Synthesis of a para-quinone macrolactam related to geldanamycin by ring closing metathesis

Article abstract of DOI:10.1016/j.tet.2004.06.147

Model studies conducted with the α,β,γ,δ-unsaturated 3-alkenyl-2,4,5-trimethoxyanilides 11 revealed that a ring closing metathesis (RCM) of these compounds is possible if the ansa chain contains more than 14 atoms. The (Z)-configurated products 12c-e were

Full text of DOI:10.1016/j.tet.2004.06.147

Tetrahedron 60 (2004) 9659–9673
Synthesis of a para-quinone macrolactam related to geldanamycin
by ring closing metathesis
*
Aude Lemarchand and Thorsten Bach
¨ ¨ ¨
Lehrstuhl fur Organische Chemie I, Department of Chemistry, Technische Universitat Munchen, Lichtenbergstr. 4,
85747 Garching, Germany
Received 26 April 2004; revised 16 June 2004; accepted 18 June 2004
Available online 24 August 2004
Abstract—Model studies conducted with the a,b,g,d-unsaturated 3-alkenyl-2,4,5-trimethoxyanilides 11 revealed that a ring closing
metathesis (RCM) of these compounds is possible if the ansa chain contains more than 14 atoms. The (Z)-configurated products 12c–e were
obtained in good yields (77–87%) and with perfect simple diastereoselectivity. Since the oxidation of the 2,4,5-trimethoxyanilides led
predominantly to undesired ortho-quinones such as 15 or to para-azaquinones such as 16 the macrocyclic 2,5-di-iso-propoxy-4-
methoxyanilide 22 was prepared. The iso-propyl protecting groups could be selectively cleaved and the intermediate para-hydroquinone
oxidized on air to the desired para-quinone 2 (86% yield). The compound shows some key features (macrolactam ring with the same ring
size, a,b,g,d-unsaturated anilide, para-quinone) of geldanamycin.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
We envisioned an access to the geldanamycin macrocycle
by ring closing metathesis (RCM)11 between carbon atoms
C-4 and C-5. Preliminary studies revealed that this strategy
is feasible.12 A first target, which contains the same para-
quinone chromophore, the (E,Z)-a,b,g,d-unsaturated
anilide, and an ansa chain identical in chain length to
geldanamycin, is compound 2 the synthesis of which was
undertaken (Fig. 1).
Geldanamycin (1)1 is an antitumor agent with a medium
50% growth inhibition (GI50) of 180 nM against 60 tumor
cell lines tested by the national cancer institute (NCI). The
GI50 against the most sensitive cell lines was found to be as
low as 13 nM.2 Its antitumor activity is attributed to a
binding to the heat shock protein 90 (Hsp 90)3,4 although
other modes of action have been discussed.5 Structures of
Hsp 90–geldanamycin complexes have been elucidated and
the most important binding motifs have been identified.6
Geldanamycin binds to the N-terminal ATP/ADP-binding
domain of Hsp 90 and inhibits the ATPase activity which is
essential for the function of the enzyme. Based on its
molecular structure, geldanamycin can be classified as an
ansamycin.7 It differs from other ansamycins (e.g., herbi-
mycin A) by the additional methoxy substituent at the
quinone ring (C-17) and by the substitution in the ansa
chain. Early synthetic efforts by Schill et al.8 established the
possibility to construct the macrocycle by C–C bond (C-15/
C-16) formation at a suitable arene and subsequent
macrolactamization. After the discovery of its antitumor
activity geldanamycin was the target of many modification
studies from which more active bioavailable compounds
derived.9 The first total synthesis of geldanamycin was
recently accomplished by Andrus and co-workers.10
Figure 1. Geldanamycin (1) and the para-quinone macrolactam 2.
In this account, we provide full details on the synthesis of
appropriate precursors which allowed us to study the RCM
for the preparation of macrocycles with different ring sizes.
We discuss the oxidation of the initially studied 2,4,5-
trimethoxyanilides and report on the structure elucidation of
the oxidation products. The mechanism of the oxidation is
briefly discussed. Finally, the synthesis of compound 2 is
Keywords: Ring closing metathesis; Ansa chain; Geldanamycin.
* Corresponding author. Tel.: C49-89-28913330; fax: C49-89-28913315;
e-mail: thorsten.bach@ch.tum.de
described starting
methoxybenzene.
from
1,4-di-iso-propoxy-2-
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.147

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A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
the use of an excess of the halide. The u-alkenyliodides 7
employed as electrophiles in the alkylation step are
literature known and were prepared according to reported
procedures.14–18 The alkylation reaction proceeded nicely
and yielded the u-alkenylarenes 8 (Scheme 2). Regio-
selective nitration using nitric acid in acetic acid8 as the
solvent furnished the nitro compounds 9 in very good yields.
The reduction to the anilines 10 was accomplished by
treatment of the nitroarenes with tin in aqueous hydrochloric
acid at 60 8C (Table 1).19
Scheme 1. Preparation of 2-methyl-2,4-pentadienoic acid (5).
2. Ring closing metathesis
The acylation of anilines 10 was initially projected with the
chloride of acid 5 or via a mixed anhydride. Despite several
attempts with SOCl2 or (COCl)2 as reagents, the chloride
could not be obtained from 5. Contrary to that, sorboyl
chloride,20 for example, was readily accessible from sorboic
acid using common conditions (SOCl2 in refluxing ben-
zene). The acylation of aniline 10c with sorboyl chloride
was facile but it was not further optimized (56% yield).
Upon attempted activation of acid 5 with pivaloyl chloride
and subsequent reaction with aniline 10c the sole product
obtained was the corresponding N-pivaloyl aniline (63%
yield). Experiments to use an in situ activation with
common peptide coupling reagents commenced with
dicyclohexyl carbodiimide (DCC). Minor product for-
mation (27% yield) was observed when aniline 10c was
treated with DCC and 1-hydroxybenzotriazole (HOBt) in
CH2Cl2 at ambient temperature for three days. An
improvement in yield and in the rate of conversion was
achieved upon addition of bases and upon changing the
solvent to DMF. The best result was recorded with di-iso-
propylethylamine (Hu¨nig base) in DMF (36% yield).
Further improvements were due to a modification of the
additive. Both 1-hydroxy-7-azabenzotriazole (HOAt) and
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazole (HOOBt)
Studies on the RCM commenced with attempts to
synthesize suitable 3-u-alkenyl-2,4,5-trimethoxyanilides
of 2-methyl-2,4-pentadienoic acid (5). The acid itself was
prepared (Scheme 1)13 from Wittig reagent 3 and acrolein
via its methyl ester which was subsequently saponified to
the free acid.
The lithiation of 1,2,4-trimethoxybenzene (6) with n-butyl
lithium (1.1 equiv) was optimized by quenching the
lithiated intermediate with iodine and by subsequent GLC
analysis. The reaction proceeded slowly at K78 8C and at
0 8C in THF as the solvent (!50% conversion after 1 h). At
ambient temperature the conversion was rapid and lithiation
was complete after less than an hour. Prolonged stirring at
room temperature led to decomposition.
Based on the preliminary experiments the lithiation of 6 was
conducted by adding n-butyl lithium to the arene and
keeping the reaction mixture for 45 min at room tempera-
ture. After cooling to 0 8C, the corresponding alkyl halide
was added. Although Schill et al. had used bromoalkanes in
their alkylation experiments8 we found the iodides superior
allowing a smoother and cleaner conversion than the
corresponding bromides and—more importantly—avoiding
Scheme 2. Preparation of the RCM precursors 11 and RCM to products 12 (for yields and further comments see Table 1).

A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
9661
Table 1. Yields of isolated products for the five individual steps in the
conversion of arene 6 to the RCM products 12 (cf. Scheme 2)
removed the RCM is not stereoselective any more. When
the anilide 13 of 2-methyl-2-pentenoic acid was employed
as a substrate the 20-membered ansa compound 14 was
obtained as a mixture of (E)- and (Z)-isomers (Scheme 3).
Since the isomers were not separable, configurations could
not be assigned to the individual isomers.
n
Iodide
8 (%)
9 (%)
10 (%)
11 (%)
12 (%)
a
1
2
3
4
5
7a
7b
7c
7d
7e
59
76
76
73
73
73
95
98
95
94
82
77
84
79
83
72
58
66
68
63
—
—
b
66c
77
87
a Only starting material (50%) and dimer/oligomer (25%) were isolated.
b Only starting material (84%) and dimer/oligomer (10%) were isolated.
c Starting material (14%) was isolated. The yield based on recovered
starting material is 77%.
gave better yields than HOBt under otherwise identical
conditions (up to 56% yield). Still, the reaction was
unsatisfactory being not fully reproducible and sluggish at
times. A significant breakthrough was achieved by sub-
stituting the activation reagent DCC. O-(7-Azabenzotriazol-
1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate
(HATU) in the presence of HOAt21 turned out to be the
reagent combination of choice which guaranteed signifi-
cantly better conversions in a generally applicable reaction.
The anilides 11 were so obtained in 58–72% yield.
Scheme 3. RCM of u-alkenylanilide 13 to a mixture of diastereomeric
lactams 14.
3. Oxidation reactions
Although there is literature precedence for the oxidation of
1,2,4-trimethoxybenzenes to 2-methoxy-para-benzo-
quinones,19,22 ansa compounds related to 12c–e had earlier
been shown to give the 4-methoxy-ortho-benzoquinones
upon oxidation with concentrated nitric acid in acetic acid
solution.8 This result was corroborated in recent studies by
Andrus et al.10,23 Upon oxidation of an immediate
geldanamycin precursor with 70% nitric acid they obtained
in 55% yield a 10:1 mixture of the undesired ortho- and the
desired para-geldanamycin. Oxidation with other reagents
(Ag2O or MnO2 impregnated with nitric acid) led to the
formation of a para-azaquinone. Subsequent model studies
showed that conformationally unrestricted 3-alkyl-2,4,5-
trimethoxyanilides yielded predominantly ortho-quinones
upon oxidation.23
Details of the RCM have been discussed already in our
preliminary paper.12 Key issues are a low concentration of
the substrate (0.5 mM) in CH2Cl2 as the solvent, the use of
conventional Grubbs I catalyst (10 mol%) with an ethyl-
idene or benzylidene ligand at the ruthenium center, and the
alkenyl chain length as the determining factor for the
success of the RCM. Indeed, ring sizes of 18–20
(compounds 12c–e) were readily accessible whereas the
formation of the 16- or 17-membered ansa compounds 12a
and 12b could not be achieved. Apparently, the nonenyl and
docenyl group do under the given restriction by the a,b,g,d-
unsaturated anilide not reach the terminal double bond of
the diene and an ansa chain with less than 15 atoms does not
form. The double bonds which are in the course of the
metathesis reaction established between carbon atom C-4
and C-5 of the products 12c–e are uniformly configurated.
The coupling constant between the protons H-4 and H-5 in
all compounds 12c–e is around Jy10 Hz. Strong NOE
contacts were observed for these protons in compound 12e
supporting the assignment of the double bond configuration
as (Z). Further 1H NMR NOESY data which are in line with
a C-4/C-5 (Z)-configuration were obtained from oxidation
products of compounds 12c and 12e (vide infra).
Our oxidation experiments were conducted with ceric
ammonium nitrate (CAN) and pyridine-2,6-dicarboxylic
acid N-oxide24 in acetonitrile/water at 0 8C. They confirmed
that an oxidation of either precursor 12c–e to a para-
quinone was not possible. The reactions with substrates 12c
and 12e led to well defined oxidation products in moderate
yields. Compound 12c gave ortho-quinone 15 (30% yield)
and compound 12e furnished para-azaquinone 16 (64%
1
yield). H NMR NOESY studies (Fig. 2) revealed that the
18-membered ansa compound 15 is perfectly planar in the
region C-16 (arene) to C-6 while the 20-membered ring is
somewhat twisted. This fact is indicated by weak NOE
contacts between H-3 and H-4 as well as between H-19 and
If the conformational restriction exerted by the C-2/C-3
double bond in the 3-alkenyl-2,4,5-trimethoxyanilide is
Figure 2. Significant NOE contacts (- - - weak, — strong) recorded in the oxidation products 15 and 16 obtained from anilides 12c and 12e by CAN oxidation.

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A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
the methyl group at C-2. If the precursor 12e exhibits a
similar conformation the NH proton may be removed by a
base in an intermediate radical cation (or cation) which in
turn is formed by single electron oxidation. In our opinion,
the removal of the NH proton, which competes with
the hydroxy-de-methoxylation24a,25 at carbon atoms C-18 or
C-17, governs the chemoselectivity of the oxidation
process. In the twisted compound 12e the deprotonation is
facile and accounts for the formation of the azaquinone, in
the flat compound 12c and in other acyclic systems the
hydroxy-de-methoxylation is faster and leads to the ortho-
quinone. The hydroxy-de-methoxylation at the less
accessible carbon atom C-21 is slow possibly due to steric
reasons.
Selective demethylation reactions by strong nucleophiles
(LiI) or Lewis acids (BBr3) were attempted with model
compounds but led only to degradation. BCl3 facilitated a
demethylation but the yields and the regioselectivity were
not satisfactory. Consequently, we looked for alternative
protection strategies for the 1,4-hydroquinone. A minimal
change in reactivity and a maximum coincidence with the
previous results was expected upon replacing the methyl
protecting groups by other alkyl groups. The iso-propyl
group was considered to be a reasonable choice and work
along these line continued.
4. Synthesis of para-quinone 2
Model studies proved that 3-alkyl-2,5-di-iso-propoxy-4-
methoxyanilides are readily deprotected with BCl3 at
K10 8C in CH2Cl2 and yield upon work-up without addition
of an oxidizing agent the corresponding para-quinones.
Based on these results the readily available 1,4-di-iso-
propoxy-2-methoxybenzene (17)26 was lithiated in
3-position with n-butyl lithium and subsequently alkylated
with iodide 7d (Scheme 4). A side product was found (4%
yield) which arose from deprotonation at the 6-position. All
further reactions starting from arene 18 were conducted in
analogy to our previous work. Selective nitration led to
nitroarene 19 which was reduced to aniline 20. After amide
bond formation the anilide underwent the RCM smoothly
and gave the desired lactam 22 in excellent yield. The
deprotection occurred less readily than in the test system. At
K10 8C there was a monodeprotection to phenol 23. After
addition of an excess of BCl3 and by warming to room
temperature the deprotection could be driven to completion
and the desired compound 2 was isolated as the sole reaction
product. The total yield in which para-quinone 2 was
obtained from arene 17 was 19%.
Scheme 4. Synthesis of the phenol 23 and the para-quinone 2 from 1,4-di-
iso-propoxy-2-methoxybenzene (17).
In conclusion, the study has shown that the construction of
para-quinones related to geldanamycin is feasible based on
a RCM strategy. The iso-propyl group was used as a
protecting group for the latent para-quinone moiety in the
corresponding hydroquinone di-iso-propyl ether. The amide
bond formation between the aniline nitrogen atom and
carbon atom C-1 of 2-methyl-2,4-pentadienoic acid was
achieved by use of the reagent combination HATU/HOAt.
The synthesis of compound 2 was achieved in an overall
yield of 19% starting from 1,4-di-iso-propoxy-2-methoxy-
benzene (17). There are of course many further challenges
ahead if this strategy is to be applied to a successful
synthesis to geldanamycin. The selective introduction of the
nitro group into a more highly functionalized precursor, the
generation of the appropriate stereogenic centers and
the protection of the hydroxy groups as well as the
carbamate formation before or after para-quinone deprotec-
tion are among the most important aspects to be addressed.
Work along these lines is currently pursued in our
laboratory.
1
Both products 23 and 2 were intensively studied by H
NMR NOESY experiments. The phenol OH proton in
compound 23 showed a strong NOE to H-19 which proves
the regioselectivity of the deprotection. The (Z)-configur-
ation of the double bond formed in the RCM step was in
both products unequivocally proven by the relatively small
coupling constants and by strong NOE contacts between
H-4 and H-5. The other NOEs in the area C-1 to C-6 were
similar to the signals recorded for compound 15 supporting
a s-trans amide bond (C-1/NH).

A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
9663
5. Experimental
Procedure C. General procedure for the reduction of
nitroarenes. To the nitroarene and tin powder (8 equiv)
under argon atmosphere, concentrated hydrochloric acid
(8 equiv, 2.8 mL/mmol) was added. The mixture was heated
for 2 h at 60 8C and cooled to 0 8C. The reaction was then
quenched by addition of aqueous NaOH (10% w/w). The pH
was adjusted to 10. The aqueous layer was extracted three
times with DCM (3!5–10 mL/mmol). The combined
organic layers were washed once with brine (5–
10 mL/mmol), dried (Na2SO4) and concentrated in vacuum.
The product was purified by flash chromatography (P/EA).
5.1. General
All reactions involving water-sensitive chemicals were
carried out in flame-dried glassware with magnetic stirring
under Ar. Tetrahydrofuran and diethyl ether were distilled
from sodium immediately prior to use. N,N-Di-iso-propyl-
ethylamine (DIPEA) and dichloromethane were distilled
from calcium hydride. All other chemicals were either
commercially available or prepared according to the cited
references. TLC: Merck glass sheets (0.25 mm silica gel 60,
F254), eluent given in brackets. Detection by UV or
coloration with cerium ammonium molybdate (CAM).
Optical rotation: Perkin–Elmer 241 MC. NMR: Bruker
Procedure D. General procedure for the peptide bond
formation with HATU/HOAt. To 2-methyl-2,4-pentadienoic
acid dissolved in DMF (1.8 mL/mmol) and cooled to 0 8C,
DIPEA (2.5 equiv) was added slowly. After being stirred
30 min at this temperature, HOAt (1.0 equiv) dissolved in
DMF (0.6 mL/mmol) was added. The mixture was stirred
for 30 min at 0 8C and HATU (1.0 equiv) dissolved in DMF
(0.6 mL/mmol) was added. After being stirred for 15 min at
0 8C and 15 min at rt, the corresponding aniline (1.0 equiv)
dissolved in DMF (3.0 mL/mmol) was added. The mixture
was stirred for 48 h at rt. DCM (50 mL/mmol) and water
(50 mL/mmol) were added. The aqueous layer was
extracted twice with DCM (2!50 mL/mmol). The com-
bined organic layers were washed with a saturated aqueous
NaHCO3 solution (5 mL/mmol), brine (5 mL/mmol), dried
(Na2SO4) and concentrated in vacuo. The product was
purified by flash chromatography (P/EA).
1
AC-250, AV-360, AV-500. H and 13C NMR spectra were
recorded at ambient temperature. Chemical shifts are
reported relative to tetramethylsilane as internal standard.
Apparent multiplets which occur as a result of the accidental
equality of coupling constants of magnetically non-
equivalent protons are marked as virtual (v.). The multi-
plicities of the 13C NMR signals were determined by DEPT
experiments. IR: Perkin–Elmer 1600 FT-IR. MS: Finnigan
MAT 8200 (EI). Elemental Analysis: Elementar Vario EL.
Flash chromatography was performed on silica gel 60
(Merck, 230–400 mesh) (ca. 50 g for 1 g of material to be
separated) with the indicated eluent. Common solvents for
chromatography [pentane (P), ethyl acetate (EA), dichloro-
methane (DCM)] were distilled prior to use.
Procedure E. General procedure for the macrocyclization.
To refluxing CH2Cl2 (1.9 L/mmol), a solution of catalyst
(0.10 equiv) in CH2Cl2 (20 mL/mmol) was added under
argon atmosphere. After 5 min a solution of the anilide in
CH2Cl2 (80.0 mL/mmol) was added. The solution was
refluxed until the reaction was complete (TLC). The solvent
was removed in vacuo and the product was purified by flash
chromatography (P/EA).
Procedure A. Alkylation of 1,2,4-trimethoxybenzene. To a
solution of 1,2,4-trimethoxybenzene in THF (1 mL/mmol),
n-butyl lithium (2.5 M in hexane, 1.1 equiv) was slowly
added at rt. After 10 min, a white precipitate appeared
indicating the formation of the lithiated compound. The
mixture was allowed to stir for 30 to 45 min at room
temperature and was subsequently cooled to 0 8C. The
iodide (1.05–1.1 equiv) was added at this temperature. The
mixture was stirred for 14 h at rt. Then, diethyl ether
(3 mL/mmol) and water (3 mL/mmol) were added. The
aqueous layer was extracted twice with diethyl ether (2!
5 mL/mmol). The combined organic layers were washed
once with brine (5 mL/mmol), dried (Na2SO4) and con-
centrated under reduced pressure. The product was purified
by flash chromatography (P/EA).
Procedure F. Oxidation with CAN. To a solution of the
anilide and pyridine-2,6-dicarboxylic acid N-oxide
(2.5 equiv) in acetonitrile (5.0 mL/mmol) and water
(1.5 mL/mmol) cooled to 0 8C, a solution of CAN
(2.5 equiv) in acetonitrile (2.5 mL/mmol) and water
(2.5 mL/mmol) was slowly added. The resulting solution
was stirred at 0 8C until no more starting material remained
according to TLC. The mixture was dissolved in water
(45 mL/mmol) and extracted three times with DCM (3!
75 mL/mmol). The combined organic layers were washed
with brine (5 mL/mmol), dried (Na2SO4) and concentrated.
Procedure B. General procedure for the nitration of arenas.
To a solution of the arene in acetic acid (2.8 mL/mmol),
concentrated nitric acid (70% w/w, 0.58 mL/mmol) in
acetic acid (1.8 mL/mmol) was slowly added at room
temperature. After 5 min the solution takes an orange color,
which turns after a few minutes into a yellow color. The
mixture was stirred for 60 min at rt. Water (5 mL/mmol) and
diethyl ether (5 mL/mmol) were added. NaHCO3 was
carefully added and the solution was stirred for 30 min.
The layers were separated and the aqueous layer was
extracted three times with diethyl ether (3!5 mL/mmol).
The combined organic layers were washed once with a
saturated solution of NaHCO3 in water (5 mL/mmol), brine
(5 mL/mmol), dried (Na2SO4) and concentrated under
reduced pressure. The product was purified by flash
chromatography (P/EA).
Procedure G. Alkylation of 1,4-di-iso-propoxy-2-methoxy-
benzene. To a solution of 1,4-di-iso-propoxy-2-methoxy-
benzene in THF (1 mL/mmol), n-butyl lithium (2.5 M in
hexane, 1.1 equiv) was slowly added at rt. The mixture was
stirred 30 to 45 min at rt, and was cooled to 0 8C. The iodide
(1.05 equiv) was added at this temperature. The mixture was
stirred for 14 h at rt. Then, diethyl ether (5 mL/mmol) and
water (5 mL/mmol) were added. The aqueous layer was
extracted twice with diethyl ether (2!4 mL/mmol). The
combined organic layers were washed once with brine
(5 mL/mmol), dried (Na2SO4) and concentrated under

9664
A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
reduced pressure. The product was purified by chromato-
graphy (P/EA).
(film): n~ (cmK1)Z3075 (w, ]CH2), 2927 (v. s, CH2), 2854
(s, CH2), 1639 (m, C]C), 1593 (m, Car]Car), 1487 (m,
CH2), 1255 (s, COC), 1224 (m), 1162 (s, COC), 1092 (s,
COC), 1024 (m); 909 (m, RCH]CH2), 789 (w, CH), 718
(w, CHar); 1H NMR (250 MHz, CDCl3): d (ppm)Z6.68 (d,
3JZ8.9 Hz, 1H, CarH), 6.53 (d, 3JZ8.9 Hz, 1H, CarH), 5.78
(ddt, 3JZ17.1 Hz, 3JZ10.2 Hz, 3JZ6.7 Hz, 1H,
CH2]CHR), 4.99–4.94 (m, 1H, HtransCH]CHR), 4.93–
4.90 (m, 1H, HcisCH]CHR), 3.81 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 3.75 (s, 3H, OCH3), 2.61 (v. t, 3Jy7.6 Hz, 2H,
CH2Ar), 2.04 (v. q, 3Jy6.7 Hz, 2H, CH2]CHCH2), 1.51–
1.27 (m, 14H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z152.5 (CarOMe), 148.2 (CarOMe), 147.3 (CarOMe),
139.4 (HRC]CH2), 126.4 (CarCH2), 114.4 (HRC]CH2),
109.7 (CarH), 105.5 (CarH), 60.9 (OCH3), 56.3 (OCH3), 56.0
(OCH3), 33.9 (CH2), 30.1 (CH2), 30.0 (CH2), 29.7 (CH2),
29.6 (CH2), 29.6 (CH2), 29.3 (CH2), 29.1 (CH2), 24.1
(CH2); MS (EI, 70 eV), m/z (%): 320 (100) [MC], 181 (31),
166 (33). Anal. C20H32O3 (320.5): calcd C, 74.96; H, 10.06;
found C, 75.03; H: 10.15.
5.1.1. 1,2,4-Trimethoxy-3-non-8-enylbenzene (8a). Pro-
cedure A was performed with 9-iodonon-1-ene (7a)14
(3.32 g, 13.2 mmol) and 1,2,4-trimethoxybenzene (2.02 g,
12.2 mmol). After flash chromatography (P/EA 90/10), the
product was obtained (2.09 g, 7.16 mmol, 59%) as a
colorless oil. TLC: RfZ0.77 (P/EA 90/10) [CAM, UV];
IR (film): n~ (cmK1)Z3075 (w, ]CH2), 2927 (v. s, CH2),
2854 (s, CH2), 1639 (m, C]C), 1593 (m, Car]Car), 1487
(m, CH2), 1255 (s, COC), 1224 (m), 1162 (s, COC), 1092 (s,
COC), 1024 (m); 909 (m, RCH]CH2), 789 (w, CH), 718
(w, CHar); 1H NMR (360 MHz, CDCl3): d (ppm)Z6.68 (d,
3JZ8.9 Hz, 1H, CarH), 6.53 (d, 3JZ8.9 Hz, 1H, CarH), 5.79
(ddt, 3JZ17.1 Hz, 3JZ10.2 Hz, 3JZ6.7 Hz, 1H,
CH2]CHR), 5.00–4.97 (m, 1H, HtransCH]CHR), 4.94–
4.91 (m, 1H, HcisCH]CHR), 3.82 (s, 3H, OCH3), 3.81 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 2.63 (v. t, 3Jy7.7 Hz, 2H,
CH2Ar), 2.08 (v. q, 3Jy6.6 Hz, 2H, CH2]CHCH2), 1.53–
1.34 (m, 10H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z152.34 (CarOMe), 148.05 (CarOMe), 147.14 (Car-
OMe), 139.18 (HRC]CH2), 126.07 (CarCH2), 114.2
(HRC]CH2), 109.6 (CarH), 105.3 (CarH), 60.7 (OCH3),
56.1 (OCH3), 55.8 (OCH3), 33.8 (CH2), 29.9 (CH2), 29.8
(CH2), 29.3 (CH2), 29.0 (CH2), 28.9 (CH2), 23.9 (CH2); MS
(EI, 70 eV), m/z (%): 292 (100) [MC], 277 (5), 181 (46), 166
(30), 151 (8), 123 (6), 91 (8), 41 (5). Anal. C18H28O3
(292.4): calcd C, 73.93; H, 9.65; found C, 73.95; H: 9.76.
5.1.4. 2-Dodec-11-enyl-1,3,4-trimethoxybenzene (8d).
Procedure A was performed with 12-iodododec-1-ene
(7d)17 (956 mg, 3.26 mmol) and 1,2,4-trimethoxybenzene
(538 mg, 3.20 mmol). After flash chromatography (P/EA
97/03), the product was obtained (778 mg, 2.33 mmol, 73%)
as a colorless oil. TLC: RfZ0.81 (P/EA 9/1) [CAM, UV];
IR (film): n~ (cmK1)Z3075 (w, ]CH2), 2927 (v. s, CH2),
2854 (s, CH2), 1639 (m, C]C), 1593 (m, Car]Car), 1487
(m, CH2), 1255 (s, COC), 1224 (m), 1162 (s, COC), 1092 (s,
COC), 1024 (m); 909 (m, RCH]CH2), 789 (w, CH), 718
(w, CHar); 1H NMR (360 MHz, CDCl3): d (ppm)Z6.69 (d,
3JZ8.8 Hz, 1H, CarH), 6.54 (d, 3JZ8.8 Hz, 1H, CarH), 5.81
(ddt, 3JZ17.1 Hz, 3JZ10.2 Hz, 3JZ6.7 Hz, 1H,
CH2]CHR), 5.02–4.97 (m, 1H, HtransCH]CHR), 4.95–
4.92 (m, 1H, HcisCH]CHR), 3.83 (s, 3H, OCH3), 3.81 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 2.65 (v. t, 3Jy7.7 Hz, 2H,
CH2Ar), 2.05 (v. q, 3Jy7.0 Hz, 2H, CH2]CHCH2), 1.56–
1.30 (m, 16H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z152.5 (CarOMe), 148.2 (CarOMe), 147.3 (CarOMe),
139.4 (HRC]CH2), 126.3 (CarCH2), 114.2 (HRC]CH2),
109.7 (CarH), 105.4 (CarH), 60.8 (OCH3), 56.3 (OCH3), 55.9
(OCH3), 33.9 (CH2), 30.1 (CH2), 30.0 (CH2), 29.7 (CH2),
29.7 (CH2), 29.6 (CH2), 29.6 (CH2), 29.2 (CH2), 29.1 (CH2),
24.1 (CH2); MS (EI, 70 eV), m/z (%): 334 (100) [MC], 181
(59), 166 (47), 151 (8), 121(6), 91 (10), 55 (5). Anal.
C21H34O3 (334.5): calcd C, 75.41; H, 10.25; found C, 75.63;
H: 10.34.
5.1.2. 2-Dec-9-enyl-1,3,4-trimethoxybenzene (8b). Pro-
cedure A was performed with 10-iododec-1-ene (7b)15
(2.70 g, 10.2 mmol) and 1,2,4-trimethoxybenzene (1.56 g,
9.30 mmol). After flash chromatography (P/EA 90/10), the
product was obtained (2.15 g, 7.03 mmol, 76%) as a
colorless oil. TLC: RfZ0.65 (P/EA 9/1) [CAM, UV]; IR
(film): n~ (cmK1)Z3075 (w, ]CH2), 2927 (v. s, CH2), 2854
(s, CH2), 1639 (m, C]C), 1593 (m, Car]Car), 1487 (m,
CH2), 1255 (s, COC), 1224 (m), 1162 (s, COC), 1092 (s,
COC), 1024 (m); 909 (m, RCH]CH2), 789 (w, CH), 718
(w, CHar); 1H NMR (360 MHz, CDCl3): d (ppm)Z6.70 (d,
3JZ8.9 Hz, 1H, CarH), 6.54 (d, 3JZ8.9 Hz, 1H, CarH), 5.82
(ddt, 3JZ17.1 Hz, 3JZ10.2 Hz, 3JZ6.7 Hz, 1H,
CH2]CHR), 5.00–4.95 (m, 1H, HtransCH]CHR), 4.94–
4.91 (m, 1H, HcisCH]CHR), 3.83 (s, 3H, OCH3), 3.82 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 2.64 (v. t, 3Jy7.7 Hz, 2H,
CH2Ar), 2.04 (v. q, 3Jy6.8 Hz, 2H, CH2]CHCH2), 1.53–
1.31 (m, 12H, CH2); 13C NMR (62.9 MHz, CDCl3): d
(ppm)Z152.5 (CarOMe), 148.2 (CarOMe), 147.3 (CarOMe),
139.4 (HRC]CH2), 126.4 (CarCH2), 114.4 (HRC]CH2),
109.7 (CarH), 105.5 (CarH), 60.9 (OCH3), 56.3 (OCH3), 56.0
(OCH3), 33.9 (CH2), 30.1 (CH2), 30.0 (CH2), 29.6 (CH2),
29.6 (CH2), 29.3 (CH2), 29.1 (CH2), 24.1 (CH2); MS (EI,
70 eV), m/z (%): 306 (100) [MC], 181 (41), 166 (41), 151
(5); HRMS: m/z calcd for C19H30O3: 306.2195; found
306.2191.
5.1.5. 1,2,4-Trimethoxy-3-tridec-12-enylbenzene (8e).
Procedure A was performed with 13-iodotridec-1-ene
(7e)18 (765 mg, 2.48 mmol) and 1,2,4-trimethoxybenzene
(378 mg, 2.25 mmol). After flash chromatography (P /
P/EA 95/05), the product was obtained (570 mg, 1.64 mmol,
73%) as a colorless oil. TLC: RfZ0.40 (P/EA 95/05) [CAM,
UV]; IR (film): n~ (cmK1)Z3075 (w, ]CH2), 2927 (v. s,
CH2), 2854 (s, CH2), 1639 (m, C]C), 1593 (m, Car]Car),
1487 (m, CH2), 1255 (s, COC), 1224 (m), 1162 (s, COC),
1092 (s, COC), 1024 (m); 909 (m, RCH]CH2), 789 (w,
CH), 718 (w, CHar); 1H NMR (360 MHz, CDCl3): d
(ppm)Z6.67 (d, 3JZ8.8 Hz, 1H, CarH), 6.52 (d, 3JZ
5.1.3. 1,2,4-Trimethoxy-3-undec-10-enylbenzene (8c).
Procedure A was performed with 11-iodoundec-1-ene
(7c)16 (1.80 g, 6.42 mmol) and 1,2,4-trimethoxybenzene
(1.01 g, 6.00 mmol). After flash chromatography (P/EA 95/
05), the product was obtained (1.46 g, 4.56 mmol, 76%) as a
colorless oil. TLC: RfZ0.46 (P/EA 95/05) [CAM, UV]; IR
3
8.8 Hz, 1H, CarH), 5.80 (ddt, JZ17.1 Hz, 3JZ10.2 Hz,
3JZ6.7 Hz, 1H, CH2]CHR), 4.98–4.93 (m, 1H,

A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
9665
HtransCH]CHR), 4.92–4.89 (m, 1H, HcisCH]CHR), 3.81
(s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 2.62
(CH2), 24.7 (CH2); MS (EI, 70 eV), m/z (%): 351 (100)
[MC], 334 (15), 226 (25), 211 (15), 196 (10), 181 (15), 166
(28), 151 (10), 137 (7), 55 (7); HRMS: m/z calcd for
C19H29NO5: 351.2046; found 351.2045.
3
3
(v. t, Jy7.7 Hz, 2H, CH2Ar), 2.04 (v. q, Jy7.0 Hz, 2H,
CH2]CHCH2), 1.56–1.23 (m, 18H, CH2); 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z152.5 (CarOMe), 148.2
(CarOMe), 147.3 (CarOMe), 139.4 (HRC]CH2), 126.3
(CarCH2), 114.2 (HRC]CH2), 109.7 (CarH), 105.4 (CarH),
60.8 (OCH3), 56.3 (OCH3), 55.9 (OCH3), 33.9 (CH2), 30.1
(CH2), 30.1 (CH2), 29.9 (CH2), 29.8 (CH2), 29.8 (CH2), 29.7
(CH2), 29.7 (CH2), 29.3 (CH2), 29.2 (CH2), 24.1 (CH2); MS
(EI, 70 eV), m/z (%): 348 (100) [MC], 181 (32), 166 (25),
121 (3). Anal. C22H36O3 (348.5): calcd C, 75.82; H, 10.41;
found C, 75.80; H: 10.30.
5.1.8. 1,2,4-Trimethoxy-5-nitro-3-undec-10-enylbenzene
(9c). Procedure B was performed with 1, 2, 4-trimethoxy-3-
undec-10-enylbenzene (8c) (1.38 g, 4.31 mmol). The
amount of reagents and solvents was adjusted accordingly.
After flash chromatography (P/EA 90/10), the product was
obtained (1.54 g, 4.22 mmol, 98%) as a yellow oil. TLC:
RfZ0.42 (P/EA90/10) [CAM, UV]; IR (film): n~ (cmK1)Z
2919 (v. s, CH2), 2854 (s, CH2), 1640 (m, C]C), 1573 (m,
C]C), 1523 (s, NO2), 1480 (s, Car]Car), 1424 (m, CH2),
1343 (m, CNO2), 1246 (m, COC), 1108 (m), 1053 (m), 1004
(w, RCH]CH2), 964 (m), 909 (w, RCH]CH2), 847 (w,
CHar), 770 (w, CHar); 1H NMR (250 MHz, CDCl3): d
5.1.6. 1,2,4-Trimethoxy-5-nitro-3-non-8-enylbenzene
(9a). Procedure B was performed with 1,2,4-trimethoxy-3-
non-8-enylbenzene (8a) (1.97 g, 6.73 mmol). After flash
chromatography (P/EA 90/10), the product was obtained
(1.66 g, 4.93 mmol, 73%) as a yellow oil. TLC: RfZ0.69
(P/EA90/10) [CAM, UV]; IR (film): n~ (cmK1)Z2919 (v. s,
CH2), 2854 (s, CH2), 1640 (m, C]C), 1573 (m, C]C),
1523 (s, NO2), 1480 (s, C]Car), 1424 (m, CH2), 1343 (m,
CNO2), 1246 (m, COC), 1108 (m), 1053 (m), 1004 (w,
RCH]CH2), 964 (m), 909 (w, RCH]CH2), 847 (w, CHar),
770 (w, CHar); 1H NMR (360 MHz, CDCl3): d (ppm)Z7.32
3
3
(ppm)Z7.35 (s, 1H, CarH), 5.78 (ddt, JZ17.1 Hz, JZ
3
10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR), 4.98–4.93 (m, 1H,
HtransCH]CHR), 4.92–4.89 (m, 1H, HcisCH]CHR), 3.91
(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 2.65
3
3
(v. t, JZ7.8 Hz, 2H, CH2Car), 2.04 (v. q, Jy6.7 Hz, 2H,
CH2]CHCH2), 1.50 (m, 2H, CH2), 1.35–1.23 (m, 12H,
CH2); 13C NMR (62.9 MHz, CDCl3): d (ppm)Z152.4
(CarOCH3), 148.5 (CarOCH3), 147.3 (CarOCH3), 139.1
(HRC]CH2), 138.5 (Car), 132.8 (Car), 114.0
(HRC]CH2), 106.6 (CarH), 62.6 (OCH3), 60.9 (OCH3),
56.1 (OCH3), 33.7 (CH2), 30.2 (CH2), 29.8 (CH2), 29.4
(CH2), 29.3 (CH2), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 24.7
(CH2); MS (EI, 70 eV), m/z (%): 365 (100) [MC], 348 (20),
226 (36), 211 (17), 196 (18), 181 (24), 166 (28), 151 (10),
137 (10), 107 (9), 97 (8), 91 (8), 55 (20), 41 (15); HRMS:
m/z calcd for C20H31NO5: 365.2202; found 365.2202.
3
3
3
(s, 1H, CarH), 5.76 (ddt, JZ17.1 Hz, JZ10.2 Hz, JZ
6.7 Hz, 1H, CH2]CHR), 4.98–4.93 (m, 1H, Htrans
-
CH]CHR), 4.91–4.88 (m, 1H, HcisCH]CHR), 3.89 (s,
3H, OCH3), 3.83 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.62
(v. t, 3Jy7.8 Hz, 2H, CH2Car), (v. q, 3Jy6.7 Hz, 2H,
CH2]CHCH2), 1.28–1.52 (m, 10H, CH2); 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z152.4 (CarOCH3), 148.5
(CarOCH3), 147.4 (CarOCH3), 139.1 (HRC]CH2), 138.0
(Car), 132.8 (Car), 114.1 (HRC]CH2), 106.6 (CarH), 62.6
(OCH3), 60.9 (OCH3), 56.1 (OCH3), 33.7 (CH2), 30.1
(CH2), 29.8 (CH2), 29.2 (CH2), 29.0 (CH2), 28.9 (CH2), 24.7
(CH2); MS (EI, 70 eV), m/z (%): 337 (100) [MC], 320 (15),
226 (25), 211 (15), 196 (10), 181 (10), 166 (26), 151 (10),
137 (7), 55 (7). Anal. C18H27NO5 (337.4): calcd C, 64.07;
H, 8.07; found C, 64.03; H: 7.99.
5.1.9. 3-Dodec-11-enyl-1,2,4-trimethoxy-5-nitrobenzene
(9d). Procedure B was performed with 2-dodec-11-enyl-
1,3,4-trimethoxybenzene (8d) (415 mg, 1.24 mmol). After
flash chromatography (P/EA 90/10), the product was
obtained (448 mg, 1.18 mmol, 95%) as a yellow oil. TLC:
RfZ0.60 (P/EA90/10) [CAM, UV]; IR (film): n~ (cmK1)Z
2919 (v. s, CH2), 2854 (s, CH2), 1640 (m, C]C), 1573 (m,
C]C), 1523 (s, NO2), 1480 (s, Car]Car), 1424 (m, CH2),
1343 (m, CNO2), 1246 (m, COC), 1108 (m), 1053 (m), 1004
(w, RCH]CH2), 964 (m), 909 (w, RCH]CH2), 847 (w,
CHar), 770 (w, CHar); 1H NMR (360 MHz, CDCl3): d
5.1.7. 3-Dec-9-enyl-1,2,4-trimethoxy-5-nitrobenzene
(9b). Procedure B was performed with 2-dec-9-enyl-1,3,4-
trimethoxybenzene (8b) (2.07 g, 6.76 mmol). After flash
chromatography (P/EA 95/5), the product was obtained
(2.28 g, 6.49 mmol, 95%) as a yellow oil. TLC: RfZ0.45
(P/EA 90/10) [CAM, UV]; IR (film): n~ (cmK1)Z2919 (v. s,
CH2), 2854 (s, CH2), 1640 (m, C]C), 1573 (m, C]C),
1523 (s, NO2), 1480 (s, C]Car), 1424 (m, CH2), 1343 (m,
CNO2), 1246 (m, COC), 1108 (m), 1053 (m), 1004 (w,
RCH]CH2), 964 (m), 909 (w, RCH]CH2), 847 (w, CHar),
770 (w, CHar); 1H NMR (250 MHz, CDCl3): d (ppm)Z7.34
3
3
(ppm)Z7.32 (s, 1H, CarH), 5.76 (ddt, JZ17.1 Hz, JZ
3
10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR), 4.98–4.93 (m, 1H,
HtransCH]CHR), 4.91–4.88 (m, 1H, HcisCH]CHR), 3.88
(s, 3H, OCH3), 3.84 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 2.62
3
3
(v. t, Jy7.8 Hz, 2H, CH2Car), 2.00 (v. q, Jy6.7 Hz, 2H,
CH2]CHCH2), 1.50 (m, 2H, CH2), 1.35–1.23 (m, 14H,
CH2); 13C NMR (90.6 MHz, CDCl3): d (ppm)Z152.4
(CarOCH3), 148.5 (CarOCH3), 147.3 (CarOCH3), 139.1
(HRC]CH2), 138.5 (Car), 132.8 (Car), 114.0
(HRC]CH2), 106.6 (CarH), 62.6 (OCH3), 60.9 (OCH3),
56.1 (OCH3), 33.7 (CH2), 30.2 (CH2), 29.8 (CH2), 29.5
(CH2), 29.4 (CH2), 29.4 (CH2), 29.3 (CH2), 29.1 (CH2), 28.9
(CH2), 24.7 (CH2); MS (EI, 70 eV), m/z (%): 379 (100)
[MC], 362 (20), 334 (15), 320 (15), 306 (8), 290 (8), 226
(23), 211 (10), 196 (10), 181 (16), 166 (14), 151 (11), 137
(9), 121 (5), 107 (8), 97 (8), 91 (8), 83 (5), 55 (14), 41 (14).
Anal. C21H33NO5 (379.5): calcd C, 66.68; H, 8.86; found C,
66.46; H: 8.76.
3
3
3
(s, 1H, CarH), 5.78 (ddt, JZ17.1 Hz, JZ10.2 Hz, JZ
6.7 Hz, 1H, CH2]CHR), 4.98–4.93 (m, 1H, Htrans
-
CH]CHR), 4.92–4.89 (m, 1H, HcisCH]CHR), 3.90 (s,
3H, OCH3), 3.87 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 2.64
(v. t, 3Jy7.8 Hz, 2H, CH2Car), (v. q, 3Jy6.7 Hz, 2H,
CH2]CHCH2), 1.28–1.52 (m, 12H, CH2); 13C NMR
(62.9 MHz, CDCl3): d (ppm)Z152.4 (CarOCH3), 148.5
(CarOCH3), 147.3 (CarOCH3), 139.1 (HRC]CH2), 138.5
(Car), 132.8 (Car), 114.0 (HRC]CH2), 106.6 (CarH), 62.6
(OCH3), 60.9 (OCH3), 56.1 (OCH3), 33.7 (CH2), 30.2
(CH2), 29.8 (CH2), 29.3 (CH2), 29.2 (CH2), 29.0 (CH2), 28.9

9666
A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
5.1.10.
1,2,4-Trimethoxy-5-nitro-3-tridec-12-enyl-
N–H), 1490 (m, CH2), 1363 (s, COC), 1224 (s), 1120 (m,
COC), 1058 (m), 1011 (m, RCH]CH2), 909 (w,
benzene (9e). Procedure B was performed with 1,2,4-
trimethoxy-3-tridec-12-enylbenzene (8e) (458 mg,
1.31 mmol). After flash chromatography (P/EA 90/10), the
product was obtained (484 mg, 1.23 mmol, 94%) as a
yellow oil. TLC: RfZ0.67 (P/EA 90/10) [CAM, UV]; IR
(film): n~ (cmK1)Z2919 (v. s, CH2), 2854 (s, CH2), 1640 (m,
C]C), 1573 (m, C]C), 1523 (s, NO2), 1480 (s, Car]Car),
1424 (m, CH2), 1343 (m, CN), 1246 (m, COC), 1108 (m),
1053 (m), 1004 (w, RCH]CH2), 964 (m), 909 (w,
RCH]CH2), 847 (w, CHar), 770 (w, CHar); 1H NMR
(360 MHz, CDCl3): d (ppm)Z7.32 (s, 1H, CarH), 5.79 (ddt,
1
RCH]CH2), 821 (w, CH); H NMR (250 MHz, CDCl3):
3
3
d (ppm)Z6.21 (s, 1H, CarH), 5.80 (ddt, JZ17.1 Hz, JZ
3
10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR), 4.97–4.92 (m, 1H,
HtransCH]CHR), 4.91–4.88 (m, 1H, HcisCH]CHR), 3.77
(s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.63
3
(br. s, 2H, NH2), 2.58 (v. t, Jy7.9 Hz, 2H, CH2Car), 2.02
3
(v. q, Jy6.9 Hz, 2H, CH2]CHCH2), 1.52 (m, 2H, CH2),
1.33–1.25 (m, 10H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z150.0 (CarOCH3), 139.9 (CarOCH3), 138.6 (Car-
OCH3), 139.3 (HRC]CH2), 136.0 (Car), 130.8 (Car), 114.4
(HRC]CH2), 98.8 (CarH), 61.3 (OCH3), 60.4 (OCH3), 56.2
(OCH3), 34.2 (CH2), 31.2 (CH2), 30.4 (CH2), 29.8 (CH2),
29.7 (CH2), 29.5 (CH2), 29.3 (CH2), 25.1 (CH2); MS (EI,
70 eV), m/z (%): 321 (100) [MC], 306 (90), 192 (5), 182
(28), 167 (18), 152 (12), 138 (12), 122 (9). Anal.
C19H31NO3 (321.4): calcd C, 70.99; H, 9.72; found C,
71.00; H: 9.70.
3JZ17.1 Hz, JZ10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR),
4.98–4.93 (m, 1H, HtransCH]CHR), 4.92–4.89 (m, 1H,
HcisCH]CHR), 3.89 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
3.83 (s, 3H, OCH3), 2.62 (v. t, Jy7.8 Hz, 2H, CH2Car),
2.00 (v. q, Jy6.7 Hz, 2H, CH2]CHCH2), 1.50 (m, 2H,
3
3
3
3
CH2), 1.35–1.23 (m, 16H, CH2); 13C NMR (90.6 MHz,
CDCl3): d (ppm)Z152.4 (CarOCH3), 148.5 (CarOCH3),
147.5 (CarOCH3), 139.2 (HRC]CH2), 138.5 (Car), 132.9
(Car), 114.0 (HRC]CH2), 106.7 (CarH), 62.7 (OCH3), 61.0
(OCH3), 56.2 (OCH3), 33.8 (CH2), 30.2 (CH2), 29.9 (CH2),
29.8 (CH2), 29.6 (CH2), 29.5 (CH2), 29.5 (CH2), 29.3 (CH2),
29.1 (CH2), 28.9 (CH2), 24.7 (CH2); MS (EI, 70 eV), m/z
(%): 393 (100) [MC], 376 (20), 359 (15), 348 (8), 226 (21),
196 (10), 181 (14), 166 (8), 151 (8), 123 (6), 95 (5), 69 (5),
55 (14), 41 (8). Anal. C22H35NO5 (393.5): calcd C, 67.15;
H, 9.05; found C, 67.58; H: 8.96.
5.1.13. 2,4,5-Trimethoxy-3-undec-10-enylphenylamine
(10c). Procedure C was performed using the nitro arene 9c
(2.30 g, 6.30 mmol). The amount of reagents and solvents
was adjusted accordingly. After flash chromatography
(P/EA 90/10), the product was obtained (1.77 g,
5.29 mmol, 84%) as a light brown oil. TLC: RfZ0.16
(P/EA 90/10) [CAM, UV]; IR (film): n~ (cmK1)Z3430 (w,
NH2), 3358 (m, NH2), 3095 (w, ]CH2), 2926 (v. s, CH2),
2854 (s, CH2), 1614 (m, N–H), 1490 (m, CH2), 1363 (s,
COC), 1224 (s), 1120 (m, COC), 1058 (m), 1011 (m,
RCH]CH2), 909 (w, RCH]CH2), 821 (w, CH); 1H NMR
(250 MHz, CDCl3): d (ppm)Z6.19 (s, 1H, CarH), 5.75 (ddt,
5.1.11. 2,4,5-Trimethoxy-3-non-8-enylphenylamine
(10a). Procedure C was performed using the nitro arene
9a (215 mg, 0.64 mmol). After flash chromatography (P/EA
90/10), the product was obtained (162 mg, 0.52 mmol, 82%)
as a colorless oil. TLC: RfZ0.16 (P/EA 90/10) [CAM, UV];
IR (film): n~ (cmK1)Z3430 (w, NH2), 3358 (m, NH2), 3095
(w, ]CH2), 2926 (v. s, CH2), 2854 (s, CH2), 1614 (m, N–
H), 1490 (m, CH2), 1363 (s, COC), 1224 (s), 1120 (m,
COC), 1058 (m), 1011 (m, RCH]CH2), 909 (w,
RCH]CH2), 821 (w, CH); H NMR (500 MHz, CDCl3):
d (ppm)Z6.18 (s, 1H, CarH), 5.76 (ddt, JZ17.1 Hz, JZ
10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR), 4.98–4.93 (m, 1H,
HtransCH]CHR), 4.92–4.89 (m, 1H, HcisCH]CHR), 3.74
(s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.50
3
3
3JZ17.1 Hz, JZ10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR),
4.97–4.92 (m, 1H, HtransCH]CHR), 4.91–4.88 (m, 1H,
HcisCH]CHR), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
3.68 (s, 3H, OCH3), 3.49 (br. s, 2H, NH2), 2.56–2.54 (m, 2H,
CH2Car), 2.00 (v. q, 3Jy6.9 Hz, 2H, CH2]CHCH2), 1.53–
1.51 (m, 2H, CH2), 1.35–1.26 (m, 12H, CH2); 13C NMR
(62.9 MHz, CDCl3): d (ppm)Z150.0 (CarOCH3), 139.9
(CarCH3), 139.6 (HRC]CH2), 139.3 (CarOCH3), 136.0
(Car), 130.8 (Car), 114.6 (HRC]CH2), 98.8 (CarH), 61.3
(OCH3), 60.4 (OCH3), 56.2 (OCH3), 34.2 (CH2), 31.2
(CH2), 30.5 (CH2), 29.9 (2CH2), 29.8 (CH2), 29.5 (CH2),
29.3 (CH2), 25.1 (CH2); MS (EI, 70 eV), m/z (%): 335 (100)
[MC], 306 (78), 182 (18), 167 (20), 152 (10), 138 (10), 122
(9). Anal. C20H33NO3 (335.5): calcd C, 71.60; H, 9.91;
found C, 71.53; H: 9.86.
1
3
3
3
3
(br. s, 2H, NH2), 2.53 (v. t, Jy7.9 Hz, 2H, CH2Car), 2.00
3
(v. q, Jy6.9 Hz, 2H, CH2]CHCH2), 1.52 (m, 2H, CH2),
1.33–1.25 (m, 8H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z149.5 (CarOCH3), 139.5 (HRC]CH2), 139.1 (Car-
OCH3), 138.9 (CarOCH3), 135.6 (Car), 130.3 (Car), 114.0
(HRC]CH2), 98.5 (CarH), 60.8 (OCH3), 59.9 (OCH3), 55.7
(OCH3), 33.7 (CH2), 30.6 (CH2), 29.9 (CH2), 29.2 (CH2),
29.0 (CH2), 28.9 (CH2), 24.7 (CH2); MS (EI, 70 eV), m/z
(%): 307 (100) [MC], 292 (87), 208 (5), 192 (8), 182 (17),
167 (25), 152 (10), 138 (17), 122 (10), 55 (7). Anal.
C18H29NO3 (307.4): calcd C, 70.32; H, 9.51; found C,
69.99; H: 9.46.
5.1.14. 2,4,5-Trimethoxy-3-dodec-11-enylphenylamine
(10d). Procedure C was performed using the nitro arene
9d (448 mg, 1.18 mmol). After flash chromatography (P/EA
90/10), the product was obtained (326 mg, 0.93 mmol, 79%)
as a transparent oil. TLC: RfZ0.15 (P/EA 90/10) [CAM,
UV]; IR (film): n~ (cmK1)Z3450 (w, NH2), 3358 (m, NH2),
3095 (w, ]CH2), 2926 (v. s, CH2), 2854 (S, CH2), 1614 (m,
NH), 1490 (m, CH2), 1363 (S, COC), 1224 (S), 1120 (m,
COC), 1058 (m), 1011 (m, RCH]CH2), 909 (w,
5.1.12. 2,4,5-Trimethoxy-3-dec-9-enylphenylamine
(10b). Procedure C was performed using the nitro arene
9b (1.99 g, 5.67 mmol). After flash chromatography (P/EA
75/25), the product was obtained (1.40 g, 4.37 mmol, 77%)
as a light brown oil. TLC: RfZ0.47 (P/EA 75/25) [CAM,
UV]; IR (film): n~ (cmK1)Z3430 (w, NH2), 3358 (m, NH2),
3095 (w, ]CH2), 2926 (v. s, CH2), 2854 (s, CH2), 1614 (m,
1
RCH]CH2), 821 (w, CH); H NMR (360 MHz, CDCl3):
3
3
d (ppm)Z6.19 (s, 1H, CarH), 5.79 (ddt, JZ17.1 Hz, JZ
3
10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR), 4.99–4.94 (m, 1H,
HtransCH]CHR), 4.92–4.89 (m, 1H, HcisCH]CHR), 3.75
(s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.60
(br. s, 2H, NH2), 2.58–2.56 (m, 2H, CH2Car), 2.00 (v. q,

A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
9667
3Jy6.9 Hz, 2H, CH2]CHCH2), 1.53–1.51 (m, 2H, CH2),
1.35–1.25 (m, 14H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z149.6 (CarOCH3), 139.6 (CarOCH3), 139.2
(HRC]CH2), 139.0 (CarOCH3), 135.6 (Car), 130.4 (Car),
114.0 (HRC]CH2), 98.5 (CarH), 60.9 (OCH3), 59.7
(OCH3), 55.8 (OCH3), 33.7 (CH2), 30.7 (CH2), 30.0
(CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (2 CH2), 29.1 (CH2),
28.9 (CH2), 25.1 (CH2); MS (EI, 70 eV), m/z (%): 349 (100)
[MC], 334 (66), 182 (18), 167 (12), 152 (6), 138 (6), 122 (6).
Anal. C21H35NO3 (349.5): calcd C, 72.17; H, 10.09; found
C, 72.28; H: 10.06.
131.9 (ColefH), 131.3 (Car), 129.5 (Car), 127.4 (]CCH3),
123.5 (]CH–HC]CH2), 114.1 (HRC]CH2), 102.8
(CarH), 61.4 (OCH3), 60.8 (OCH3), 55.9 (OCH3), 33.8
(CH2), 30.5 (CH2), 29.9 (CH2), 29.2 (CH2), 29.0 (CH2), 28.9
(CH2), 24.7 (CH2), 13.0 (CH3); MS (EI, 70 eV), m/z (%):
401 (100) [MC], 386 (8), 370 (10), 153 (7), 95 (66), 67 (20);
HRMS: m/z calcd for C24H35NO4: 401.2566; found
401.2566.
5.1.17. 2-Methylpenta-2,4-dienoic acid (3-dec-9-enyl-
2,4,5-trimethoxyphenyl)-amide (11b). Procedure D was
performed with the aniline 10b (122 mg, 380 mmol). After
flash chromatography (P/EA 95/05), the product was
obtained (92 mg, 221 mmol, 58%) as a light brown oil.
TLC: RfZ0.32 (P/EA 90/10) [CAM, UV]; IR (film): n~
(cmK1)Z3436 (m, NH), 2926 (v. s, CH2), 2854 (s, CH2),
1673 (s, C]O), 1600 (m, C]C), 1514 (s), 1455 (s), 1410
(s), 1221 (s, CN), 1171 (m), 1104 (s), 1058 (s), 1007 (s,
RCH]CH2), 909 (m, RCH]CH2), 851 (m, CH); 1H NMR
(360 MHz, CDCl3): d (ppm)Z8.07 (s, 1H, NH), 8.00 (s, 1H,
5.1.15. 2,4,5-Trimethoxy-3-tridec-12-enylphenylamine
(10e). Procedure C was performed using the nitro arene 9e
(210 mg, 0.53 mmol). After flash chromatography (P/EA
80/20), the product was obtained (159 mg, 0.44 mmol, 83%)
as a transparent oil. TLC: RfZ0.21 (P/EA 80/20) [CAM,
UV]; IR (film): n~ (cmK1)Z3450 (w, NH), 3358 (m, NH),
3095 (w, ]CH2), 2926 (v. s, CH2), 2854 (s, CH2), 1614 (m,
N–H), 1490 (m, CH2), 1363 (s, COC), 1224 (s), 1120 (m,
COC), 1058 (m), 1011 (m, RCH]CH2), 909 (w,
3
CarH), 7.01 [d, JZ11.1 Hz, 1H, CH2]CH–CH]C(CO)],
1
RCH]CH2), 821 (w, CH); H NMR (360 MHz, CDCl3):
6.68 (ddd, 3JZ16.8 Hz, 3JZ11.1 Hz, 3JZ10.1 Hz, 1H,
3
3
3
3
d (ppm)Z6.19 (s, 1H, CarH), 5.79 (ddt, JZ17.1 Hz, JZ
CH2]CH–CH]C), 5.80 (ddt, JZ17.1 Hz, JZ10.2 Hz,
3
3
10.2 Hz, JZ6.7 Hz, 1H, CH2]CHR), 4.99–4.94 (m, 1H,
3JZ6.7 Hz, 1H, CH2]CHR), 5.56 (d, JZ16.8 Hz, 1H,
3
HtransCH]CHR), 4.93–4.90 (m, 1H, HcisCH]CHR), 3.73
(s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.60
(br. s, 2H, NH2), 2.57–2.55 (m, 2H, CH2Car), 2.00 (v. q,
3Jy6.9 Hz, 2H, CH2]CHCH2), 1.53–1.51 (m, 2H, CH2),
1.35–1.26 (m, 16H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z149.6 (CarOCH3), 139.7 (CarOCH3), 139.2
(HRC]CH2), 139.0 (CarOCH3), 135.6 (Car), 130.5 (Car),
114.0 (HRC]CH2), 98.5 (CarH), 60.9 (OCH3), 60.0
(OCH3), 55.8 (OCH3), 33.8 (CH2), 30.7 (CH2), 30.1
(CH2), 29.7 (CH2), 29.6 (2 CH2), 29.5 (CH2), 29.4 (CH2),
29.1 (CH2), 28.9 (CH2), 24.8 (CH2); MS (EI, 70 eV), m/z
(%): 363 (100) [MC], 348 (54), 182 (18), 167 (12), 152 (8),
138 (8), 122 (8), 55 (6), 41 (6) [C3HC4 ]. Anal. C22H37NO3
(363.5): calcd C, 72.69; H, 10.26; found C, 72.57; H: 10.28.
HtransCH]CH–CH]C), 5.45 (d, JZ10.2 Hz, 1H, Hcis-
CH]CH–CH]C), 4.98 (m, 1H, HtransCH]CHR), 4.90
(m, 1H, HcisCH]CHR), 3.86 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 2.62 (t, 3JZ6.4 Hz, 2H,
3
CH2Car), 2.09 (br. s, 3H, ]CCH3), 2.03 (v. q, Jy7.0 Hz,
2H, CH2]CHCH2), 1.58–1.53 (m, 2H, CH2), 1.37–1.30 (m,
10H, CH2); 13C NMR (90.6 MHz, CDCl3): d (ppm)Z166.6
(C]O), 149.2 (CarOCH3), 143.5 (CarOCH3), 141.0 (Car-
OCH3), 139.2 (HRC]CH2), 134.5 (ColefH), 131.9 (ColefH),
131.3 (Car), 129.5 (Car), 127.3 (]CCH3), 123.5 (]CH–
HC]CH2), 114.1 (HRC]CH2), 102.7 (CarH), 61.4
(OCH3), 60.8 (OCH3), 55.9 (OCH3), 33.8 (CH2), 30.5
(CH2), 30.0 (CH2), 29.4 (2 CH2), 29.1 (CH2), 28.9 (CH2),
24.7 (CH2), 13.0 (CH3); MS (EI, 70 eV), m/z (%): 415 (100)
[MC], 384 (10), 332 (5), 166 (6), 95 (57), 67 (17). Anal.
C25H37NO4 (415.6): calcd C, 72.26; H, 8.97; found C,
72.15; H: 8.85.
5.1.16. 2-Methylpenta-2,4-dienoic acid (2,4,5-tri-
methoxy-3-non-8-enylphenyl)-amide (11a). Procedure D
was performed with the aniline 10a (50 mg, 163 mmol).
After flash chromatography (P/EA 80/20), the product was
obtained (47 mg, 117 mmol, 72%) as a light yellow oil.
TLC: RfZ0.32 (P/EA 90/10) [CAM, UV]; IR (film): n~
(cmK1)Z3436 (m, NH), 2926 (v. s, CH2), 2854 (s, CH2),
1673 (s, C]O), 1600 (m, C]C), 1514 (s), 1455 (s), 1410
(s), 1221 (s, CN), 1171 (m), 1104 (s), 1058 (s), 1007 (s,
RCH]CH2), 909 (m, RCH]CH2), 851 (m, CH); 1H NMR
(360 MHz, CDCl3): d (ppm)Z8.07 (s, 1H, NH), 8.00 (s, 1H,
5.1.18. 2-Methylpenta-2,4-dienoic acid (2,4,5-tri-
methoxy-3-undec-10-enylphenyl)-amide (11c). Procedure
D was performed with the aniline 10c (200 mg, 597 mmol).
After flash chromatography (P/EA 90/10), the product was
obtained (169 mg, 393 mmol, 66%) as a light brown oil.
TLC: RfZ0.33 (P/EA 90/10) [CAM, UV]; IR (film): n~
(cmK1)Z3436 (m, NH), 2926 (v. s, CH2), 2854 (s, CH2),
1673 (s, C]O), 1600 (m, C]C), 1514 (s), 1455 (s), 1410
(s), 1221 (s, CN), 1171 (m), 1104 (s), 1058 (s), 1007 (s,
RCH]CH2), 909 (m, RCH]CH2), 851 (m, CH); 1H NMR
(250 MHz, CDCl3): d (ppm)Z8.08 (s, 1H, NH), 7.99 (s, 1H,
3
CarH), 7.01 [d, JZ10.2 Hz, 1H, CH2]CH–CH]C(CO)],
6.68 (ddd, 3JZ16.7 Hz, 3JZ10.2 Hz, 3JZ10.0 Hz, 1H,
3
3
CH2]CH–CH]C), 5.80 (ddt, JZ17.1 Hz, JZ10.2 Hz,
3
3
3JZ6.7 Hz, 1H, CH2]CHR), 5.56 (d, JZ16.7 Hz, 1H,
CarH), 7.02 [d, JZ11.1 Hz, 1H, CH2]CH–CH]C(CO)],
3
HtransCH]CH–CH]C), 5.45 (d, JZ10.2 Hz, 1H, Hcis-
6.67 (ddd, 3JZ16.8 Hz, 3JZ11.1 Hz, 3JZ10.1 Hz, 1H,
3
3
CH]CH–CH]C), 4.99–4.93 (m, 1H, HtransCH]CHR),
4.91–4.88 (m, 1H, HcisCH]CHR), 3.86 (s, 3H, OCH3),
3.80 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 2.62 (v. t,
3Jy6.4 Hz, 2H, CH2Car), 2.09 (d, 4JZ0.9 Hz, 3H,
]CCH3), 2.03 (v. q, 3Jy7.0 Hz, 2H, CH2]CHCH2),
1.57–1.31 (m, 10H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z166.6 (C]O), 149.2 (CarOCH3), 143.5 (CarOCH3),
141.0 (CarOCH3), 139.2 (HRC]CH2), 134.5 (ColefH),
CH2]CH–CH]C), 5.80 (ddt, JZ17.1 Hz, JZ10.2 Hz,
3
3JZ6.7 Hz, 1H, CH2]CHR), 5.55 (d, JZ16.8 Hz, 1H,
3
HtransCH]CH–CH]C), 5.46 (d, JZ10.2 Hz, 1H, Hcis-
CH]CH–CH]C), 4.97 (m, 1H, HtransCH]CHR), 4.91
(m, 1H, HcisCH]CHR), 3.86 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 2.61 (t, 3JZ6.4 Hz, 2H,
3
CH2Car), 2.09 (br. s, 3H, ]CCH3), 2.02 (v. q, Jy7.0 Hz,
2H, CH2]CHCH2), 1.60–1.54 (m, 2H, CH2), 1.35–1.27 (m,

9668
A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
12H, CH2); 13C NMR (62.9 MHz, CDCl3): d (ppm)Z166.9
(C]O), 149.6 (CarOCH3), 143.9 (CarOCH3), 141.4 (Car-
OCH3), 139.6 (HRC]CH2), 135.0 (ColefH), 132.3 (ColefH),
131.7 (Car), 130.0 (Car), 127.7 (]CCH3), 124.0 (]CH–
HC]CH2), 114.4 (HRC]CH2), 103.1 (CarH), 61.8
(OCH3), 61.3 (OCH3), 56.2 (OCH3), 34.2 (CH2), 31.0
(CH2), 30.4 (CH2), 29.9 (2 CH2), 29.8 (CH2), 29.5 (CH2),
29.3 (CH2), 25.1 (CH2), 13.4 (CH3); MS (EI, 70 eV), m/z
(%): 429 (95) [MC], 414 (15), 398 (10), 346 (9), 320 (9),
167 (6), 95 (100), 67 (26), 41 (6). Anal. C26H39NO4 (429.6):
calcd C, 72.69; H, 9.15; found C, 72.59; H: 9.01.
4.92–4.88 (m, 1H, HcisCH]CHR), 3.84 (s, 3H, OCH3),
3.78 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 2.61 (t, 3JZ6.4 Hz,
2H, CH2Car), 2.08 (d, 4JZ1.1 Hz, 3H, ]CCH3), 2.02 (v. q,
3Jy7.0 Hz, 2H, CH2]CHCH2), 1.56–1.49 (m, 2H, CH2),
1.35–1.27 (m, 16H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z166.6 (C]O), 149.3 (CarOCH3), 143.6 (CarOCH3),
141.1 (CarOCH3), 139.2 (HRC]CH2), 134.5 (ColefH),
132.0 (ColefH), 131.4 (Car), 129.6 (Car), 127.4 (]CCH3),
123.5 (]CH–HC]CH2), 114.0 (HRC]CH2), 102.8
(CarH), 61.4 (OCH3), 60.9 (OCH3), 55.9 (OCH3), 33.8
(CH2), 30.6 (CH2), 30.0 (CH2), 29.7 (CH2), 29.6 (2 CH2),
29.5 (CH2), 29.4 (CH2), 29.1 (CH2), 28.9 (CH2), 24.8 (CH2),
13.0 (CH3); MS (EI, 70 eV), m/z (%): 457 (100) [MC], 442
(10), 426 (8), 374 (5), 167 (6), 149 (8), 95 (74), 67 (12), 57
(6), 40 (6). Anal. C28H43NO4 (457.6): calcd C, 73.48; H,
9.47; found C, 73.53; H: 9.30.
5.1.19. 2-Methylpenta-2,4-dienoic acid (2,4,5-tri-
methoxy-3-dodec-11-enylphenyl)-amide (11d). Procedure
D was performed with the aniline 10d (191 mg, 547 mmol).
The amount of reagents and solvents was adjusted
accordingly. After flash chromatography (P/EA 90/10), the
product was obtained (165 mg, 372 mmol, 68%) as a light
brown oil. TLC: RfZ0.38 (P/EA 90/10) [CAM, UV]; IR
(film): n~ (cmK1)Z3436 (m, NH), 2926 (v. s, CH2), 2854 (s,
CH2), 1673 (s, C]O), 1600 (m, C]C), 1514 (s), 1455 (s),
1410 (s), 1221 (s, CN), 1171 (m), 1104 (s), 1058 (s), 1007 (s,
RCH]CH2), 909 (m, RCH]CH2), 851 (m, CH); 1H NMR
(360 MHz, CDCl3): d (ppm)Z8.03 (s, 1H, NH), 7.96 (s, 1H,
5.1.21. (4E,6Z)-18,19,21-Trimethoxy-4-methyl-2-aza-
bicyclo[15.3.1]henicosa-1(21),4,6,17,19-pentaen-3-one
(12c). Procedure E was performed with the anilide 11c
(50 mg, 116 mmol) and Grubbs catalyst (9.5 mg, 11.5 mmol,
10 mol%) in DCM (230 mL). After flash chromatography
(P/EA 90/10), the product was obtained (31 mg, 77 mmol,
66%) as a white solid. Starting material was isolated (7 mg,
16 mmol, 14%). TLC: RfZ0.32 (P/EA 90/10) [CAM, UV];
1H NMR (360 MHz, CDCl3): d (ppm)Z8.35 (s br, 1H, NH),
3
CarH), 6.97 [d, JZ11.1 Hz, 1H, CH2]CH–CH]C(CO)],
6.66 (ddd, 3JZ16.8 Hz, 3JZ11.1 Hz, 3JZ10.1 Hz, 1H,
3
3
3
CH2]CH–CH]C), 5.78 (ddt, JZ17.1 Hz, JZ10.2 Hz,
8.01 (s, 1H, CarH), 7.01 [d, JZ11.3 Hz, 1H, CH]CH–
3
3JZ6.7 Hz, 1H, CH2]CHR), 5.55 (d, JZ16.8 Hz, 1H,
CH]C(CO)], 6.28 [v. t, 3Jy10.9 Hz, 1H, CH]CH–
CH]C(CO)], 5.97 [v. q, 3Jy9.1 Hz, 1H, CH]CH–
CH]C(CO)], 3.85 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
3.68 (s, 3H, OCH3), 2.61 (br, 1H, CH2), 2.09 (br, 1H, CH2),
2.02 (br. s, 3H, ]CCH3), 1.58–1.10 (m, 16H, CH2); 13C
NMR (90.6 MHz, CDCl3): d (ppm)Z168.6 (C]O), 149.5
(CarOCH3), 142.8 (CarOCH3), 141.2 (CarOCH3), 138.5
(ColefH), 133.2 (Car), 128.8 (Car), 127.9 (]CCH3), 127.4
(ColefH), 123.7 (ColefH), 100.7 (CarH), 61.3 (OCH3), 61.0
(OCH3), 55.9 (OCH3), 30.1 (CH2), 30.0 (CH2), 29.8 (CH2),
29.7 (CH2), 28.7 (CH2), 28.0 (CH2), 27.4 (CH2), 25.9 (CH2),
22.1 (CH2), 12.4 (CH3); MS (EI, 70 eV), m/z (%): 401 (100)
[MC], 386 (22), 370 (50), 206 (6), 182 (7), 167 (8), 152 (7).
Anal. C24H35NO4 (401.5): calcd C, 71.79; H, 8.79; found C,
71.77; H: 8.66.
3
HtransCH]CH–CH]C), 5.46 (d, JZ10.2 Hz, 1H, Hcis-
CH]CH–CH]C), 4.97–4.91 (m, 1H, HtransCH]CHR),
4.89–4.86 (m, 1H, HcisCH]CHR), 3.82 (s, 3H, OCH3),
3.77 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 2.58 (v. t,
3Jy6.4 Hz, 2H, CH2Car), 2.06 (br. s, 3H, ]CCH3), 2.02 (v.
q, 3Jy7.0 Hz, 2H, CH2]CHCH2), 1.53 (m, 2H, CH2),
1.35–1.27 (m, 14H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z166.4 (C]O), 149.2 (CarOCH3), 143.5 (CarOCH3),
141.0 (CarOCH3), 139.1 (HRC]CH2), 134.4 (ColefH),
131.9 (ColefH), 131.3 (Car), 129.4 (Car), 127.3 (]CCH3),
123.4 (]CH–HC]CH2), 114.0 (HRC]CH2), 102.7
(CarH), 61.3 (OCH3), 60.7 (OCH3), 55.8 (OCH3), 33.7
(CH2), 30.4 (CH2), 29.9 (CH2), 29.5 (CH2), 29.4 (2 CH2),
29.3 (CH2), 29.0 (CH2), 28.9 (CH2), 24.7 (CH2), 12.9
(CH3); MS (EI, 70 eV), m/z (%): 443 (100) [MC], 428 (10),
95 (80), 67 (12), 40 (6). Anal. C27H41NO4 (443.6): calcd C,
73.10; H, 9.32; found C, 73.05; H: 9.41.
5.1.22. (4E,6Z)-19,20,22-Trimethoxy-4-methyl-2-aza-
bicyclo[16.3.1]docosa-1(22),4,6,18,20-pentaen-3-one
(12d). Procedure E was performed with the anilide 11d
(50 mg, 112 mmol) and Grubbs catalyst (9.0 mg, 11.2 mmol,
10 mol%) in DCM (220 mL). After flash chromatography
(P/EA 90/10), the product was obtained (35 mg, 86 mmol,
77%) as a transparent to light green transparent oil. TLC:
RfZ0.29 (P/EA/DCM 50/10/50) [CAM, UV]; IR (film): n~
(cmK1)Z3428 (br, NH), 2974 (s, CH3), 2926 (v. s, CH2),
2854 (v. s, CH2), 1667 (s, C]O), 1592 (m, C]C), 1504 (s,
NH), 1434 (s, C]C), 1229 (m), 1105 (s, C–O–C), 1027 (m),
5.1.20. 2-Methylpenta-2,4-dienoic acid (2,4,5-tri-
methoxy-3-tridec-12-enylphenyl)-amide (11e). Procedure
D was performed with the aniline 10e (131 mg, 361 mmol).
After flash chromatography (P/EA 90/10), the product was
obtained (105 mg, 229 mmol, 63%) as a light brown oil.
TLC: RfZ0.33 (P/EA 90/10) [CAM, UV]; IR (film): n~
(cmK1)Z3436 (m, NH), 2926 (v. s, CH2), 2854 (s, CH2),
1673 (s, C]O), 1600 (m, C]C), 1514 (s), 1455 (s), 1410
(s), 1221 (s, C–N), 1171 (m), 1104 (s), 1058 (s), 1007 (s,
RCH]CH2), 909 (m, RCH]CH2), 851 (m, CH); 1H NMR
(360 MHz, CDCl3): d (ppm)Z8.05 (s, 1H, NH), 7.98 (s, 1H,
1
954 (w), 909 (w), 852 (w), 734 (w); H NMR (360 MHz,
CDCl3): d (ppm)Z8.23 (br. s, 1H, NH), 7.95 (s, 1H, CarH),
6.99 [d, 3JZ11.3 Hz, 1H, CH]CH–CH]C(CO)], 6.32 [v.
t, 3Jy10.9 Hz, 1H, CH]CH–CH]C(CO)], 5.96 [v. q,
3Jy9.1 Hz, 1H, CH]CH–CH]C(CO)], 3.87 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 2.70 (t,
3
CarH), 6.98 [d, JZ11.1 Hz, 1H, CH2]CH–CH]C(CO)],
6.67 (ddd, 3JZ16.8 Hz, 3JZ11.1 Hz, 3JZ10.1 Hz, 1H,
3
3
CH2]CH–CH]C), 5.80 (ddt, JZ17.1 Hz, JZ10.2 Hz,
3
3
3JZ6.7 Hz, 1H, CH2]CHR), 5.55 (d, JZ16.8 Hz, 1H,
3JZ6.5 Hz, 2H, CH2), 2.21 (v. q, Jy8.0 Hz, 2H, CH2),
3
HtransCH]CH–CH]C), 5.46 (d, JZ10.2 Hz, 1H, Hcis-
CH]CH–CH]C), 4.99–4.93 (m, 1H, HtransCH]CHR),
2.04 (d, 4JZ0.7 Hz, 3H, ]CCH3), 1.68–1.65 (m, 2H, CH2),
1.47–1.10 (m, 14H, CH2); 13C NMR (90.6 MHz, CDCl3): d

A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
9669
(ppm)Z168.4 (C]O), 149.4 (CarOCH3), 143.3 (CarOCH3),
141.2 (CarOCH3), 137.9 (ColefH), 133.5 (Car), 128.8 (Car),
127.6 (]CCH3), 126.7 (ColefH), 124.1 (ColefH), 101.4
(CarH), 61.3 (OCH3), 60.9 (OCH3), 55.9 (OCH3), 29.7
(CH2), 29.6 (CH2), 29.4 (CH2), 28.8 (CH2), 28.6 (CH2), 28.5
(CH2), 28.1 (CH2), 27.4 (CH2), 27.2 (CH2), 22.1 (CH2), 12.6
(CH3); MS (EI, 70 eV), m/z (%): 415 (100) [MC], 400 (22),
384 (23), 182 (6), 167 (8), 152 (6). Anal. C25H37NO4
(415.6): calcd C, 72.26; H, 8.97; found C, 72.42; H: 9.11.
19H, CH3, CH2); 13C NMR (90.6 MHz, CDCl3): d (ppm)Z
174.0 (C]O), 149.3 (CarO), 143.5 (CarO), 140.1 (CarO),
139.4 (HC]CH2), 135.6 (CH2HC]CH2), 129.5 (Car),
127.3 (Car), 117.4 (HRC]CH2), 114.2 (HC]CH2), 102.9
(CarH), 61.5 (OCH3), 61.0 (OCH3), 56.0 (OCH3), 42.7
[CH(CO)CH3], 38.5 [CH2CH(CO)CH3], 33.9 (CH2), 30.7
(CH2), 30.1 (CH2), 29.8 (CH2), 29.7 (2 CH2), 29.7 (CH2),
29.6 (CH2), 29.6 (CH2), 29.3 (CH2), 29.1 (CH2), 24.9 (CH2),
17.6 (CH3); MS (ESI), m/z (%): 460.9 (100) [MCHC].
5.1.23. (4E,6Z)-20,21,23-Trimethoxy-4-methyl-2-aza-
bicyclo[17.3.1]tricosa-1(23),4,6,19,21-pentaen-3-one
(12e). Procedure E was performed with the anilide 11e
(50 mg, 109 mmol) and first generation of Grubbs catalyst
(8.3 mg, 11.0 mmol, 10 mol%) in DCM (200 mL). After
flash chromatography (P/EA 90/10), the product was
obtained (41 mg, 96 mmol, 87%) as a white solid. TLC:
RfZ0.57 (P/EA/DCM 50/10/50) [CAM, UV]; 1H NMR
(360 MHz, CDCl3): d (ppm)Z8.29 (s br, 1H, NH), 7.99 (s,
1H, CarH), 7.03 [d, 3JZ11.1 Hz, 1H, CH]CH–
CH]C(CO)], 6.33 [v. t, 3Jy11.0 Hz, 1H, CH]CH–
CH]C(CO)], 5.90 [v. q, 3Jy9.0 Hz, 1H, CH]CH–
CH]C(CO)], 3.87 (s, 3H, OCH3), 3.79 (s, 3H, OCH3),
3.73 (s, 3H, OCH3), 2.65 (t, 3JZ7.1 Hz, 2H, CH2), 2.27 (v.
5.1.25. 20,21,23-Trimethoxy-4-methyl-2-aza-bicyclo-
[17.3.1]tricosa-1(23),6,19,21-tetraen-3-one (14). Pro-
cedure E was performed with anilide 13 (26 mg, 57 mmol)
and Grubbs catalyst (4.7 mg, 5.7 mmol, 10 mol%) in DCM
(113 mL). After flash chromatography (P/EA 90/10), the
product was obtained (21 mg, 49 mmol, 86%) as a white
solid. The d.r. of the product was 66:34. It was not possible
to determine which isomer was the major product. TLC:
RfZ0.62 (P/EA/DCM 50/10/50) [CAM, UV]; 1H NMR
(360 MHz, CDCl3): d (ppm)Z7.96 (br. s, 0.33H, NH-
minor), 7.93 (br. s, 0.66H, NH-major), 7.72 (s, 0.33H, CarH-
minor), 7.66 (s, 0.66H, CarH), 5.50 (m, 2H, CH]CH), 3.85
(s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.63 (s, 3H, OCH3),
2.65–1.97 (m, 6H, CH2), 1.63–1.58 (m, 2H, CH2), 1.30–1.27
(m, 20H, CH2); 13C NMR (90.6 MHz, CDCl3): d (ppm)Z
174.2 (C]O, major), 174.1 (C]O, minor), 149.3 (Car-
OCH3, major), 149.3 (CarOCH3, minor). 143.6 (CarOCH3),
141.3 (CarOCH3), 134.2 (ColefH, major), 133.3 (ColefH,
minor). 129.3 (Car), 129.4 (Car), 127.3 (]CCH3), 126.7
(ColefH, major), 126.0 (ColefH, minor), 102.9 (CarH, major),
102.5 (CarH, minor), 61.2 (OCH3 minor), 61.1 (OCH3,
major), 61.0 (OCH3 minor), 61.0 (OCH3, major), 56.0
(OCH3), 43.7 (CH2), 43.3 (CH2), 37.8 (CH2), 32.5 (CH2),
32.2 (CH2, major), 29.5 (CH2), 28.9 (CH2), 28.7 CH2), 28.6
CH2), 28.6 (CH2), 28.5 (CH2), 28.3 (CH2), 28.1 (CH2), 27.8
(CH2), 27.2 (CH2), 27.2 (CH2), 24.2 (CH2), 23.6 (CH2), 22.7
(CH2), 18.1 (CH3, major), 17.1 (CH3, minor); MS (EI,
70 eV), m/z (%): 431 (100) [MC], 416 (21), 400 (5), 208 (5),
182 (8), 167 (10), 149 (10), 71 (6), 57 (12), 41 (7); HRMS:
m/z calcd for C26H41NO4: 431.3036; found 431.3033.
3
q, Jy7.1 Hz, 2H, CH2), 2.04 (s, 3H, ]CCH3), 1.61–1.57
(m, 2H, CH2), 1.47–1.27 (m, 16H, CH2); 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z167.5 (C]O), 149.4 (Car-
OCH3), 143.0 (CarOCH3), 141.1 (CarOCH3), 138.4 (ColefH),
133.0 (Car), 129.4 (Car), 127.7 (]CCH3), 126.2 (ColefH),
123.7 (ColefH), 101.6 (CarH), 61.1 (OCH3), 61.0 (OCH3),
55.9 (OCH3), 29.6 (CH2), 29.3 (CH2), 29.2 (CH2), 29.0
(CH2), 28.5 (CH2), 28.0 (CH2), 27.9 (CH2), 27.7 (CH2), 27.7
(CH2), 27.2 (CH2), 22.7 (CH2), 12.6 (CH3); MS (EI, 70 eV),
m/z (%): 429 (100) [MC], 414 (21), 398 (22), 386 (8), 365
(7), 335 (7), 322 (7), 292 (14), 280 (10), 249 (8), 236 (5),
206 (6), 182 (8), 167 (8), 152 (7), 95 (6), 40 (7). Anal.
C26H39NO4 (429.6): calcd C, 72.69; H, 9.15; found C,
72.79; H: 8.98.
5.1.24. 2-Methylpent-2-enoic acid (2,4,5-trimethoxy-3-
tridec-12-enylphenyl)-amide (13). To 2-methylpent-2-
enoic acid (30 mg, 263 mmol) dissolved in THF (0.3 mL),
HOBt (42 mg, 322 mmol) and DCC (66 mg, 322 mmol) were
added. The mixture was placed under argon atmosphere and
stirred for 5 min at rt. Aniline 10e (30 mg, 83 mmol)
dissolved in THF (0.2 mL) was added. The mixture was
stirred for 48 h at rt. Diethyl ether (5 mL) and water (5 mL)
were added. The aqueous layer was extracted twice with
diethyl ether (2!5 mL). The combined organic layers were
washed with saturated NaHCO3 (10 mL), brine (10 mL),
dried (Na2SO4) and concentrated in vacuo. After flash
chromatography (P/EA 90/10), the product was obtained
(26 mg, 57 mmol, 69%) as a transparent oil. TLC: RfZ0.39
5.1.26. (4E,6Z)-21-Methoxy-4-methyl-2-aza-bicyclo-
[15.3.1]henicosa-1(21),4,6,17,18(21)-tetraen-3,18,19-
trione (15). General procedure F was performed with
compound 12c (28 mg, 69 mmol). The product was purified
by flash chromatography (P/EA 75/25). The ortho-quinone
(8.0 mg, 21 mmol, 30%) was isolated as a red film. TLC:
1
RfZ0.22 (P/EA 75/25) [CAM, UV]. H NMR (360 MHz,
CDCl3): d (ppm)Z8.57 (s br, 1H, NH), 7.31 (s, 1H, CquinH),
7.05 [d, 3JZ11.1 Hz, 1H, CH]CH–CH]C(CO)], 6.33 [v.
t, 3Jy10.9 Hz, 1H, CH]CH–CH]C(CO)], 6.12 [v. q,
3Jy9.1 Hz, 1H, CH]CH–CH]C(CO)], 3.94 (s, 3H,
OCH3), 2.66 (br, 1H, CH2), 2.29 (br, 2H, CH2), 2.19 (s,
3H, ]CCH3), 1.58–1.24 (m, 16H, CH2); 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z180.3 (Cquin]O), 179.4
(Cquin]O), 168.2 (C]O), 159.3 (C-20), 144.1 (Cquin),
140.9 (C-5), 131.9 (C-2), 129.5 (Cquin), 129.2 (C-3), 123.3
(C-4), 107.1 (C-18), 62.6 (OCH3), 29.6 (CH2), 29.6 (CH2),
29.3 (CH2), 28.6 (CH2), 28.0 (CH2), 27.7 (CH2), 27.4 (CH2),
26.0 (CH2), 21.8 (CH2), 12.3 (CH3); MS (EI, 70 eV), m/z
(%): 371 (100) [MC], 354 (22), 340 (10), 328 (12), 274 (6),
244 (6), 178 (5), 152 (24), 138 (14), 110 (44), 95 (30), 79
1
(P/EA 90/10) [CAM, UV]; H NMR (360 MHz, CDCl3): d
(ppm)Z7.92 (s, 1H, CarH), 7.68 (s, 1H, NH), 5.82 (m, 2H,
CH2]CH), 5.13 (d, 3JZ17.2 Hz, 1H, HtransCH]CH), 5.06
(d, 3JZ10.2 Hz, 1H, HcisCH]CH), 4.98 (br. d, 3JZ
17.2 Hz, 1H, HtransCH]CH), 4.91 (br. d, 3JZ10.2 Hz,
1H, HcisCH]CH2), 3.84 (s, 3H, OCH33), 3.78 (s, 3H,
OCH3), 3.71 (s, 3H, OCH3), 2.61 (v. t, Jy6.4 Hz, 2H,
CH2Car), 2.52–2.47 (m, 2H, CH2]CHCH2), 2.28–2.22 [m,
1H, CH2CH(CO)CH3], 2.02 (v. q, 3Jy7.0 Hz, 2H,
CH2]CHCH2), 1.56–1.50 (m, 2H, CH2), 1.36–1.26 (m,

9670
A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
(32), 67 (40), 55 (22), 41 (36); HRMS: m/z calcd for
C22H29NO4: 371.2097; found 371.2086.
5.1.29. 1,4-Di-iso-propoxy-3-dodec-11-enyl-2-methoxy-
5-nitrobenzene (19). Procedure B was performed with
1,4-di-iso-propoxy-2-methoxy-3-dodec-11-enylbenzene
(18) (507 mg, 1.30 mmol). After flash chromatography
(P/EA 98/02), the product was obtained (472 mg,
1.08 mmol, 83%) as a yellow oil. TLC: RfZ0.43 (P/EA
95/05) [CAM, UV]; IR (film): n~ (cmK1)Z3075 (w, ]CH),
2977 (s, CH3), 2926 (v. s, CH2), 2853 (s, CH2), 1640 (m,
C]C), 1570 (m, Car]Car), 1522 (s, NO2), 1471 (s,
Car]Car), 1383 (m, CH3), 1371 (m, CH3), 1345 (s, CN),
1241 (s, COC), 1122 (s, COC), 974 (w, RCH]CH2), 910
(m, RCH]CH2), 787 (w, CH); 1H NMR (360 MHz,
CDCl3): d (ppm)Z7.28 (s, 1H, CarH), 5.81 (ddt, 3JZ
17.0 Hz, 3JZ10.1 Hz, 3JZ6.8 Hz, 1H, CH2]CHR), 5.01–
4.97 (m, 1H, HtransCH]CHR), 4.94–4.91 (m, 1H, Hcis-
CH]CHR), 4.52 [sept., 3JZ6.1 Hz, 1H, OCH(CH3)2], 4.11
5.1.27. (4E,6Z)-21,23-Dimethoxy-4-methyl-2-aza-bi-
cyclo[17.3.1]tricosa-1,4,6,19(23),21-pentaen-3,20-dione
(16). General procedure F was performed with compound
12e (38 mg, 89 mmol). The amount of reagents and solvents
was adjusted accordingly. The mixture was stirred at
K10 8C during 40 min. After the work-up, the product
was purified by flash chromatography (P/EA 90/10). The
aza-quinone (24 mg, 57 mmol, 64%) was isolated as a
1
yellow film. TLC: RfZ0.67 (P/EA 50/50) [CAM, UV]; H
3
NMR (500 MHz, CDCl3): d (ppm)Z7.28 (d, JZ11.1 Hz,
3
1H, CH]CH–CH]C(CO)], 6.36 [v. t, Jy10.9 Hz, 1H,
CH]CH–CH]C(CO)], 5.92 [v. q, 3Jy9.1 Hz, 1H,
CH]CH–CH]C(CO)], 5.80 (s, 1H, CquinH), 4.01 (s, 3H,
3
3
[sept., JZ6.1 Hz, 1H, OCH(CH3)2], 3.91 (s, 3H, OCH3),
OCH3), 3.74 (s, 3H, OCH3), 2.55 (v. t, Jy7.0 Hz, 1H,
2.63 (t, 3JZ7.9 Hz, 2H, CH2Ar), 2.04 (v. q, 3Jy7.0 Hz, 2H,
CH2]CHCH2), 1.55–1.49 (m, 2H, CH2), 1.38–1.26 [m,
26H, CH2, OCH(CH3)2]; 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z153.4 (CarOiPr), 146.2 (CarOiPr), 144.6 (CarOMe),
139.5 (Car), 139.4 (HRC]CH2), 133.7 (Car), 114.2
(HRC]CH2), 109.4 (CarH), 78.1 [OCH(CH3)2], 71.8
[OCH(CH3)2], 61.0 (OCH3), 34.0 (CH2), 30.2 (CH2), 29.9
(CH2), 29.8 (CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.3
(CH2), 29.1 (CH2), 25.5 (CH2), 22.4 [CH(CH3)2], 22.1
[CH(CH3)2]; MS (EI, 70 eV), m/z (%): 435 (22) [MC], 393
(100), 351 (8), 334 (26), 316 (56), 284 (20), 256 (5), 198
(24), 180 (22), 168 (30), 153 (18), 139 (9), 123 (12), 95 (12),
69 (18), 55 (32), 43 (60). Anal. C25H41NO5 (435.6): calcd C,
68.93; H, 9.49; found C, 69.05; H: 9.55.
3
CquinCH2), 2.20 (v. q, Jy7.9 Hz, 2H, CH2), 2.04 (s, 3H,
]CCH3), 1.52–1.24 (m, 20H, CH2); 13C NMR (90.6 MHz,
CDCl3): d (ppm)Z182.3 (Cquin]O), 182.3 (Cquin]N),
158.7 (C]O), 159.3 (C-20), 155.7 (Cquin), 153.8 (Cquin),
141.9 (C-5), 136.0 (C-3), 132.5 (C-2), 131.0 (Cquin), 123.9
(C-4), 107.1 (CquinH), 62.6 (C-22-OCH3), 56.1 (C-19-
OCH3) 28.8 (CH2), 28.5 (CH2), 28.3 (CH2), 28.0 (CH2),
28.0 (CH2), 27.9 (CH2), 27.6 (CH2), 27.6 (CH2), 27.0 (CH2),
26.9 (CH2), 23.0 (CH2), 11.6 (CH3); MS (EI, 70 eV), m/z
(%): 413 (100) [MC], 398 (22), 382 (24), 354 (14), 318 (5),
274 (10), 242 (11), 229 (10), 180 (20), 164 (14), 136 (10),
110 (14), 95 (25), 79 (42), 67 (40), 55 (36), 41 (50); HRMS:
m/z calcd for C25H35NO4: 413.2566; found 413.2582.
5.1.28. 1,4-Di-iso-propoxy-2-methoxy-3-dodec-11-enyl-
benzene (18). Procedure G was performed with 12-
iodododec-1-ene (7d) (633 mg, 2.15 mmol) and 1,4-di-iso-
propoxy-2-methoxy-benzene (17)26 (3.06 g, 3.06 mmol).
After flash chromatography (P/EA 99/01), the product was
isolated (517 mg, 1.32 mmol, 61%) as a light yellow oil. A
by product 2,5-di-iso-propoxy-1-methoxy-3-dodec-11-enyl
benzene was also isolated (33mg, 0.08 mmol, 4%) as a
colorless oil. TLC: RfZ0.51 (P/EA 95/5) [CAM, UV]; IR
(film): n~ (cmK1)Z3075 (w, ]CH2), 2929 (v. s, CH2), 2856
(s, CH2), 1640 (m, C]C), 1587 (w, Car]Car), 1478 (s, CO),
1251 (s, COC), 1118 (s, COC), 983 (m, RCH]CH2), 909
(m, RCH]CH2), 787 (m), 775 (w, CH); 1H NMR
(360 MHz, CDCl3): d (ppm)Z6.68 (d, 3JZ8.9 Hz, 1H,
CarH), 6.51 (d, 3JZ8.9 Hz, 1H, CarH), 5.82 (ddt, 3JZ
17.1 Hz, 3JZ10.2 Hz, 3JZ6.2 Hz, 1H, CH2]CHR), 5.03–
4.98 (m, 1H, HtransCH]CHR), 4.96–4.93 (m, 1H, Hcis-
CH]CHR), 4.43 [sept., 3JZ6.2 Hz, 2H, OCH(CH3)2], 3.84
(s, 3H, OCH3), 2.61 (t, 3JZ7.7 Hz, 2H, CH2Ar), 2.04 (v. q,
3Jy7.0 Hz, 2H, CH2]CHCH2), 1.55–1.49 (m, 2H, CH2),
1.33–1.29 [m, 26H, CH2, OCH(CH3)2]; 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z151.0 (CarOiPr), 150.0
(CarOiPr), 144.8 (CarOMe), 139.4 (HRC]CH2), 127.5
(CarCH2), 114.7 (CarH), 114.2 (HRC]CH2), 108.4
(CarH), 71.9 [OCH(CH3)2], 70.5 [OCH(CH3)2], 60.7
(OCH3), 34.0 (CH2), 30.1 (CH2), 30.1 (CH2), 29.8 (CH2),
29.7 (CH2), 29.7 (CH2), 29.6 (CH2), 29.3 (CH2), 29.1 (CH2),
24.3 (CH2), 22.5 [CH(CH3)2], 22.4 [CH(CH3)2]; MS (EI,
70 eV), m/z (%): 390 (70) [MC], 348 (22), 306 (100), 195
(6), 153 (47), 141 (6), 125 (14), 107 (10), 75 (6), 55 (10), 43
(13). Anal. C25H42O3 (390.6): calcd C, 76.87; H, 10.74;
found C, 76.86; H: 10.79.
5.1.30. 1,4-Di-iso-propoxy-3-dodec-11-enyl-2-methoxy-
phenyl amine (20). Procedure C was performed with 1,4-
di-iso-propoxy-3-dodec-11-enyl-2-methoxy-5-nitrobenzene
(19) (200 mg, 460 mmol). After flash chromatography
(P/EA 90/10), the product was obtained (147 mg,
363 mmol, 79%) as a yellow oil. TLC: RfZ0.17 (P/EA 90/
10) [CAM, UV]; IR (film): n~ (cmK1)Z3450 (w, NH2), 3360
(w, NH2), 3075 (w, ]CH), 2973 (S, CH3), 2925 (v. s, CH2),
2853 (s, CH2), 1640 (s, C]C), 1613 (s, N–H), 1483 (s,
Car]Car), 1381 (m, CH3), 1371 (m, CH3), 1222 (s, COC),
1110 (s, COC), 1025 (s), 949 (w, RCH]CH2), 910 (m,
RCH]CH2), 816 (w, CH); 1H NMR (360 MHz, CDCl3): d
3
3
(ppm)Z6.19 (s, 1H, CarH), 5.80 (ddt, JZ17.0 Hz, JZ
3
10.2 Hz, JZ6.6 Hz, 1H, CH2]CHR), 5.01–4.96 (m, 1H,
HtransCH]CHR), 4.94–4.91 (m, 1H, HcisCH]CHR), 4.39
[sept., 3JZ6.1 Hz, 1H, OCH(CH3)2], 4.16 [sept., 3JZ
6.1 Hz, 1H, OCH(CH3)2], 3.75 (s, 3H, OCH3), 3.38 (br. s,
3
2H, NH2), 2.56 (t, JZ8.0 Hz, 2H, CH2Ar), 2.04 (v. q,
3Jy7.0 Hz, 2H, CH2]CHCH2), 1.55–1.49 (m, 2H, CH2),
1.36–1.28 [m, 26H, CH2, OCH(CH3)2]; 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z147.3 (CarOiPr), 141.4
(CarOiPr), 139.3 (HRC]CH2), 137.3 (Car), 136.3 (Car),
131.2 (Car), 114.2 (HRC]CH2), 102.2 (CarH), 75.0
[OCH(CH3)2], 71.1 [OCH(CH3)2], 60.8 (OCH3), 33.9
(CH2), 30.3 (CH2), 29.7 (CH2), 29.7 (CH2), 29.6 (CH2),
29.5 (CH2), 29.3 (CH2), 29.1 (CH2), 25.7 (CH2), 22.9
[CH(CH3)2], 22.4 [CH(CH3)2]; MS (EI, 70 eV), m/z (%):
405 (60) [MC], 362 (30), 320 (100), 288 (8), 178 (6), 167
(10), 152 (20), 138 (10), 123 (8), 55 (6), 43 (10). Anal.
C25H43NO3 (405.6): calcd C, 74.03; H, 10.73; found C,
73.99; H: 10.69.

A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
9671
5.1.31. 2-Methyl-penta-2,4-dienoic acid (1,4-di-iso-pro-
poxy-3-dodec-11-enyl-2-methoxyphenyl)-amide (21).
Procedure D was performed with the aniline 20 (116 mg,
286 mmol). After flash chromatography (P/EA 95/05), the
product was obtained (93 mg, 186 mmol, 65%) as a light
yellow oil. TLC: RfZ0.38 (P/EA 90/10) [CAM, UV]; IR
(film): n~ (cmK1)Z3432 (m, NH), 2974 (s, CH2), 2926 (v. s,
CH2), 2853 (s, CH2), 1673 (s, C]O), 1600 (m, C]C), 1514
(s), 1468 (m), 1434 (m), 1420 (s), 1381 (m, CH3), 1371 (m,
CH3), 1222 (s, C–N), 1110 (s, COC), 1031 (w), 1007 (s,
28.6 (CH2), 28.0 (CH2), 27.7 (CH2), 27.4 (CH2), 23.3 (CH2),
22.9 [CH(CH3)2], 22.5 [CH(CH3)2], 22.4 [CH(CH3)2], 22.4
[CH(CH3)2], 12.8 (CH3); MS (EI, 70 eV), m/z (%): 471 (72)
[MC], 428 (38), 386 (100), 358 (21), 152 (12), 150 (11), 123
(9), 95 (18), 67 (11), 55 (6), 41 (6); HRMS: m/z calcd for
C29H45NO4: 471.3349; found 471.3357.
5.1.33. (4E,6Z)-20-Hydroxy-22-iso-propoxy-19-meth-
oxy-4-methyl-2-aza-bicyclo[16.3.1]docosa-1(21),4,6,18
(22),19-pentaen-3-one (23). To a solution of the macro-
cyclic compound 22 (24.0 mg, 51.0 mmol) in DCM
(4.0 mL) cooled to K10 8C under argon atmosphere, BCl3
(1.0 mL, 1.0 mmol, 1.0 M in hexane) was slowly added. The
resulting solution was stirred at K10 8C for 40 min. No
more starting material remained according to TLC (P/EA
75/25). The mixture was then quenched by the careful
addition of 3.0 mL of NaOH (4.0 M in water). Separation of
the organic layer was followed by further extraction of the
aqueous layer with DCM (2!5 mL). The combined organic
layers were washed, dried over Na2SO4 and concentrated.
After flash chromatography (P/EA 80/20), the para-quinone
was obtained (7.0 mg, 18.2 mmol, 36%) as a yellow oil. The
mono-deprotected (14.0 mg, 32.6 mmol, 64%) compound
was isolated as a white solid. TLC: RfZ0.29 (P/EA 75/25)
1
RCH]CH2), 914 (m, RCH]CH2); H NMR (360 MHz,
CDCl3): d (ppm)Z8.14 (s, 1H, NH), 8.01 (s, 1H, CarH), 7.03
3
[d, JZ10.2 Hz, 1H, CH2]CH–CH]C(CO)], 6.66 (ddd,
3JZ16.9 Hz, 3JZ10.6 Hz, 3JZ10.2 Hz, 1H, CH2]CH–
3
3
CH]C), 5.80 (ddt, JZ17.2 Hz, 3JZ10.2 Hz, JZ6.8 Hz,
1H, CH2]CHR), 5.54 (d, 3JZ16.9 Hz, 1H, Htrans
-
-
CH]CH–CH]C), 5.43 (d, 3JZ10.2 Hz, 1H, Hcis
CH]CH–CH]C), 5.01–4.95 (m, 1H, HtransCH]CHR),
4.93–4.90 (m, 1H, HcisCH]CHR), 4.57 [sept., 3JZ6.1 Hz,
1H, OCH(CH3)2], 4.13 [sept., 3JZ6.1 Hz, 1H,
OCH(CH3)2], 3.81 (s, 3H, OCH3), 2.58 (t, 3JZ7.9 Hz,
2H, CH2Ar), 2.09 (d, 4JZ0.9 Hz, 3H, ]CCH3), 2.03 (v. q,
3Jy7.0 Hz, 2H, CH2]CHCH2), 1.55–1.50 (m, 2H, CH2),
1.33–1.29 [m, 26H, CH2, OCH(CH3)2]; 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z166.3 (C]O), 147.0 (Car-
OiPr), 144.8 (CarOCH3), 139.3 (HRC]CH2), 138.6 (Car-
OiPr), 134.6 (ColefH), 132.2 (ColefH), 131.5 (]CCH3),
130.1 (CarCH2), 128.3 (CarNH), 123.4 (]CH–HC]CH2),
114.2 (HRC]CH2), 105.3 (CarH), 76.7 [OCH(CH3)2], 70.9
[OCH(CH3)2], 60.8 (OCH3), 33.9 (CH2), 30.3 (CH2), 30.2
(CH2), 29.7 (CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.3
(CH2), 29.0 (CH2), 25.6 (CH2), 22.8 [CH(CH3)2], 22.4
[CH(CH3)2], 13.2 (CH3); MS (EI, 70 eV), m/z (%): 499 (40)
[MC], 456 (16), 414 (20), 362 (5), 320 (14), 95 (100), 67
(23), 41 (6). Anal. C31H49NO4 (499.7): calcd C, 74.51; H,
9.87; found C, 74.60; H: 9.88.
1
[CAM, UV]; H NMR (500 MHz, CDCl3): d (ppm)Z8.29
(br. s, 1H, NH), 8.03 (s, 1H, CarH), 7.18 (s, 1H, OH), 6.97
3
[d, Jy11.3 Hz, 1H, CH]CH–CH]C(CO)], 6.31 [v. t,
3Jy10.9 Hz, 1H, CH]CH–CH]C(CO)], 5.95 [v. q,
3
3Jy9.1 Hz, 1H, CH]CH–CH]C(CO)], 4.00 [sept., JZ
6.1 Hz, 1H, OCH(CH3)2], 3.83 (s, 3H, OCH3), 2.76–2.70
(m, 2H, CH2), 2.37–2.35 (m, 1H, CH2), 2.06–2.05 (m, 3H,
]CCH3), 1.70–0.85 [m, 23H, CH2, CH(CH3)2]; 13C NMR
(90.6 MHz, CDCl3): d (ppm)Z168.8 (C]O), 146.2
(CarOH), 142.2 (CarOCH3), 138.7 (CarOiPr), 138.1 (ColefH),
133.7 (Car), 128.7 (Car), 127.1 (ColefH), 124.2 (ColefH),
104.8 (CarH), 77.1 [OCH(CH3)2], 60.9 (OCH3), 30.0 (CH2),
29.6 (CH2), 28.9 (CH2), 28.6 (CH2), 28.4 (CH2), 28.0 (CH2),
27.7 (CH2), 27.3 (CH2), 23.4 (CH2), 22.8 [CH(CH3)2], 22.3
[CH(CH3)2], 12.9 (CH3).
5.1.32. (4E,6Z)-20,22-Di-iso-propoxy-19-methoxy-4-
methyl-2-aza-bicyclo[16.3.1]docosa-1(22),4,6,18,20-pen-
taen-3-one (22). Procedure E was performed with the
anilide 21 (50 mg, 100 mmol) and Grubbs catalyst (8.2 mg,
10.1 mmol, 10 mol%) in DCM (200 mL). After flash
chromatography (P/EA 90/10), the product was obtained
(41 mg, 87 mmol, 87%) as a light green transparent oil.
TLC: RfZ0.85 (P/EA/DCM 50/10/50) [CAM, UV]; IR
(film): n~ (cmK1)Z3428 (br, NH), 2974 (s, n~ CH3), 2926 (v.
s, CH2), 2854 (v. s, CH2), 1667 (s, C]O), 1592 (m, C]C),
1504 (s, NH), 1434 (s, C]C), 1382 [s, (CH3)2CH], 1332
[m, (CH3)2CH], 1229 (m), 1105 (s, C–O–C), 1027 (m), 954
(w), 909 (w), 852 (w), 734 (w); 1H NMR (500 MHz,
CDCl3): d (ppm)Z8.24 (br. s, 1H, NH), 7.93 (s, 1H, CarH),
6.98 [d, 3JZ11.3 Hz, 1H, CH]CH–CH]C(CO)], 6.31 [v.
t, 3Jy10.9 Hz, 1H, CH]CH–CH]C(CO)], 5.94 [v. q,
5.1.34. 19-Methoxy-4-methyl-2-aza-bicyclo[16.3.1]dodo-
cosa-1(21),4,6,18-tetraene-3,20,22-trione (2). To a sol-
ution of the macrocyclic compound 22 (45.0 mg, 106 mmol)
in DCM (10.4 mL) cooled to K10 8C under argon
atmosphere, BCl3 (1.0 mL, 1.0 mmol, 1.0 M in hexane,
10 equiv) was slowly added. The resulting solution was
stirred at K10 8C for 2 h. Some mono deprotected material
remained according to TLC (P/EA 75/25). BCl3 (1.0 mL,
1.0 mmol, 1.0 M in hexane, 10 equiv) was slowly added.
The mixture was then allowed to warm up to rt and stirred
for 4 h. After a TLC control showing the completion of the
reaction, the mixture was quenched by the careful addition
of 5.0 mL of NaOH (4.0 M in water). Separation of the
organic layer was followed by further extraction of the
aqueous layer with DCM (2!10 mL). The combined
organic layers were washed, dried over Na2SO4 and
concentrated. After flash chromatography (P/EA 75/25),
the para-quinone was obtained (31.0 mg, 90.9 mmol, 86%)
as a yellow orange microcrystalline solid. TLC: RfZ0.84
(P/EA 75/25) [CAM, UV]; IR: n~ (cmK1)Z3557 (br, NH),
2917 (s, CH2), 2847 (v. s, CH2), 1695 (s, C]O), 1649 (s,
C]O), 1607 (s, C]O), 1497 (s, NH), 1361 (s), 1320 (s),
1247 (m), 1194 (s, COC), 1042 (m), 962 (w), 864 (m), 798
3
3Jy9.0 Hz, 1H, CH]CH–CH]C(CO)], 4.58 [sept., JZ
6.1 Hz, 1H, OCH(CH3)2], 4.01 [sept., 3JZ6.1 Hz, 1H,
OCH(CH3)2], 3.81 (s, 3H, OCH3), 2.74–2.70 (m, 2H, CH2),
2.04 (br, 3H, ]CCH3), 1.70–0.85 [m, 30H, CH2,
CH(CH3)2]; 13C NMR (90.6 MHz, CDCl3): d (ppm)Z
168.1 (C]O), 147.2 (CarO), 144.6 (CarO), 139.0 (CarO),
137.9 (ColefH), 133.9 (Car), 129.3 (Car), 128.4 (]CCH3),
126.7 (ColefH), 124.3 (ColefH), 104.0 (CarH), 76.9
[OCH(CH3)2], 71.0 [OCH(CH3)2], 60.8 (OCH3), 30.1
(CH2), 29.6 (CH2), 29.6 (CH2), 28.9 (CH2), 28.7 (CH2),

9672
A. Lemarchand, T. Bach / Tetrahedron 60 (2004) 9659–9673
1
Barbacci, E. G.; Miller, P. E.; Morin, M. J.; Foster, B. A.;
Pollack, V. A.; Savage, D. M.; Sloan, D. E.; Pustilnik,
L. R.; Moyer, J. D.; Moyer, M. P. J. Med. Chem. 1995, 38,
3806–3812. (b) Schnur, R. C.; Corman, M. L.; Gallaschun,
R. J.; Cooper, B. A.; Dee, M. F.; Doty, J. L.; Muzzi,
M. L.; DiOrio, C. I.; Barbacci, E. G.; Miller, P. E.; Pollack,
V. A.; Savage, D. M.; Sloan, D. E.; Pustilnik, L. R.; Moyer,
J. D.; Moyer, M. P. J. Med. Chem. 1995, 38, 3813–3820.
(c) Kuduk, S. D.; Zheng, F. F.; Sepp-Lorenzino, L.; Ouerfelli,
Q.; Rosen, N.; Danishefsky, S. Bioorg. Med. Chem. Lett. 1999,
9, 1233–1238. (d) Kuduk, S. D.; Harris, C. R.; Zheng,
F. F.; Sepp-Lorenzino, L.; Ouerfelli, Q.; Rosen, N.;
Danishefsky, S. Bioorg. Med. Chem. Lett. 2000, 10,
1025–1028. (e) Kasuya, Y.; Lu, Z.-R.; Kopeckova, P.;
(w), 737 (w), 691 (m); H NMR (500 MHz, CDCl3): d
(ppm)Z8.86 (s, 1H, NH), 7.25 (s, 1H, CquinH), 7.07 [d, 3JZ
11.3 Hz, 1H, CH]CH–CH]C(CO)], 6.30 [v. t,
3Jy11.0 Hz, 1H, CH]CH–CH]C(CO)], 6.04 [v. q,
3Jy9.1 Hz, 1H, CH]CH–CH]C(CO)], 4.12 (s, 3H,
OCH3), 2.52 (t, 3JZ6.7 Hz 2H, CquinCH2), 2.24 (v. q,
3Jy8.0 Hz 2H, ]CHCH2), 1.98–1.96 (m, 3H, ]CCH3),
1.55–1.23 (m, 30H, CH2); 13C NMR (90.6 MHz, CDCl3): d
(ppm)Z184.5 (Cquin]O), 183.8 (Cquin]O), 168.8 (C]O),
156.9 (CquinOMe), 140.2 (CH2CH]CH), 138.1 (CquinNH),
132.0 [CH]C(CO)], 129.2 CH]C(CO)], 128.6 (Cquin
-
CH2), 123.8 (CH2CH]CH), 111.3 (CquinH), 61.7 (OCH3),
29.6 (CH2), 29.5 (CH2), 29.5 (CH2), 28.8 (CH2), 28.6 (CH2),
28.2 (CH2), 27.9 (CH2), 27.2 (CH2), 27.2 (CH2), 20.8 (CH2),
12.5 (CH3); MS (EI, 70 eV), m/z (%): 385 (100) [MC], 368
(38), 342 (10), 314 (5), 300 (3), 274 (8), 272 (7), 244 (5),
152 (20), 121 (14), 110 (31), 95 (30), 67 (32), 55 (30), 41
(30). Anal. C23H31NO4 (385.5): calcd C, 71.66; H, 8.11;
found C, 71.78; H: 8.10.
ˇ
Kopecek, J. Bioorg. Med. Chem. Lett. 2000, 10, 1303–1306.
ˇ
(f) Kasuya, Y.; Lu, Z.-R.; Kopeckova, P.; Kopecek, J. Bioorg.
Med. Chem. Lett. 2001, 11, 2089–2091. (g) Hargreaves, R.;
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10. (a) Andrus, M. B.; Meredith, E. L.; Simmons, B. L.; Soma
Sekhar, B. B. V.; Hicken, E. J. Org. Lett. 2002, 4, 3549–3552.
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Acknowledgements
Support of our research by the Deutsche Forschungs-
gemeinschaft (DFG) and by the Fonds der Chemischen
Industrie is gratefully acknowledged. A.L. thanks the
Deutsche Akademische Austauschdienst for a graduate
¨
fellowship. We thank Dr. Volker P. Bohm (BASF AG) for a
generous donation of metathesis catalysts.
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