95
(d, 1 H, HC(5), J = 16.2 Hz); 6.98 (d, 1 H, HC(2), J = 1.7 Hz);
7.02 (dd, 1 H, HC(6), J1 = 8.2 Hz, J2 = 1.7 Hz); 7.09 (d, 1 H,
HC(3), J = 11.0 Hz); 7.31 (dd, 1 H, HC(4), J1 = 16.2 Hz, J2 =
= 11.0 Hz); 7.34 (d, 1 H, HC(5), J = 8.2 Hz); 9.51 (s, 1 H,
HC(1)). 13C NMR, : 25.72 (C(1´)); 56.14 (OMe); 69.03 (C(2´));
73.00 (CH2Ph); 110.48 (C(2)); 120.73 (C(6)); 123.76 (C(4));
124.70 (C(4)); 127.36, 127.49, 128.28 (Ph); 130.50 (C(5));
B. The condensation of cinnamic aldehyde 5 with imine 4b
was carried out as described in method A for imine 4a. The
composition of the reaction products and the yield of the target
dienal 1c were close to those obtained in method A.
C. The process was carried out as described in method A.
Imine 4a (2.57 g, 11 mmol) was deprotonated using LDA, then
cooled to –80 C, followed by a sequential addition of HMPA
(2.3 mL) and aldehyde 5 (7.6 mmol). Then, the mixture was
stirred for 1 h at –80 C and warmed up to 0 C over 3.5 h. Then,
the mixture was treated as described in method A and after chroꢀ
matography on SiO2, dienal 1c was obtained, which contained
2% of isomer 1´c, and cinnamic alcohol 15 in 27% and 30%
yields, respectively.
D. The silyl derivative 16 (3.71 g, 10.7 mmol) was deprotoꢀ
nated as described in method A for imine 4a, then aldehyde 5
(7.2 mmol) was added at –80 C. The reaction mixture was
stirred for 1.5 h at –80 C, then warmed up to –20 C over 2.5 h
and kept at –20 C for 13 h, followed by treatment as described
in method A. The standard treatment of the combined ethereal
extracts (3.1 g) led to a mixture of reaction products containing
dienal 1c, its (2Z,4E)ꢀisomer (1´c), and the starting aldehyde 5
in the ratio of 1 : 1.5 : 1; the content of cinnamic alcohol 15 in
the mixture did not exceed 2% (1H NMR data). The double
chromatography of this mixture on SiO2 as described in method
A furnished dienal 1c (16% yield) and dienal 1´c (18% yield).
(2Z,4E)ꢀ2ꢀ(2ꢀBenzyloxyethyl)ꢀ5ꢀ(4ꢀchloroꢀ3ꢀmethoxyphenꢀ
yl)pentaꢀ2,4ꢀdienal (1´c). HRMS, m/z; found: [M + Na]+,
379.1064; C21H21ClO3; calculated: [M + Na]+, 379.1071. UV
(max/nm, ()): 336 (22100), 245 (6600), 218 (13700). IR, /cm–1
:
3468, 3087, 3030, 2929, 2859, 1721, 1664, 1617, 1588, 1571,
1491, 1455, 1412, 1363, 1298, 1257, 1196, 1178, 1135, 1099,
1063, 1029, 969, 911, 868, 806, 737, 699, 620, 456. 1H NMR, :
2.64 (t, 2 H, H2C(1´), J = 6.4 Hz); 3.61 (t, 2 H, H2C(2´),
J = 6.4 Hz); 3.96 (s, 3 H, H3CO); 4.52 (s, 2 H, H2CPh); 6.77 (d,
1 H, HC(5), J = 15.2 Hz); 7.01 (d, 1 H, HC(2), J = 1.7 Hz);
7.04 (dd, 1 H, HC(6), J1 = 8.3 Hz, J2 = 1.7 Hz); 7.12 (d, 1 H,
HC(3), J = 11.9 Hz); 7.33 (m, 5 H, Ph); 7.37 (d, 1 H, HC(5),
J = 8.3 Hz); 7.70 (dd, 1 H, HC(4), J1 = 15.2 Hz, J2 = 11.9 Hz);
10.38 (s, 1 H, HC(1)). 13C NMR, : 30.88 (C(1´)); 56.17 (OMe);
68.84 (C(2´)); 72.89 (CH2Ph); 110.28 (C(2)); 120.43 (C(6));
121.72 (C(4)); 123.57 (C(4)); 127.57, 127.66, 128.39 (Ph);
130.54 (C(5)); 136.00 (C(1)); 138.31 (Ph); 139.45 (C(2), C(5));
146.09 (C(3)); 155.29 (C(3)); 189.82 (C(1)).
The residue (1.5 g) from the combined chloroform extracts
containing imine 13 was hydrolyzed as described in method A to
obtain after chromatography on SiO2 an additional amount
(0.75 g, 26%) of dienal 1c.
Heating a solution of dienal 1´c in chloroform in a sealed
tube at 100 C during 1 h quantitatively gives the target dienal 1c,
the content of (2Z,4E)ꢀisomer in which does not exceed 2%
(1H NMR data). The total yield of the target (2E,4E)ꢀdienal 1c
was 60%.
4ꢀChloroꢀ3ꢀmethoxycinnamic alcohol (15, alternative syntheꢀ
sis) was obtained by the reduction of aldehyde 5 upon the action
of NaBH4 in EtOH according to the standard procedure, The
yield was 98%, m.p. 64—65 C (from a mixture of Et2O—hexane
(1 : 1)). Found (%): C, 60.40; H, 5.56; Cl, 17.76. C10H11ClO2.
Calculated (%): C, 60.46; H, 5.58; Cl, 17.85. HRMS, m/z: found:
199.0522; calculated for C10H11ClO2: [M + H]+, 199.0520.

Strobilurin B
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1621
UV spectrum, max/nm (): 296 (4630), 256 (17375), 218 (23860).
IR, /cm–1: 3611, 3447, 3019, 2966, 2942, 2918, 2870, 2840,
1593, 1575, 1491, 1465, 1409, 1382, 1295, 1254, 1223, 1207,
1193, 1174, 1144, 1087, 1066, 1031, 1007. 968, 859, 797, 728,
696, 668. 1H NMR, : 3.91 (s, 3 H, H3CO); 4.33 (d, 2 H,
CH2OH, J = 5.3 Hz); 6.34 (dt, 1 H, HC(2), J1 = 15.9 Hz,
J2 = 5.3 Hz); 6.57 (d, 1 H, HC(3), J = 15.9 Hz); 6.91 (d, 1 H,
HC(6´), J = 8.2 Hz); 6.92 (s, 1 H, HC(2´)); 7.29 (d, 1 H, HC(5´),
J = 8.2 Hz). 13C NMR, : 56.01 (OMe); 63.37 (C(1)); 109.85
(C(2´)); 119.50 (C(6´)); 121.69 (C(4´)); 129.30 (C(2)); 130.03
(C(3)); 130.15 (C(5´); 136.69 (C(1´)); 154.98 (C(3´)).
6. H. Sutter, Tetrahedron Lett., 1989, 30, 5417.
7. N. Ya. Grigorieva, A. G. Smirnov, V. A. Popovskу, A. V.
Stepanov, Russ. Chem. Bull. (Int. Ed.), 2009, 58, 312 [Izv.
Akad. Nauk, Ser. Khim., 2009, 310].
8. F. Claudi, G. Giorgioni, A. D. Stefano, M. P. Abbracchio,
A. M. Paoletti, W. Baduini, J. Med. Chem., 1992, 35, 4408.
9. I. N. Nazarov, S. M. Makin, Zh. Obshch. Khim., 1959, 29,
3685 [J. Gen. Chem. USSR (Engl. Transl.), 1959, 29]; S. M.
Makin, G. A. Ermakova, O. A. Shavrygina, A. P. Pleshaꢀ
kova, V. N. Voznesenskii, Zh. Org. Khim., 1979, 15, 1852
[J. Org. Chem. USSR (Engl. Transl.), 1979, 15].
10. N. Ya. Grigorieva, O. N. Yudina, O. A. Pinsker, E.D. Daeꢀ
va, A. M. Moiseenkov, Bull. Acad. Sci. USSR, Div. Chem.
Sci. (Engl. Transl.), 1990, 39, 84 [Izv. Akad. Nauk SSSR,
Ser. Khim., 1990, 97].
11. I. M. Avrutov, N. Ya. Grigorieva, V. S. Bogdanov, A. M.
Moiseenkov, Bull. Acad. Sci. USSR, Div. Chem. Sci.
(Engl. Transl.), 1987, 36, 2033 [Izv. Akad. Nauk SSSR, Ser.
Khim., 1987, 2194].
References
1. N. Ya. Grigorieva, A. G. Smirnov, V. A. Popovsky, A. V.
Stepanov, Mendeleev Commun., 2008, 18, 84.
2. J. M. Clough, Nat. Prod. Rep., 1993, 10, 565.
3. H. Sauter, W. Steglich, T. Anke, Angew. Chem., Int. Ed.,
1999, 38, 1329.
12. R. Baudouy, Ph. Prince, Tetrahedron, 1989, 45, 2067.
4. N. Ya. Grigorieva, V. A. Popovskii, A. V. Stepanov, E. D.
Lubuzh, Izv. Akad. Nauk, Ser. Khim., 2010, 2033 [Russ. Chem.
Bull., Int. Ed., 2010, 59, 2086].
5. K. Beautement, J. M. Clough, P. J. de Fraine, Ch. R. A.
Godfrey, Pestic. Sci., 1991, 31, 499.
Received May 21, 2012;
in revised form June 21, 2012