Efficient synthesis of 18-40 membered macrocyclic polyoxadiamides and polyoxatetraamides via ring closing metathesis

Article abstract of DOI:10.1016/j.tet.2005.10.031

Ring closing metathesis of the appropriate 1,ω-dienes led to efficient synthetic approaches towards the corresponding macrocyclic polyoxadiamides and tetraamides with 18-40 membered ring sizes in good to excellent yields using Grubbs' catalyst.

Full text of DOI:10.1016/j.tet.2005.10.031

Tetrahedron 62 (2006) 1001–1014
Efficient synthesis of 18–40 membered macrocyclic
polyoxadiamides and polyoxatetraamides
via ring closing metathesis
*
Yehia A. Ibrahim and Elizabeth John
Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat 13060, Kuwait
Received 15 June 2005; accepted 13 October 2005
Available online 7 November 2005
Abstract—Ring closing metathesis of the appropriate 1,u-dienes led to efficient synthetic approaches towards the corresponding
macrocyclic polyoxadiamides and tetraamides with 18–40 membered ring sizes in good to excellent yields using Grubbs’ catalyst.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
o-allyloxybenzoyl chloride 11 afforded o-(o-allyloxy-
benzamido)phenol 12. The latter was converted into its
potassium salt 13, which was then reacted with the
appropriate bis-chloroacetanilide derivatives 14a–e to
afford the corresponding 1,u-dienes 15a–e in 63–93%
yields. RCM of 15a–e proceeded smoothly to give the
corresponding macrocycles 1a–e in 52–97% yields with
Grubbs’ catalyst I (2.5–5 mol%) in refluxing CH2Cl2 for
24 h. The results are presented in Table 1.
Recently, ring closing metathesis (RCM)1 has found
increasing application in the synthesis of macrocyclic
compounds.2–12 The application of RCM as the key
macrocyclization step in the synthesis of crown compounds
has opened efficient routes towards macrocyclic crown
compounds of important applications in supramolecular
chemistry.6,13–16
The present work describes new routes for the synthesis of
macrocyclic polyethers containing diamide and tetraamide
groups inside the macrocyclic ring via RCM using
Grubbs’catalyst I as the key macrocyclization step. The
results obtained provide an efficient synthetic procedure to
the macrocyclic polyoxadiamides 3b–e, 4, 5, 6a,b, 7a,b,
9a,b with 18–34 membered ring sizes and the macrocyclic
polyoxatetraamides 1a–e, 2b,d, 8a,b with 28–40 membered
ring sizes. The new macrocyclic crown-amides 1–9
synthesized in the present investigation are of potential
interesting diverse applications, which have been reviewed
in our recent publications (Fig. 1).16
On the other hand, 1,u-dienes 17b,d were readily obtained
as outlined in Scheme 2. Thus, reacting the potassium salt of
o-allyloxyacetamidophenol 8 with each of 14b,d afforded
the corresponding desired 1,u-dienes 17b,d. RCM of the
latter dienes proceeded smoothly to give the corresponding
macrocycles 2b,d in 70 and 60% yields, respectively, upon
heating with Grubbs’ catalyst I (5 mol%) in refluxing
CH2Cl2 for 24 h. The results are presented in Table 1.
Scheme 3 outlines the synthetic routes followed for the
synthesis of the 1,u-dienes 21–23, required for the RCM
synthesis of macrocycles 3b–e, 4 and 5. Thus, alkylation
of methyl salicylate 18 with 2-allyloxyethyl p-toluene-
sulfonate afforded methyl 2-(2-allyloxyethoxy)benzoate,
which was hydrolysed to the corresponding acid. The latter
was then converted to the corresponding acid chloride 19 by
the action of SOCl2. Reaction of 19 with each of the amines
20b–e, ethylenediamine and o-phenylenediamine afforded
the corresponding 1,u-dienes 21b–e, 22 and 23, respecti-
vely. Compounds 22 and 23 were also, prepared by reacting
the dipotassium salts of each of 1,2-bis(2-hydroxy-
benzamido)ethane and 1,2-bis(2-hydroxybenzamido)-
benzene with 2-allyloxyethyl p-toluenesulfonate. RCM of
2. Results and discussion
Scheme 1 illustrates our synthetic routes towards the
precursors 1,u-dienes 15a–e needed for the RCM synthesis
of 1a–e. Thus, acylation of o-aminophenol 10 with
Keywords: Ring closing metathesis; 1,u-Dienes; Bis-anilides; Diazapoly-
oxacycloalkenediones; Tetraazapolyoxacycloalkenetetraones.
*
Corresponding author. Tel.: C965 4985546; fax: C965 4816482;
e-mail: yehiaai@kuc01.kuniv.edu.kw
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.031

1002
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
X
O
O
X
X
O
O
O
O
NH
HN
NH
HN
O
O
NH
HN
O
O
O
O
O
O
O
O
O
O
O
O
NH
HN
NH
HN
O
O
O
O
O
O
O
O
1a-e
2b,d
a X = -, b X = CH2, c X = (CH2OCH2), d X = (CH2OCH2)2, e X = o-C6H4
3b-e
O
O
O
O
PCy3
Ru
Cl
Cl
N
H
N
H
N
N
H
H
Ph
PCy3
O
O
O
O
O
O
O
O
Grubbs' catalyst (I)
4
5
O
O
O
O
O
N
H
N
H
N
O
N
H
H
O
O
O
O
X
X
X
O
X
O
O
NH
X
X
X
NH
O
H
N
H
N
NH
H
N
O
O
O
O
6a,b
7a,b
8a,b
9a,b
a X = O
b X = OCH2CH2O
Figure 1.
compounds 21–23 afforded corresponding macrocyclic
compounds 3–5 in 60–99% yields upon heating with
Grubbs’ catalyst I (2.5–5 mol%) in refluxing CH2Cl2 for
4–24 h. The results are presented in Table 2.
increase in products was noticed (after the time indicated in
Tables 1–3) of reflux in CH2Cl2. The RCM products 1–9
were shown from their 1H and 13C NMR to consist of the E
and Z isomers in different ratios as shown in Tables 1–3.
On the other hand, 1,u-dienes 30–33 were readily obtained
as outlined in Scheme 4. Thus, acylation of each of the
o-allyloxyaniline 24a and o-(2-allyloxyethoxy)aniline 24b
with chloroacetyl chloride afforded the corresponding
chloroacetanilide derivatives 25a,b, respectively. Reacting
the latter with the potassium salt of the appropriate phenolic
compounds 26–29 afforded the corresponding desired
1,u-dienes 30–33. RCM of the latter dienes proceeded
smoothly to give the corresponding macrocycles 6–9 in
73–100% yields upon heating with Grubbs’ catalyst I
(2.5–7.5 mol%) in refluxing CH2Cl2 for 2–24 h (Table 3).
The E:Z isomers of the olefinic crown-diamides were
readily assigned and their ratios were determined from the
1H and 13C NMR spectra. The major products in all
RCM reactions were shown to be the E isomers
with the characteristic 13C signal of the OCH2 (of the
OCH2CH]CHCH2O), which appears further downfield
1
than that for the corresponding Z isomer. In H NMR the
OCH2CH] and OCH2CH] signals of E isomers appear as
broad singlets. On the other hand, those similar proton
signals for the Z isomer split into a doublet and triplet with
JZ3–5 Hz.
In all RCM reactions, the progress of the reaction was
1
monitored by TLC and H NMR analysis where no further
The present work describes an efficient synthetic access
towards macrocyclic crown-diamide and crown-tetraamide

Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1003
OK
NH
OH
NH
COCl
OH
O
KOH/MeOH
100%
O
+
O
40%
NH2
O
O
13
X
12
10
11
O
O
X
O
O
NH
HN
NH
HN
14a-e
63-93%
O
O
O
O
Cl
Cl
O
O
RCM (I, 2.5-5 mol%)/DCM/24 h reflux
NH
O
HN
1a-e
52-97%
O O
O
a X = -
b X = CH2
c X = (CH2OCH2)
d X = (CH2OCH2)2
e X = o-C6H4
15a-e
Scheme 1.
Table 1. Catalyst %, yields and E/Z ratios of macrocycles 1a–e, 2b,d
3. Experimental
Entry
Substrate
(mol%) Catalyst/substrate, Yield
reaction time (h)
Product
E:Z ratio
3.1. General
(%)
1
2
3
4
5
6
7
15a
15b
15c
15d
15e
17b
17d
2.5, 24
5.0, 24
2.5, 24
2.5, 24
2.5, 24
5.0, 24
5.0, 24
97
91
52
78
88
70
60
1a 5:1
1b 7:1
1c 5:1
1d 5:1
1e 13:1
2b 2.5:1
2d 3.5:1
All melting points are uncorrected. IR spectra were recorded
in KBr disks using Perkin Elmer System 2000 FT-IR
spectrophotometer. 1H and 13C NMR spectra were recorded
on a Bruker DPX 400, 400 MHz super-conducting NMR
spectrometer. Mass spectra were measured on VG Auto-
spec-Q (high resolution, high performance, tri-sector GC/
MS/MS) and with LCMS using Agilent 1100 series LC/
MSD with an API-ES/APCI ionization mode. Micro-
analyses were performed on LECO CH NS-932 Elemental
Analyzer. The starting o-allyloxybenzoyl chloride 11,17
bis-amines 14a–e,16e bis-amides 20b–e,18 1,2-bis(2-
hydroxybenzamido)ethane19 and 1,2-bis(2-hydroxybenz-
amido)benzene19 were prepared as reported.
derivatives, with potential diverse applications in supra-
molecular chemistry and as starting compounds for further
synthetic transformations utilizing the RCM techniques for
the macrocyclization step. The examples of RCM presented
here represent one of the best macrocyclization reaction
techniques for the synthesis of crown compounds. It also,
expands the utility of RCM methodology and its application
to the synthesis of cyclic olefins of large ring sizes with
different functional groups.
3.1.1. 2-(o-Allyloxybenzamido)phenol 12. To an ice cold
(0–5 8C) stirred solution of 10 (5.3 g, 49 mmol) and
O
O
X
OH
NH
HN
1) KOH/MeOH
RCM (I, 5 mol%)/DCM
O
O
NH
2b,d
O
O
4-24 h reflux, 60-70%
2) 14b,d/DMF
O
O
NH
HN
O
O
b X = CH2
17b,d
O
O
16
d X = (CH2OCH2)2
Scheme 2.

1004
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
O
O
O
O
N
N
H
H
N
H
N
H
1) KOH/MeOH
O
O
O
O
RCM (I, 2.5mol%)/DCM
4
2) CH2=CHCH2OCH2CH2OTs
OH
HO
24 h reflux, 96%
22
HN2
NH2
COCl
O
COOCH3
OH
1) CH2=CHCH2OCH2CH2OTs/K2CO3/Acetone
2) KOH/H2O
3) SOCl2
O
18
19
X
O
O
O
O
N
N
NH2
X
HN2
H
H
OH
HO
20b-e
HN2
O
NH2
1) KOH/MeOH
O
O
2) CH2=CHCH2OCH2CH2OTs
O
NH
HN
N
N
H
H
O
O
O
O
O
O
O
O
O
O
21b-e
23
RCM
(I, 5 mol%)/DCM
24 h reflux, 60%
RCM
(I, 2.5-5 mol%)/DCM
24 hreflux, 85-99%
3b-e
5
b
d
X = CH2, c X = (CH2OCH2)
X = (CH2OCH2)2, e X =o-C6H4
Scheme 3.
removed in vacuo and remaining precipitate was crystal-
lized from DCM/pet. ether (40–60) to give 5.5 g (42%) of
colorless crystals, mp 130–131 8C. MS: m/zZ269 (MC,
30%). IR: 3326, 3077, 1640, 1598, 1542, 1482, 1457, 1329,
1283, 1232, 1162, 1089, 997, 786, 762, 722. 1H NMR
(CDCl3): d 10.38 (s, 1H, NH), 9.61 (s, 1H, OH), 8.33 (dd,
1H, JZ8.0, 1.5 Hz), 7.55 (dt, 1H, JZ8.3, 1.5 Hz), 7.19 (t,
2H, JZ7.6 Hz), 7.09 (m, 2H), 6.98 (d, 1H, JZ7.7 Hz), 6.91
(t, 1H, JZ7.5 Hz), 6.21 (m, 1H, CH]), 5.57 (d, 1H, JZ
17.2 Hz, CH2]), 5.50 (d, 1H, JZ10.3 Hz, CH2]), 4.80 (d,
2H, JZ6.0 Hz, OCH2). Anal. Calcd for C16H15NO3 (269.3):
C 71.36; H 5.61; N 5.20. Found: C 71.10; H 5.61; N 5.44.
Table 2. Catalyst %, yields and E/Z ratios of macrocycles 3b–e, 4, 5
Entry
Substrate
(mol%) Catalyst/substrate, Yield
reaction time (h)
Product
E:Z ratio
(%)
1
2
3
4
5
6
21b
21c
21d
21e
22
2.5, 24
5.0, 24
2.5, 24
2.5, 24
2.5, 4
99
85
99
98
96
60
3b 3:1
3c 1.7:1
3d 2:1
3e 3:1
4 2.5:1
5 1.4:1
23
5.0, 24
triethylamine (6.8 mL, 50 mmol) in DCM (20 mL) was
added 11 (9.5 g, 48 mmol) in DCM (15 mL). The reaction
mixture was stirred for 1 h in ice and stirring was continued
overnight at room temperature. The resulting solution was
extracted with DCM, neutralized with concd HCl, washed
with water, Na2CO3 solution and water again and then dried
over anhydrous sodium sulfate. The solvent was then
3.1.2. Synthesis of 15a–e and 17b,d. General procedure.
To a solution of KOH (0.13 g, 2.2 mmol) in methanol
(5 mL) was added 12 or 16 (2.2 mmol). The mixture was
stirred at room temperature for 15 min and the solvent was

Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1005
O
OH
N
H
X
X
O
ClCH2COCl
X
X
OH
O
NH2
NH
H
N
26
25a,b
O
24a,b
O
Cl
30a,b
OH
NH
RCM
OH
NH
(I, 2.5-5 mol%)/DCM
24 h reflux, 73-92%
O
O
OH
OH
O
6a,b
O
NH
OH
28
29
27 (racemic)
O
O
O
N
O
N
H
N
H
H
O
X
O
NH
X
X
O
O
X
X
NH
O
O
NH
H
N
H
N
O
O
O
32a, b
O
33a,b
31a,b
RCM
RCM
RCM
(I, 2.5 mol%)/DCM
2-4 h reflux, 75-82%
(I, 2.5-5 mol%)/DCM
24 h reflux, 91-97%
(I, 5-7.5 mol%)/DCM
3 h reflux, 80-100%
9a,b
8a,b
7a,b
a X = O
b X = OCH2CH2O
Scheme 4.
1688, 1663, 1600, 1536, 1482, 1455, 1331, 1293, 1252,
1
1229, 1163, 1118, 1093, 1047, 999, 915, 750. H NMR
Table 3. Catalyst %, yields and E/Z ratios of macrocycles 6–9
Entry
Substrate
(mol%) Catalyst/substrate, Yield
reaction time (h)
Product
E:Z ratio
(CDCl3): d 10.19 (s, 2H, NH), 8.56 (s, 2H, NH), 8.48 (m,
2H), 8.25 (d, 2H, JZ7.6 Hz), 8.20 (d, 2H, JZ7.6 Hz), 7.42
(t, 2H, JZ7.8 Hz), 7.09 (t, 2H, JZ7.4 Hz), 7.02 (m, 6H),
6.71 (m, 6H), 6.42 (d, 2H, JZ7.5 Hz), 5.83 (m, 2H, CH]),
5.13 (m, 4H, ]CH2), 4.44 (s, 4H, OCH2CO), 4.25 (d, 4H,
JZ4.5 Hz, OCH2CH]), 3.19 (s, 4H, OCH2). Anal. Calcd
for C50H46N4O10 (862.9): C 69.59; H 5.37; N 6.49. Found:
C 69.50; H 5.52; N 6.77.
(%)
1
2
3
4
5
6
7
8
30a
30b
31a
31b
32a
32b
33a
33b
2.5, 24
5, 24
2.5, 24
5, 24
7.5, 3
5, 3
2.5, 4
2.5, 2
92
73
91
97
100
80
75
82
6a 3.6:1
6b 2:1
7a 3:1
7b 3:1
8a 2:1
8b 2.6:1
9a 1:1
9b 2.5:1
3.1.2.2. Compound 15b. Yield 0.8 g (91%); colorless
crystals (EtOH), mp 130–131 8C, RfZ0.6. LCMS; m/zZ
877 (MC1). IR: 3400, 3344, 3064, 2937, 1674, 1601, 1536,
1484, 1456, 1335, 1293, 1227, 1120, 1051, 998, 931, 851,
752. 1H NMR (CDCl3): d 10.52 (s, 2H, NH), 8.70 (dd, 2H,
JZ7.8, 1.7 Hz), 8.63 (s, 2H, NH), 8.29 (d, 4H, JZ7.8 Hz),
7.51 (dt, 2H, JZ7.7, 1.8 Hz), 7.09 (m, 6H), 6.95 (d, 2H, JZ
8.3 Hz), 6.86 (m, 4H), 6.67 (dt, 2H, JZ7.8, 1.4 Hz), 6.34 (d,
2H, JZ8.0 Hz), 5.98 (m, 2H, CH]), 5.30 (d, 2H, JZ
17.2 Hz, ]CH2), 5.19 (d, 2H, JZ10.5 Hz, ]CH2), 4.69 (s,
4H, OCH2CO), 4.57 (d, 4H, JZ5.7 Hz, OCH2CH]), 3.43
(t, 4H, JZ5.2 Hz, OCH2CH2), 1.18 (quint, 2H, JZ5.2 Hz,
OCH2CH2). Anal. Calcd for C51H48N4O10 (876.9): C 69.85;
H 5.52; N 6.39. Found: C 69.63; H 5.43; N 6.29.
then removed in vacuo. To the remaining potassium salt was
added DMF (2 mL) and the appropriate dichloro derivatives
14a–e (1 mmol). The reaction mixture was then heated
under reflux for 5 min. The mixture was then cooled, diluted
with water (20 mL) and the precipitate was collected,
washed with cold water and finally crystallized (except
17d, which was obtained as an oil) to give the corresponding
dienes 15a–e and 17b, which were also characterized
by their Rf values using DCM–pet. ether (40–60)–EtOAc
(6/4/3).
3.1.2.1. Compound 15a. Yield 0.8 g (93%); colorless
crystals (EtOH), mp 130–131 8C, RfZ0.7. LCMS;
m/zZ863 (MC1). IR: 3400, 3344, 3071, 2933, 2875,

1006
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
3.1.2.3. Compound 15c. Yield 0.7 g (77%); colorless
1689, 1603, 1535, 1486, 1456, 1292, 1255, 1207, 1117,
1045, 930, 750. 1H NMR (CDCl3): d 9.06 (s, 2H, NH), 8.76
(s, 2H, NH), 8.43 (m, 2H), 8.34 (d, 2H, JZ7.9 Hz), 6.92 (m,
12H), 5.80 (m, 2H, CH]), 5.25 (dd, 2H, JZ17.3, 1.0 Hz,
]CH2), 5.11 (d, 2H, JZ10.2 Hz, ]CH2), 4.71 (s, 4H,
OCH2CO), 4.08 (s, 4H, OCH2CO), 4.04 (d, 4H, JZ5.6 Hz,
OCH2CH]), 3.99 (t, 4H, JZ4.8 Hz, OCH2CH2O), 3.49 (t,
4H, JZ4.8 Hz, OCH2CH2O), 3.33 (s, 4H, OCH2CH2O).
Anal. Calcd for C44H50N4O12 (826.9): C 63.91; H 6.09; N
6.78. Found: C 63.68; H 6.31; N 6.77.
crystals (EtOH), mp 160–161 8C, RfZ0.6. LCMS; m/zZ
907 (MC1). IR: 3391, 3341, 3069, 2936, 2874, 1691, 1658,
1601, 1535, 1483, 1455, 1333, 1295, 1254, 1229, 1135,
1
1118, 1047, 753. H NMR (CDCl3): d 10.49 (s, 2H, NH),
8.67 (d, 2H, JZ8.0 Hz), 8.63 (s, 2H, NH), 8.36 (d, 2H, JZ
8.0 Hz), 8.27 (d, 2H, JZ8.0 Hz), 7.48 (t, 2H, JZ8.0 Hz),
7.13 (t, 2H, JZ8.0 Hz), 7.05 (m, 4H), 6.92 (m, 8H), 6.41 (d,
2H, JZ8.0 Hz), 5.99 (m, 2H, CH]), 5.29 (d, 2H, JZ
16.5 Hz, ]CH2), 5.19 (d, 2H, JZ10.4 Hz, ]CH2), 4.64 (s,
4H, OCH2CO), 4.53 (d, 4H, JZ5.6 Hz, OCH2CH]), 3.43
(t, 4H, JZ4.4 Hz, OCH2CH2O), 3.95 (t, 4H, JZ4.4 Hz,
OCH2CH2O). Anal. Calcd for C52H50N4O11 (907.0): C
68.86; H 5.56; N 6.18. Found: C 68.71; H 5.45; N 6.47.
3.1.3. Methyl 2-(2-allyloxyethoxy)benzoate. A mixture
of methyl salicylate (10 g, 65 mmol), 2-allyloxyethyl
p-toluenesulfate (8.5 g, 33 mmol) and anhydrous K2CO3
(4.5 g, 33 mmol) in dry acetone (50 mL) was heated under
reflux for 48 h. The solid precipitate was filtered off and the
solvent was evaporated in vacuo. The remaining oil was
dissolved in DCM, washed twice with aq KOH (10%), dried
over anhydrous Na2SO4 and the solvent was then removed
in vacuo and the remaining oil was purified by column
chromatography over silica gel using DCM/pet ether
(40–60) as an eluent to give 6.8 g (87%) of colorless oil,
RfZ0.3 [DCM/pet. ether (40–60) 2:1]. LCMS; m/zZ251
(MC1). IR: 3078, 2947, 2871, 1727, 1600, 1491, 1450,
1304, 1252, 1133, 1088, 1050, 926, 758. 1H NMR (CDCl3):
d 7.80 (dd, 1H, JZ8.0, 1.6 Hz), 7.46 (dt, 1H, JZ8.8,
1.7 Hz), 7.01 (m, 2H), 5.97 (m, 1H, CH]), 5.33 (dd, 1H,
JZ17.2, 1.6 Hz, CH2]), 5.22 (dd, 1H, JZ9.4, 0.9 Hz,
CH2]), 4.23 (t, 2H, JZ5.08 Hz, CH2), 4.15 (d, 2H, JZ
5.5 Hz, CH2), 3.89 (m, 4H, CH2), 3.89 (s, 3H, CH3). Anal.
Calcd for C13H16O4 (236.3): C 66.09; H 6.83. Found: C
65.95; H 6.62.
3.1.2.4. Compound 15d. Yield 0.6 g (63%); colorless
crystals (EtOH/CHCl3), mp 143–144 8C, RfZ0.4. LCMS;
m/zZ952 (MC1). IR: 3396, 3344, 3064, 3012, 2920, 1663,
1600, 1535, 1483, 1456, 1333, 1293, 1254, 1226, 1117,
1048, 932, 752. 1H NMR (CDCl3): d 10.49 (s, 2H, NH), 8.83
(s, 2H, NH), 8.67 (dd, 2H, JZ7.6, 1.9 Hz), 8.40 (dd, 2H, JZ
7.7, 1.6 Hz), 8.29 (dd, 2H, JZ7.8, 1.6 Hz), 7.45 (dt, 2H, JZ
8.0, 1.6 Hz), 7.10 (t, 2H, JZ7.6 Hz), 7.02 (m, 8H), 6.92 (m,
4H), 6.76 (dd, 2H, JZ8.0, 1.2 Hz), 6.05 (m, 2H, CH]),
5.33 (d, 2H, JZ17.2 Hz, ]CH2), 5.24 (d, 2H, JZ10.5 Hz,
]CH2), 4.72 (s, 4H, OCH2CO), 4.57 (d, 4H, JZ5.6 Hz,
OCH2CH]), 3.67 (t, 4H, JZ5.2 Hz, OCH2CH2O), 3.15 (t,
4H, JZ5.2 Hz, OCH2CH2O), 3.07 (s, 4H, OCH2CH2O).
Anal. Calcd for C54H54N4O12 (951.0): C 68.20; H 5.72; N
5.89. Found: C 67.98; H 5.57; N 6.10.
3.1.2.5. Compound 15e. Yield 0.8 g (85%); colorless
crystals (EtOH), mp 228–229 8C, RfZ0.8. LCMS; m/zZ
939 (MC1). IR: 3393, 3322, 3070, 3005, 2935, 2884, 1691,
1654, 1599, 1527, 1482, 1454, 1332, 1290, 1248, 1231,
1188, 1136, 1114, 1091, 1044, 997, 949, 929, 895, 790, 753.
1H NMR (CDCl3): d 10.20 (s, 2H, NH), 8.78 (d, 2H, JZ
7.7 Hz), 8.62 (s, 2H, NH), 8.43 (m, 2H), 8.23 (d, 2H, JZ
7.5 Hz), 7.45 (t, 2H, JZ7.5 Hz), 6.96 (m, 16H), 6.43 (m,
2H), 6.38 (m, 2H), 5.73 (m, 2H, CH]), 5.20 (d, 2H, JZ
17 Hz, ]CH2), 5.08 (d, 2H, JZ10.2 Hz, ]CH2), 4.62 (s,
4H, OCH2CO), 4.36 (s, 4H, OCH2Ar), 4.27 (d, 4H, JZ
5.5 Hz, OCH2CH]). Anal. Calcd for C56H50N4O10 (939):
C 71.63; H 5.37; N 5.97. Found: C 71.34; H 5.46; N 6.20.
3.1.4. 2-(2-Allyloxyethoxy)benzoic acid. A mixture of
methyl 2-(2-allyloxyethoxy)benzoate (1.2 g, 5 mmol) in aq
KOH (10%, 10 mL) was heated under reflux for 24 h. The
mixture was neutralized with concd HCl and extracted with
DCM, washed with water, separated and dried over
anhydrous sodium sulfate. The solvent was then removed
in vacuo to give 0.8 g (72%) of colorless oil, which was used
in the next step without further purification. LCMS; m/zZ
223 (MC1). IR: 3300–2871 (br) 3071, 2928, 2871, 1731,
1603, 1486, 1456, 1387, 1351, 1297, 1240, 1162, 1124,
1038, 926, 756. 1H NMR (CDCl3): d 9.89 (br, 1H), 8.17 (dd,
1H, JZ7.8, 1.1 Hz), 7.56 (dt, 1H, JZ7.9, 1.6 Hz), 7.15 (t,
1H, JZ7.4 Hz), 7.06 (d, 1H, JZ8.4 Hz), 5.93 (m, 1H,
CH]), 5.32 (dd, 1H, JZ16, 1.1 Hz, CH2]), 5.24 (d, 1H,
JZ10.4 Hz, CH2]), 4.39 (t, 2H, JZ4.5 Hz, CH2), 4.09 (d,
2H, JZ5.8 Hz, CH2), 3.87 (t, 2H, JZ4.5 Hz, CH2).
3.1.2.6. Compound 17b. Yield 0.4 g (53%); colorless
crystals (EtOH), mp 126–127 8C, RfZ0.7. LCMS; m/zZ
753 (MC1). IR: 3388, 3270, 3070, 2934, 2879, 1679, 1603,
1537, 1486, 1456, 1290, 1260, 1119, 750. 1H NMR
(CDCl3): d 9.03 (s, 2H, NH), 8.63 (s, 2H, NH), 8.44 (m,
2H), 8.30 (m, 2H), 7.06 (m, 4H), 6.97 (m, 4H), 6.92 (m, 2H),
6.58 (m, 2H), 5.82 (m, 2H, CH]), 5.27 (d, 2H, JZ17.2 Hz,
]CH2), 5.15 (d, 2H, JZ10.4 Hz, ]CH2), 4.74 (s, 4H,
OCH2CO), 4.06 (t, 4H, JZ5.6 Hz, OCH2CH]), 4.05 (s,
4H, OCH2CO), 3.71 (t, 4H, JZ5.5 Hz, OCH2CH2), 1.72
(quint, 2H, JZ5.5 Hz, OCH2CH2). Anal. Calcd for
C41H44N4O10 (752.8): C 65.41; H 5.89; N 7.44. Found: C
65.32; H, 5.85; N 7.60.
3.1.5. 2-(2-Allyloxyethoxy)benzoyl chloride 19. A mixture
of 2-(2-allyloxyethoxy)benzoic acid (2.22 g, 10 mmol) and
SOCl2 (1.5 mL, 20 mmol) was heated under reflux at 100 8C
for 1.5 h. The excess SOCl2 was removed in vacuo to give
2.2 g (92%) of colorless oil, which was used directly in the
next step without further purification.
3.1.6. Preparation of the bis-amides 21–23. General
procedure. A. To a cold solution (0–5 8C) of each of 20b–e,
ethylenediamine or o-phenylenediamine (0.8 mmol) and
triethylamine (0.25 g, 2.5 mmol) in DCM (20 mL), was
added 19 (0.44 g, 1.7 mmol) in DCM (5 mL) dropwise with
stirring. After complete addition the reaction mixture was
3.1.2.7. Compound 17d. Yield 0.12 g (15%); pale
yellow oil purified using column chromatography using
EtOAc/pet. ether (40–60) as an eluent, RfZ0.6/EtOAc.
LCMS; m/zZ827 (MC1). IR: 3389, 3070, 2923, 2854,

Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1007
stirred for 1 h at 0–5 8C and stirring was continued overnight
at room temperature. The organic layer was extracted with
DCM, washed with concd HCl (5 mL), water twice,
NaHCO3 solution and finally water. The organic layer was
separated, dried over anhydrous sodium sulfate, the solvent
was then removed in vacuo and the remaining material was
purified by column chromatography. All compounds
were characterized by Rf values using the solvent mixture
DCM–pet. ether (40–60)–EtOAc in (6/4/2).
JZ10.3 Hz, CH2]), 4.38 (t, 4H, JZ4.9 Hz, CH2), 4.19
(t, 4H, JZ4.7 Hz, OCH2), 3.95 (d, 4H, JZ5.6 Hz,
OCH2CH]), 3.83 (t, 4H, JZ4.9 Hz, OCH2), 3.75 (t, 4H,
JZ4.7 Hz, OCH2), 3.52 (s, 4H, CH2). 13C NMR (CDCl3): d
163.3, 156.6, 148.0, 134.2, 132.9, 132.3, 128.8, 124.8,
123.9, 121.8, 121.6, 121.5, 117.2, 113.6, 112.3, 72.2, 70.8,
69.4, 69.1, 68.5, 68.0. Anal. Calcd for C42H48N2O10 (740.9):
C 68.09; H 6.53; N 3.78. Found: C 67.87; H 6.65; N 3.86.
3.1.6.4. Compound 21e. Yield 0.27 g (46%), colorless
oil, RfZ0.9. LCMS; m/zZ729 (MC1). IR: 3343, 3072,
2933, 2874, 1661, 1599, 1535, 1480, 1454, 1332, 1293,
B. To a mixture of each of 1,2-bis(2-hydroxybenzamido)-
ethane
and
1,2-bis(2-hydroxybenzamido)benzene
1
(0.8 mmol), anhydrous K2CO3 (0.4 g, 3 mmol) and 2-allyl-
oxyethyl p-toluenesulfonate (0.5 g, 2 mmol) in dry DMF
(2 mL) was heated at 100 8C for 10 h. The product was then
extracted with DCM, washed several times with water,
separated and dried over anhydrous sodium sulfate. The
solvent was then removed in vacuo and the remaining
product was purified to give the corresponding products 22
and 23, respectively.
1233, 1162, 1133, 1092, 1046, 100, 922, 752. H NMR
(CDCl3): d 10.40 (s, 2H, NH), 8.54 (d, 2H, JZ8.0 Hz), 8.30
(dd, 2H, JZ7.8, 1.2 Hz), 7.53 (m, 2H), 7.45 (dt, 2H, JZ7.7,
1.4 Hz), 7.39 (m, 2H), 7.13 (t, 2H, JZ7.5 Hz), 6.98 (m, 4H),
6.87 (m, 4H), 5.63 (m, 2H, CH]), 5.29 (s, 4H, OCH2Ar),
5.04 (dd, 2H, JZ17.5, 1 Hz, CH2]), 4.98 (d, 2H, JZ
10.3 Hz, CH2]), 3.87 (t, 4H, JZ4.7 Hz, OCH2), 3.76 (d,
4H, JZ5.4 Hz, OCH2), 3.37 (t, 4H, JZ4.7 Hz, OCH2).
Anal. Calcd for C44H44N2O8 (728.9): C 72.51; H 6.09; N
3.84. Found: C 72.56; H 5.99; N 4.10.
3.1.6.1. Compound 21b. Yield 0.26 g (50%), colorless
oil, RfZ0.8. LCMS; m/zZ667 (MC1). IR: 3346, 3072,
2938, 2878, 1660, 1599, 1535, 1481, 1454, 1332, 1291,
1252, 1234, 1162, 1134, 1117, 1091, 1048, 995, 927, 753.
1H NMR (CDCl3): d 10.22 (s, 2H, NH), 8.46 (d, 2H, JZ
7.6 Hz), 8.27 (dd, 2H, JZ8.0, 1.8 Hz), 7.45 (dt, 2H, JZ7.9,
1.7 Hz), 7.14 (t, 2H, JZ7.5 Hz), 6.98 (m, 6H), 6.87 (dd, 2H,
JZ8.0, 1.4 Hz), 5.67 (m, 2H, CH]), 5.06 (dd, 2H, JZ17.3,
1.5 Hz, CH2]), 4.99 (dd, 2H, JZ10.4, 1.2 Hz, CH2]),
4.30 (m, 8H, CH2), 3.86 (d, 4H, JZ5.6 Hz), 3.72 (t, 4H, JZ
4.8 Hz), 2.33 (quint, 2H, JZ4.6 Hz). 13C/DEPT NMR
(CDCl3): d 163.1 (C), 156.4 (C), 147.9 (C), 133.9 (CH),
132.9 (CH), 132.1 (CH), 128.2 (C), 123.9 (CH), 122.7 (C),
121.8 (CH), 121.7 (CH), 121.2 (CH), 117.1 (CH2), 113.9
(CH), 111.6 (CH), 72.0 (CH2), 69.2 (CH2), 67.7 (CH2), 65.0
(CH2), 28.7 (CH2). Anal. Calcd for C39H42N2O8 (666.8): C
70.25; H 6.35; N 4.20. Found: C 69.89; H 6.33; N 4.09.
3.1.6.5. Compound 22. Yield 0.19 g (51%, A), 0.2 g
(52%, B), colorless crystals from EtOAc, mp 95–96 8C.
LCMS; m/zZ469 (MC1). IR: 3354, 3071, 2943, 2861,
1646, 1600, 1539, 1483, 1448, 1296, 1245, 1087, 1051,
1020, 999, 925, 766. 1H NMR (CDCl3): d 8.46 (s, 2H, NH),
8.19 (dd, 2H, JZ7.7, 1.3 Hz), 7.42 (dt, 2H, JZ7.7, 1.3 Hz),
7.08 (t, 2H, JZ7.5 Hz), 6.96 (d, 2H, JZ8.2 Hz), 5.85 (m,
2H, CH]), 5.27 (d, 2H, JZ17.7 Hz, CH2]), 5.20 (d, 2H,
JZ13.8 Hz, CH2]), 4.23 (t, 4H, JZ4.6 Hz, OCH2CH2),
3.97 (d, 4H, JZ5.6 Hz, OCH2CH]), 3.73 (t, 4H, JZ
4.6 Hz, OCH2CH2), 3.68 (m, 4H, NCH2). Anal. Calcd for
C26H32N2O6 (468.5): C 66.65; H 6.88; N 5.98. Found: C
66.52; H 6.84; N 6.11.
3.1.6.6. Compound 23. Yield 0.88 g (85%, A), 0.74 g
(71%, B), colorless oil, RfZ0.8. LCMS; m/zZ517 (MC1).
IR: 3320, 3075, 2934, 2869, 1662, 1598, 1529, 1510, 1480,
1454, 1300, 1231, 1111, 1045, 927, 756. 1H NMR (CDCl3):
d 10.02 (s, 2H, NH), 8.22 (dd, 2H, JZ7.8, 1.4 Hz), 7.80 (m,
2H), 7.46 (dt, 2H, JZ8.0, 1.5 Hz), 7.26 (m, 2H), 7.10 (t, 2H,
JZ7.5 Hz), 7.03 (d, 2H, JZ8.2 Hz), 5.68 (m, 2H, CH]),
5.11 (dd, 2H, JZ17.3, 1.4 Hz, CH2]), 5.05 (d, 2H, JZ
10.3 Hz, CH2]), 4.22 (t, 4H, JZ4.8 Hz, OCH2CH2), 3.86
(d, 4H, JZ5.6 Hz, OCH2CH]), 3.65 (t, 4H, JZ4.8 Hz,
OCH2CH2). Anal. Calcd for C30H32N2O6 (516.6): C 69.75;
H 6.24; N 5.42. Found: C 69.50; H 6.28; N 5.70.
3.1.6.2. Compound 21c. Yield 0.33 g (59%), colorless
oil, RfZ0.7. LCMS; m/zZ697 (MC1). IR: 3342, 3072,
2932, 2874, 1660, 1599, 1534, 1481, 1454, 1332, 1291,
1
1235, 1132, 1093, 1048, 929, 753. H NMR (CDCl3): d
10.24 (s, 2H, NH), 8.53 (m, 2H), 8.22 (dd, 2H, JZ7.6,
1.6 Hz), 7.40 (dt, 2H, JZ7.8, 2 Hz), 7.10 (t, 2H, JZ7.6 Hz),
7.04 (m, 4H), 6.95 (d, 2H, JZ8.4 Hz), 6.86 (m, 2H), 5.72
(m, 2H, CH]), 5.11 (dd, 2H, JZ17.3, 1.6 Hz, CH2]), 5.03
(dd, 2H, JZ10.5, 1 Hz, CH2]), 4.31 (t, 4H, JZ4.9 Hz,
OCH2CH2), 4.16 (t, 4H, JZ4.7 Hz, OCH2CH2), 3.90 (dd,
4H, JZ5.7, 1 Hz, OCH2CH]), 3.84 (t, 4H, JZ4.7 Hz,
OCH2CH2), 3.78 (t, 4H, JZ4.9 Hz, OCH2CH2). Anal.
Calcd for C40H44N2O9 (696.8): C 68.95; H 6.36; N 4.02.
Found: C 69.15; H 6.18; N 3.98.
3.1.7. 2-(2-Allyloxyethoxy)acetanilide. A. A mixture of
o-acetamidophenol (1.5 g, 10 mmol), 2-allyloxyethyl
p-toluenesulfate (2.56 g, 10 mmol) and anhydrous K2CO3
(5.5 g) in dry DMF (5 mL) was heated at 100 8C for 4 h.
Crushed ice was then added to the mixture, the precipitate
was washed three times with cold KOH soln (10%) and then
with cold water twice and then extracted with DCM, and
dried over anhydrous Na2SO4. The solvent was then
removed in vacuo to give 1.98 g (86%) of the product as a
pale yellow oil, which was used in the next step without
further purification. MS: m/zZ235.1 (MC, 70%). IR: 3531,
3423, 3309, 2932, 2872, 1684, 1601, 1531, 1487, 1450,
1371, 1327, 1289, 1255, 1213, 1118, 1036, 929, 752.
3.1.6.3. Compound 21d. Yield 0.26 g (44%), colorless
crystals, mp 56–57 8C, RfZ0.5. LCMS; m/zZ741 (MC1).
IR: 3340, 3073, 2927, 2874, 1660, 1599, 1536, 1480, 1456,
1333, 1291, 1254, 1235, 1221, 1162, 1134, 1115, 1091,
1048, 997, 928, 754. 1H NMR (CDCl3): d 10.24 (s, 2H, NH),
8.54 (dd, 2H, JZ7.4, 2.3 Hz), 8.24 (dd, 2H, JZ7.8, 1.4 Hz),
7.43 (dt, 2H, JZ8.4, 1.5 Hz), 7.12 (t, 2H, JZ7.5 Hz), 7.05
(m, 6H), 6.92 (dd, 2H, JZ7.7, 2.3 Hz), 5.76 (m, 2H, CH]),
5.14 (dd, 2H, JZ17.2, 1.3 Hz, CH2]), 5.06 (d, 2H,

1008
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1H NMR (CDCl3): d 8.27 (dd, 1H, JZ7.6, 1.5 Hz), 8.24 (s,
1H, NH), 6.90 (m, 2H), 6.82 (dd, 1H, JZ7.6, 1.5 Hz), 5.83
(m, 1H, ]CH), 5.23 (dd, 1H, JZ17.1, 1.2 Hz, ]CH2), 5.13
(d, 1H, JZ10.3 Hz, ]CH2), 4.04 (t, 2H, JZ4.5 Hz,
OCH2CH2), 3.97 (d, 2H, JZ5.6 Hz, CH2CH]), 3.66 (t,
2H, JZ4.5 Hz, OCH2CH2), 2.07 (s, 3H, CH3).
3075, 3014, 2938, 2871, 1763, 1689, 1603, 1534, 1487,
1454, 1408, 1338, 1290, 1257, 1210, 1118, 1043, 996, 928,
752. 1H NMR (CDCl3): d 9.11 (s, 1H, NH), 8.34 (d, 1H, JZ
7.8 Hz), 7.09 (t, 1H, JZ7.8 Hz), 7.01 (t, 1H, JZ7.8 Hz),
6.92 (d, 1H, JZ7.8 Hz), 5.96 (m, 1H, CH]), 5.32 (d, 1H,
JZ17.3 Hz, CH2]), 5.23 (d, 1H, JZ10.4 Hz, CH2]), 4.23
(t, 2H, JZ4.5 Hz, OCH2CH2), 4.20 (s, 2H, COCH2), 4.10
(d, 2H, JZ5.6 Hz, CH2CH]), 3.83 (t, 2H, JZ4.5 Hz,
OCH2CH2). 13C NMR (CDCl3): d 163.6, 147.5, 133.3,
127.2, 124.5, 121.5, 119.7, 117.5, 112, 72.4, 68.6, 68.4,
43.1. Anal. Calcd for C13H16NClO3 (269.7): C 57.89; H
5.98; N 5.19. Found: C 57.62; H 5.75; N 5.40.
B. To a solution of KOH (0.56 g, 10 mmol) in methanol
(15 mL), was added o-acetamidophenol (1.5 g, 10 mmol).
The mixture was then stirred at room temperature for 15 min
and the solvent was then removed in vacuo. To the
remaining potassium salt was added DMF (2 mL) and
2-allyloxyethyl p-toluenesulfate (2.56 g, 10 mmol). The
reaction mixture was then heated under reflux for 5 min.
The mixture was cooled, diluted with water (20 mL) and
extracted with DCM, washed with cold water, dried over
Na2SO4 and evaporated to give 2.09 g (91%) of the product
as a pale yellow oil, which was used in the next step without
further purification.
3.1.10. Synthesis of compounds 30–33. General pro-
cedures. A mixture of each of the appropriate chloro-
acetanilide 25a,b (1 mmol) and the appropriate phenolic
derivative 26–29 (1 mmol) and powdered K2CO3 (4 mmol)
in anhydrous DMF (1.5 mL) was stirred at 100 8C for 1 h.
After cooling crushed ice was added and the mixture was
extracted with DCM. The organic layer was separated,
washed with water and dried over anhydrous sodium sulfate.
The solvent was removed in vacuo and remaining product
was crystallized from the proper solvent.
3.1.8. 2-(2-Allyloxyethoxy)aniline hydrochloride 24b. A
mixture of 2-(2-allyloxyethoxy)acetanilide (10 mmol) and
concd HCl (2 mL) in ethanol (10 mL) was heated under
reflux for 2 h. The solvent was then removed in vacuo and the
residue obtained was washed with ether and crystallized from
ethyl acetate to give 1.5 g (65%) of the product as colorless
crystals, mp 124 8C. MS: m/zZ193 [(C11H15NO2)C, 30%].
IR: 3412, 2873, 2591, 1630, 102, 1461, 1267, 1098, 1026,
3.1.10.1. Compound 30a. Yield 0.24 g (49%), colorless
crystals (EtOH), mp 144 8C. LCMS; m/zZ489 (MC1). IR:
3436, 3383, 3023, 2970, 2868, 1684, 1601, 1539, 1503,
1485, 1456, 1421, 1336, 1292, 1253, 1203, 1131, 1115,
1046, 1017, 928, 751. 1H NMR (CDCl3): d 9.19 (s, 2H, NH),
8.43 (dd, 2H, JZ7.5, 1.9 Hz), 7.03 (m, 8H), 6.59 (dd, 2H,
JZ7.8, 1.5 Hz), 5.86 (m, 2H, ]CH), 5.30 (dd, 2H, JZ17.3,
1.1 Hz,]CH2), 5.16 (dd, 2H, JZ10.6, 0.9 Hz, ]CH2), 4.70
(s, 4H, OCH2CO), 4.15 (d, 4H, JZ5.0 Hz, OCH2CH]).
Anal. Calcd for C28H28N2O6 (488.6): C 68.84; H 5.78; N
5.73. Found: C 68.62; H 5.88; N 5.76.
1
931, 755. H NMR (CDCl3): d 10.49 (br s, 3H, NH2HCl),
7.74 (d, 1H, JZ7.5 Hz), 7.33 (t, 1H, JZ7.5 Hz), 7.00 (m,
2H), 5.84 (m, 1H, CH]), 5.21 (d, 1H, JZ17.2 Hz, CH2]),
5.09 (d, 1H, JZ10.2 Hz, CH2]), 4.25 (br, 2H, OCH2CH2),
4.03 (d, 2H, JZ5 Hz, CH2CH]), 3.92 (br, 2H, OCH2CH2).
Anal. Calcd for C11H16NO2Cl (229.7): C 57.52; H 7.02; N
6.10. Found: C 57.26; H 6.90; N 6.28.
3.1.9. Chloroacetanilides 25a,b. General procedure. To a
cold (0–5 8C) solution of each of 24a,b (50 mmol) and
triethylamine (10.6 mL, 76 mmol) in DCM (25 mL) was
added dropwise with stirring chloroacetyl chloride (3.8 mL,
50 mmol) in DCM (25 mL). The reaction mixture was
stirred for 1 h in ice and stirring was continued overnight at
room temperature. The resulting solution was neutralized
with HCl, washed with Na2CO3 solution and water,
extracted with DCM, dried over sodium sulfate and the
solvent was removed in vacuo to give the corresponding
product 25a,b.
3.1.10.2. Compound 30b. Yield 0.5 g (87%), pale
yellow. MS: m/zZ576.2 (MC, 100%). IR: 3393, 3070,
2932, 2863, 1690, 1601, 1536, 1503, 1486, 1457, 1256,
1
1211, 1118, 1048, 928, 750. H NMR (CDCl3): d 9.18 (s,
2H, NH), 8.39 (dd, 2H, JZ7.8, 1.6 Hz), 7.01 (m, 8H), 6.67
(d, 2H, JZ7.9 Hz), 5.74 (m, 2H, ]CH), 5.14 (dd, 2H, JZ
17.2, 1.4 Hz, ]CH2), 5.02 (d, 2H, JZ10.4 Hz, ]CH2),
4.72 (s, 4H, OCH2CO), 3.91 (d, 4H, JZ5.5 Hz,
OCH2CH]), 3.83 (t, 4H, JZ4.7 Hz, OCH2CH2O), 3.63
(t, 4H, JZ4.7 Hz, OCH2CH2O). Anal. Calcd for
C32H36N2O8 (576.7): C 66.65; H 6.29; N 4.86. Found: C
64.18; H 5.93; N 5.86.
3.1.9.1. o-Allyloxychloroacetanilide 25a. Yield 10.8 g
(96%), pale yellow oil. MS: m/zZ225 (MC, 20%). IR:
3388, 2872, 1683, 1603, 1537, 1487, 1456, 1411, 1337,
1291, 1255, 1207, 1117, 997, 914, 748. 1H NMR (CDCl3): d
9.06 (s, 1H, NH), 8.35 (dd, 1H, JZ8, 1.2 Hz), 7.07 (dt, 1H,
JZ8, 1.2 Hz), 6.98 (t, 1H, JZ8 Hz), 6.88 (d, 1H, JZ8 Hz),
6.06 (m, 1H, CH]), 5.47 (dd, 1H, JZ16, 1.1 Hz, CH2]),
5.32 (dd, 1H, JZ9.4, 1 Hz, CH2]), 4.58 (d, 2H, JZ4.9 Hz,
CH2CH]), 4.20 (s, 2H, COCH2). Anal. Calcd for
C11H12NO2Cl (225.7): C 58.55; H 5.36; N 6.21. Found: C
58.32; H 5.37; N 6.40.
3.1.10.3. Compound 31a. Yield 0.12 g (18%), colorless
crystals (acetone), mp 141–142 8C. LCMS; m/zZ665
(MC1). IR: 3387, 3061, 2918, 2852, 1690, 1599, 1534,
1507, 1483, 1457, 1360, 1326, 1272, 1253, 1210, 1149, 1121,
1066, 992, 924, 813, 751. 1H NMR (CDCl3): d 8.42 (s, 2H,
NH), 8.08 (dd, 2H, JZ7.9, 1.4 Hz), 7.97 (d, 2H, JZ9.0 Hz),
7.87 (d, 2H, JZ8.2 Hz), 7.43 (d, 2H, JZ9 Hz), 7.37 (t, 2H,
JZ7.4 Hz), 7.28 (t, 2H, JZ9 Hz), 7.18 (d, 2H, JZ8.4 Hz),
6.98 (t, 2H, JZ7.8 Hz), 6.89 (d, 2H, JZ7.6 Hz), 6.72 (d, 2H,
JZ7.8 Hz), 5.57 (m, 2H, CH]), 5.07 (dd, 2H, JZ17.3,
1.3 Hz, ]CH2), 4.95 (dd, 2H, JZ10.6, 1.2 Hz, ]CH2),
4.59, 4.52 (2d, 4H, JZ15.5 Hz, OCH2CO), 4.25 (d, 4H, JZ
5 Hz, OCH2CH]). Anal. Calcd for C42H36N2O6 (664.8):
C 75.89; H 5.46; N 4.21. Found: C 75.67; H 5.62; N 4.22.
3.1.9.2. N-[2-(2-Allyloxyethoxy)phenyl]chloroacet-
amide 25b. Yield 11.3 g (84%), pale yellow oil. MS:
m/zZ271 (MC1, 25%), 269 (MC, 78%). IR: 3505, 3383,

Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1009
3.1.10.4. Compound 31b. Yield 0.7 g (93%), colorless
crystals (EtOH), mp 144–145 8C. LCMS; m/zZ753
(MC1). IR: 3391, 3063, 2870, 1693, 1601, 1533, 1484,
1458, 1332, 1294, 1254, 1216, 1117, 1094, 1046, 996, 930,
755. H NMR (CDCl3): d 10.54 (s, 1H, NH), 8.91 (s, 1H,
1
NH), 8.72 (dd, 1H, JZ8.8, 1.2 Hz), 8.43 (d, 1H, JZ7.6 Hz),
8.34 (d, 1H, JZ8.0 Hz), 7.50 (t, 1H, JZ8.0 Hz), 7.09 (m,
5H), 6.95 (d, 2H, JZ8.5 Hz), 6.84 (d, 1H, JZ8.0 Hz), 6.06
(m, 1H, CH]), 5.63 (m, 1H, CH]), 5.36 (d, 1H, JZ
17.2 Hz, CH2]), 5.27 (d, 1H, JZ10.4 Hz, CH2]), 5.06 (d,
1H, JZ17.2 Hz, CH2]), 4.98 (d, 1H, JZ10.4 Hz, CH2]),
4.75 (s, 2H, OCH2CO), 4.60 (d, 2H, JZ5.5 Hz,
OCH2CH]), 3.82 (t, 2H, JZ4.9 Hz, OCH2CH2), 3.71 (d,
2H, JZ5.5 Hz, OCH2CH]), 3.29 (t, 2H, JZ4.9 Hz,
OCH2CH2). Anal. Calcd for C29H30N2O6 (502.6): C
69.31; H 6.02; N 5.57. Found: C 69.05; H 5.77; N 5.78.
1
1457, 1325, 1254, 1211, 1147, 1114, 1063, 927, 754. H
NMR (CDCl3): d 8.47 (s, 2H, NH), 8.07 (dd, 2H, JZ7.9,
1.2 Hz), 7.97 (d, 2H, JZ9 Hz), 7.88 (d, 2H, JZ8.2 Hz),
7.44 (d, 2H, JZ9 Hz), 7.39 (t, 2H, JZ7.6 Hz), 7.28 (t, 2H,
JZ7.6 Hz), 7.20 (d, 2H, JZ8.4 Hz), 7.03 (dt, 2H, JZ7.8,
1.2 Hz), 6.92 (t, 2H, JZ7.7 Hz), 6.81 (d, 2H, JZ8.0 Hz),
5.70 (m, 2H, CH]), 5.09 (dd, 2H, JZ17.4, 1.6 Hz, CH2]),
5.04 (d, 2H, JZ10.5 Hz, CH2]), 4.55 (s, 4H, OCH2CO),
3.89 (m, 4H, OCH2CH2), 3.67 (d, 4H, JZ5.5 Hz,
OCH2CH]), 3.22 (m, 4H, OCH2CH2). Anal. Calcd for
C46H44N2O8 (752.9): C 73.39; H 5.89; N 3.72. Found: C
73.07; H 5.96; N 3.91.
3.1.11. Ring closing metathesis of 15a–e, 17b,d, 21b–e,
22, 23, 30a,b, 31a,b, 32a,b and 33a,b. General procedure.
A solution of each of the substrates 15a–e, 17b,d, 21b–e, 22,
23, 30a,b, 31a,b, 32a,b and 33a,b (0.2 mmol) in DCM
(25 mL) and Grubbs’ catalyst (4–12 mg, ca. 2.5–7.5 mol%
of the substrate) was heated under reflux for 2–24 h
(Tables 1–3). The reaction mixture was then mixed with
silica gel (100–200 mm, 0.5 g), stirred for 30 min, filtered
and the silica was extracted twice with DCM (50 mL). After
removing the solvent from the DCM extract, the remaining
products were analyzed by 1H NMR (Tables 1–3). All
macrocycles were characterized by their Rf. All E and Z
isomers were identified by their 1H and 13C NMR signals in
their mixture.
3.1.10.5. Compound 32a. Yield 0.2 g (29%), colorless
crystals (EtOH), mp 167–168 8C. LCMS; m/zZ679
(MC1). IR: 3397, 3374, 3350, 1698, 1640, 1602, 1542,
1
1489, 1453, 1299, 1254, 1223, 1116, 1043, 1005, 750. H
NMR (CDCl3): d 8.65 (s, 2H, NH), 8.53 (s, 2H, NH), 8.25
(d, 2H, JZ7.8 Hz), 8.11 (d, 2H, JZ7.4 Hz), 7.35 (t, 2H, JZ
7.5 Hz), 7.03 (m, 4H), 6.92 (t, 2H, JZ7.7 Hz), 6.83 (d, 2H,
JZ8.2 Hz), 6.78 (d, 2H, JZ8.0 Hz), 5.81 (m, 2H, CH]),
5.19 (m, 4H, CH2]), 4.72 (s, 4H, OCH2CO), 4.41 (d, 4H,
JZ4.7 Hz, OCH2CH]), 3.82 (s, 4H, NCH2). Anal. Calcd
for C38H38N4O8 (678.8): C 67.24; H 5.64; N 8.25. Found: C
66.98; H 5.71; N 8.46.
3.1.10.6. Compound 32b. Yield 0.65 g (85%), colorless
crystals (EtOAc), mp 67–68 8C. LCMS; m/zZ767 (MC1).
IR: 3385, 3334, 2929, 2862, 1692, 1642, 1601, 1537, 1485,
3.1.11.1. Compound 1a. (E and Z): Yield 162 mg (97%),
colorless crystals (EtOH), mp 243–244 8C, RfZ0.6 [EtOAc/
pet. ether (40–60) 2:1]. LCMS; m/zZ835 (MC1). IR: 3394,
3356, 3068, 2929, 1688, 1663, 1600, 1532, 1482, 1455,
1330, 1294, 1250, 1222, 1119, 1092, 1046, 1008, 955, 748.
1H NMR (CDCl3) (E isomer): d 9.97 (s, 2H, NH), 8.78 (s,
2H, NH), 8.53 (dd, 2H, JZ8.0, 1.3 Hz), 8.11 (dd, 2H, JZ
7.7, 1.5 Hz), 7.80 (dd, 2H, JZ7.9, 1.2 Hz), 7.41 (dt, 2H, JZ
8.0, 1.6 Hz), 7.07 (m, 4H), 6.92 (dt, 2H, JZ7.4, 1.3 Hz),
6.79 (m, 4H), 6.70 (d, 2H, JZ7.9 Hz), 6.43 (d, 2H, JZ
7.8 Hz), 6.33 (t, 2H, JZ7.8 Hz), 6.27 (s, 2H, CH]), 4.73 (s,
4H, OCH2CO), 4.53 (s, 4H, CH2CH]), 3.52 (s, 4H,
OCH2CH2). 13C NMR (CDCl3) (E isomer): d 165.7, 162.6,
156.0, 146.5, 146.2, 133.3, 132.8, 128.6, 128, 125.2, 124.8,
123.9, 122.8, 121.9, 121.5, 121.1, 120.9, 118.3, 112.2,
111.4, 109.6, 69.6, 69.1, 66.6. 1H NMR (CDCl3) (Z isomer):
d 10.19 (s, 2H, NH), 8.74 (s, 2H, NH), 8.57 (d, 2H, JZ
8.3 Hz), 8.18 (d, 2H, JZ7.8 Hz), 7.98 (d, 2H, JZ7.8 Hz),
7.41 (t, 2H, JZ8.0 Hz), 7.08 (m, 4H), 6.98 (t, 2H, JZ
7.8 Hz), 6.82 (m, 4H), 6.64 (d, 2H, JZ8.8 Hz), 6.52 (d, 2H,
JZ7.5 Hz), 6.33 (t, 2H, JZ7.8 Hz), 5.89 (t, 2H, JZ3.6 Hz,
CH]), 4.75 (s, 4H, OCH2CO), 4.61 (d, 4H, JZ3.6 Hz,
CH2CH]), 3.80 (s, 4H, OCH2CH2). 13C NMR (CDCl3) (Z
isomer): d 165.7, 165.69, 155.7, 146.7, 146.6, 133.3, 132.8,
129.6, 127.8, 125.9, 124.9, 123.6, 122.8, 121.7, 121.6,
121.1, 120.9, 119.3, 113.2, 112.1, 110.9, 70.1, 67.3, 64.9.
Anal. Calcd for C48H42N4O10 (834.9): C 69.06; H 5.07; N
6.71. Found: C 69.01; H 5.03; N 6.45.
1
1453, 1295, 1255, 1206, 1161, 1117, 1046, 928, 752. H
NMR (CDCl3): d 8.86 (s, 4H, NH), 8.14 (d, 2H, JZ7.8 Hz),
8.03 (dd, 2H, JZ7.7, 1 Hz), 7.28 (t, 2H, JZ8.1 Hz), 6.96
(m, 4H), 6.85 (t, 2H, JZ7.7 Hz), 6.77 (d, 2H, JZ8.3 Hz),
6.74 (d, 2H, JZ8.4 Hz), 5.77 (m, 2H, CH]), 5.18 (d, 2H,
JZ17.2 Hz, CH2]), 5.10 (d, 2H, JZ10.4 Hz, CH2]), 4.66
(s, 4H, OCH2CO), 3.98 (t, 4H, JZ4.7 Hz, OCH2CH2), 3.90
(d, 4H, JZ5.5 Hz, OCH2CH]), 3.78 (s, 4H, NCH2), 3.58
(t, 4H, JZ4.7 Hz, OCH2CH2). Anal. Calcd for
C42H46N4O10 (766.9): C 65.78; H 6.05; N 7.31. Found: C
66.01; H 5.93; N 7.22.
3.1.10.7. Compound 33a. Yield 0.2 g (44%), colorless
crystals (EtOH), mp 128 8C. LCMS; m/zZ459 (MC1). IR:
3396, 3333, 3071, 2873, 1685, 1659, 1601, 1531, 1483,
1457, 1334, 1293, 1253, 1226, 1163, 1132, 1091, 1046, 998,
1
753. H NMR (CDCl3): d 10.54 (s, 1H, NH), 8.88 (s, 1H,
NH), 8.71 (dd, 1H, JZ7.7, 1.6 Hz), 8.43 (dd, 1H, JZ7.8,
1.3 Hz), 8.35 (dd, 1H, JZ7.9, 1.5 Hz), 7.49 (dt, 1H, JZ8.6,
1.5 Hz), 7.06 (m, 7H), 6.79 (d, 1H, JZ8.0 Hz), 6.07 (m, 1H,
CH]), 5.56 (m, 1H, CH]), 5.37 (d, 1H, JZ17.3 Hz,
CH2]), 5.27 (d, 1H, JZ10.3 Hz, CH2]), 5.04 (dd, 1H, JZ
17.2, 0.8 Hz, CH2]), 4.94 (dd, 1H, JZ10.5, 0.6 Hz,
CH2]), 4.77 (s, 2H, OCH2CO), 4.61 (d, 2H, JZ5.6 Hz,
OCH2CH]), 4.20 (d, 2H, JZ5.3 Hz, OCH2CH]). Anal.
Calcd for C27H26N2O5 (458.5): C 70.73; H 5.72; N 6.11.
Found: C 70.71; H 5.82; N 6.21.
3.1.11.2. Compound 1b. (E and Z): Yield 154 mg (91%),
purified using column chromatography with eluent
DCM–pet. ether (40–60)–EtOAc (6/4/3), colorless crystals
[DCM/pet. ether (40–60)] mp 176–177 8C, RfZ0.6 [EtOAc/
pet. ether (40–60) 2:1]. LCMS; m/zZ849 (MC1). IR: 3399,
3.1.10.8. Compound 33b. Yield 0.2 g (40%), colorless
crystals (EtOH), mp 126 8C. LCMS; m/zZ503 (MC1). IR:
3398, 3353, 3015, 2922, 2852, 1665, 1602, 1539, 1482,

1010
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
3353, 3069, 3034, 2931, 1686, 1664, 1601, 1534, 1483,
1455, 1330, 1293, 1252, 1214, 1116, 1092, 1048, 1004, 751.
1H NMR (CDCl3) (E isomer): d 10.14 (s, 2H, NH), 8.85 (s,
2H, NH), 8.71 (d, 2H, JZ8.0 Hz), 8.24 (m, 4H), 7.42 (t, 2H,
JZ7.7 Hz), 7.17 (m, 4H), 7.10 (t, 2H, JZ7.8 Hz), 6.99 (d,
2H, JZ8.2 Hz), 6.81 (d, 2H, JZ8.3 Hz), 6.72 (m, 4H), 6.47
(m, 2H), 6.01 (s, 2H, CH]), 4.72 (s, 4H, OCH2CO), 4.48 (s,
4H, OCH2CH]), 3.82 (t, 4H, JZ5.5 Hz, OCH2), 1.78
(m, 14H), 6.73 (d, 2H, JZ7 Hz), 6.09 (t, 2H, JZ3.7 Hz,
]CH), 4.82 (d, 4H, JZ3.7 Hz, OCH2CH]), 4.75 (s, 4H,
OCH2CO), 3.88 (t, 4H, JZ4 Hz, OCH2CH2), 3.43 (t, 4H,
JZ4 Hz, OCH2CH2), 3.23 (s, 4H, OCH2CH2O). 13C NMR
(CDCl3) (Z isomer): d 166.1, 163.2, 156.1, 147.0, 146.8,
133.2, 132.4, 129.2, 128.7, 126.8, 123.9, 123.2, 121.9,
121.8, 121.6, 121.2, 120.3, 112.6, 112.5, 112.0, 70.4, 69.1,
65.0. Anal. Calcd for C52H50N4O12 (923): C 67.67; H 5.46;
N 6.07. Found: C 67.69; H 5.49; N 6.12.
1
(quint, 2H, JZ5.5 Hz, OCH2CH2). H NMR (CDCl3) (Z
isomer): d 10.09 (s, 2H, NH), 8.83 (s, 2H, NH), 8.77 (d, 2H,
JZ9.3 Hz), 8.29 (m, 2H), 7.44 (t, 2H, JZ8.6 Hz), 7.25 (m,
4H), 7.17 (d, 2H, JZ8.8 Hz), 7.05 (t, 2H, JZ8.3 Hz), 6.81
(d, 2H, JZ4 Hz), 6.72 (m, 4H), 6.61 (t, 2H, JZ8.8 Hz), 6.05
(t, 2H, JZ7.8 Hz), 5.55 (br, 2H, CH]), 4.65 (s, 4H,
OCH2CO), 4.52 (s, 4H, OCH2CH]), 3.91 (t, 4H, JZ
6.1 Hz, OCH2), 1.78 (quint, 2H, JZ5.5 Hz, OCH2CH2).
Anal. Calcd for C49H44N4O10 (848.9): C 69.33; H 5.22; N
6.60. Found: C 69.11; H 5.54; N 6.31.
3.1.11.5. Compound 1e. (E): Yield 160 mg (88%),
colorless crystals (EtOH), mp 229–230 8C, RfZ0.8 [EtOAc/
pet. ether (40–60) 2:1]. LCMS; m/zZ911 (MC1). IR: 3401,
3347, 3070, 3023, 2934, 1695, 1651, 1599, 1536, 1482,
1455, 1332, 1295, 1250, 1220, 1163, 1138, 1116, 1092,
1047, 1008, 751. 1H NMR (DMSO-d6): d 10.31 (s, 2H, NH),
9.50 (s, 2H, NH), 8.39 (d, 2H, JZ7.7 Hz), 8.02 (d, 2H, JZ
7.4 Hz), 7.92 (d, 2H, JZ7.4 Hz), 7.30 (m, 2H), 7.26 (t, 2H,
JZ7.3 Hz), 7.08 (m, 14H), 6.93 (d, 4H, JZ7.3 Hz), 6.02
(br, 2H, ]CH), 5.15 (s, 4H, OCH2Ar), 4.83 (s, 4H,
OCH2CO), 4.59 (s, 4H, OCH2CH]). 13C NMR (DMSO-d6
dZ39.5): d 166.5, 162.4, 155.9, 148.8, 147.2, 134.4, 133.3,
131.5, 129.1, 128.1, 127.9, 127.8, 126.4, 125.4, 124.1,
122.7, 121.6, 121.5, 121.2, 120.8, 120.7, 113.3, 112.9,
3.1.11.3. Compound 1c. (E and Z): Yield 91 mg (52%),
colorless crystals [DCM/pet. ether (40–60)], mp 237 8C,
RfZ0.6 [EtOAc/pet. ether (40–60) 2:1]. LCMS; m/zZ879
(MC1). IR: 3406, 3067, 2926, 1694, 1659, 1601, 1534,
1
1482, 1454, 1333, 1293, 1253, 1219, 1130, 1048, 752. H
1
112.3, 68.7, 67.9, 67.7. H NMR (DMSO-d6): d 10.41 (s,
NMR (CDCl3) (E isomer): d 10.33 (s, 2H, NH), 8.80 (s, 2H,
NH), 8.71 (d, 2H, JZ7.2 Hz), 8.23 (dd, 2H, JZ8.0, 1.6 Hz),
8.19 (m, 2H), 7.29 (dt, 2H, JZ8.0, 1.5 Hz), 7.19 (t, 2H, JZ
7.6 Hz), 7.07 (t, 2H, JZ7.6 Hz), 7.01 (dt, 2H, JZ7.8,
1.3 Hz), 6.90 (d, 2H, JZ7.8 Hz), 6.74 (m, 6H), 6.46 (m,
2H), 6.22 (t, 2H, JZ3.8 Hz, ]CH), 4.72 (s, 4H, OCH2CO),
4.60 (d, 4H, JZ3.8 Hz, OCH2CH]), 3.74 (t, 4H, JZ4 Hz,
OCH2CH2O), 3.40 (t, 4H, JZ4 Hz, OCH2CH2O). 13C NMR
(CDCl3) (E isomer): d 166, 163.1, 156.3, 147.1, 146.6,
133.4, 132.3, 129.5, 129.4, 126.4, 124.6, 124, 124, 122, 122,
2H, NH), 9.66 (s, 2H, NH), 8.50 (d, 2H, JZ7.7 Hz), 8.02 (d,
2H, JZ7.4 Hz), 7.92 (d, 2H, JZ7.4 Hz), 7.30 (m, 2H), 7.26
(t, 2H, JZ7.3 Hz), 7.08 (m, 14H), 6.93 (d, 4H, JZ7.3 Hz),
5.57 (br, 2H, ]CH), 5.15 (s, 4H, OCH2Ar), 4.83 (s, 4H,
OCH2CO), 4.82 (br, 4H, OCH2CH]). Anal. Calcd for
C54H46N4O10 (910.9): C 71.20; H 5.09; N 6.15. Found: C
70.45; H 5.12; N 6.33.
3.1.11.6. Compound 2b. (E and Z): Yield 101 mg (70%),
colorless crystals mp 217–218 8C, purified using column
chromatography using DCM/pet. ether (40–60)/EtOAc,
RfZ0.4 [EtOAc/pet. ether (40–60) 2:1]. LCMS; m/zZ725
(MC1). IR: 3396, 3379, 3067, 2960, 2860, 1691, 1602,
1529, 1487, 1456, 1331, 1291, 1253, 1200, 1093, 1047, 750.
1H NMR (CDCl3) (E isomer): d 8.86 (s, 2H, NH), 8.79 (s,
2H, NH), 8.51 (dd, 2H, JZ7.2, 1.4 Hz), 8.40 (dd, 2H, JZ7,
2 Hz), 7.07 (m, 10H), 6.66 (d, 2H, JZ8.5 Hz), 5.68 (s, 2H,
CH]), 4.67 (s, 4H, OCH2CO), 3.98 (t, 4H, JZ5.6 Hz,
OCH2CH2), 3.78 (s, 4H, OCH2CO), 3.65 (s, 4H,
OCH2CH]), 2.00 (quint, 2H, JZ5.6 Hz, OCH2CH2). 13C
NMR (CDCl3) (E isomer): d 167.3, 165.6, 147.0, 146.0,
128.4, 128.2, 126.4, 124.9, 124.4, 123.9, 121.5, 120.2,
1
121.2, 119.5, 114, 113.1, 111.6, 70.5, 70.1, 70, 68.4. H
NMR (CDCl3) (Z isomer): d 10.26 (s, 2H, NH), 8.88 (s, 2H,
NH), 8.71 (d, 2H, JZ7.2 Hz), 8.23 (dd, 2H, JZ8.0, 1.6 Hz),
8.19 (m, 2H), 7.39 (m, 2H), 7.20 (m, 6H), 7.05 (m, 2H), 6.74
(m, 6H), 6.35 (m, 2H), 5.67 (t, 2H, JZ3.5 Hz, CH]), 4.64
(d, 4H, JZ3.5 Hz, OCH2CH]), 4.61 (s, 4H, OCH2CO),
3.74 (t, 4H, JZ4 Hz, OCH2CH2O), 3.40 (t, 4H, JZ4 Hz,
OCH2CH2O). Anal. Calcd for C50H46N4O11 (878.9): C
68.33; H 5.28; N 6.37. Found: C 67.97; H 5.06; N 6.19.
3.1.11.4. Compound 1d. (E and Z): Yield 144 mg (78%),
colorless crystals [DCM/pet. ether (40–60)], mp 201–
202 8C, RfZ0.4 [EtOAc/pet. ether (40–60) 2:1]. LCMS;
m/zZ923 (MC1). IR: 3392, 3342, 3068, 2936, 2875, 1686,
1659, 1600, 1532, 1481, 1456, 1330, 1293, 1254, 1220,
1
120.0, 114.2, 110.8, 70.9, 70.4, 69.9, 64.1, 29.0. H NMR
(CDCl3) (Z isomer): d 8.86 (s, 2H, NH), 8.72 (s, 2H, NH),
8.40 (dd, 2H, JZ7, 2 Hz), 8.32 (d, 2H, JZ7.38 Hz), 7.07
(m, 10H), 6.69 (d, 2H, JZ8.1 Hz), 5.44 (t, 2H, JZ3.8 Hz,
CH]), 4.72 (s, 4H, OCH2CO), 3.98 (m, 8H, OCH2CH2,
OCH2CH]), 3.89 (s, 4H, OCH2CO), 2.00 (quint, 2H, JZ
5.6 Hz, OCH2CH2). 13C NMR (CDCl3) (Z isomer): d 167.1,
165.6, 147.4, 146.1, 128.3, 127.6, 126.2, 125.0, 124.6,
123.5, 121.0, 120.7, 120.5, 113.5, 110.7, 69.7, 69.6, 66.7,
64.3, 28.9. Anal. Calcd for C39H40N4O10 (724.8): C 64.63;
H 5.56; N 7.73. Found: C 64.48; H 5.74; N 7.78.
1
1163, 1134, 1118, 1092, 1048, 750. H NMR (CDCl3) (E
isomer): d 10.35 (s, 2H, NH), 8.81 (s, 2H, NH), 8.71 (dd, 2H,
JZ8.1, 1.3 Hz), 8.38 (dd, 2H, JZ7.9, 1.4 Hz), 8.23 (dd, 2H,
JZ7.7, 1.6 Hz), 7.00 (m, 14H), 6.86 (d, 2H, JZ8.1 Hz),
6.68 (d, 2H, JZ7.6 Hz), 6.43 (m, 2H, ]CH), 4.82 (s, 4H,
OCH2CO), 4.67 (m, 4H, OCH2CH]), 3.84 (t, 4H, JZ
3.9 Hz, OCH2CH2), 3.45 (t, 4H, JZ3.9 Hz, OCH2CH2),
3.32 (s, 4H, OCH2CH2O). 13C NMR (CDCl3) (E isomer): d
166.3, 163.2, 156.1, 147.0, 146.8, 133.6, 132.6, 129.7,
128.9, 126.7, 124.6, 123.7, 123.0, 121.7, 121.4, 121.1,
120.0, 112.2, 112.1, 112.0, 111.9, 70.3, 69.5, 69.4, 69.3,
68.3.1H NMR (CDCl3) (Z isomer): d 10.40 (s, 2H, NH), 8.75
(s, 2H, NH), 8.71 (dd, 2H, JZ8.1, 1.3 Hz), 8.32 (d, 2H, JZ
6 Hz), 8.25 (d, 2H, JZ7.7 Hz), 7.21 (t, 2H, JZ7.3 Hz), 7.00
3.1.11.7. Compound 2d. (E and Z): Yield 96 mg (60%),
colorless crystals mp 198–199 8C, purified using column
chromatography using DCM/pet. ether (40–60)/EtOAc,
RfZ0.1 [EtOAc/pet. ether (40–60) 2:1]. LCMS; m/zZ799

Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1011
(MC1). IR: 3386, 2920, 1687, 1601, 1533, 1454, 1254,
1202, 1117, 1052, 955, 750. 1H NMR (CDCl3) (E isomer): d
9.04 (s, 2H, NH), 8.77 (s, 2H, NH), 8.40 (m, 2H), 8.35 (d,
2H, JZ7.6 Hz), 7.02 (m, 10H), 6.86 (d, 2H, JZ8.2 Hz),
5.87 (s, 2H, CH]), 4.77 (s, 4H, OCH2CO), 4.05 (m, 12H,
OCH2CH2, OCH2CH], OCH2CO), 3.63 (t, 4H, JZ4.3 Hz,
OCH2CH2), 3.50 (s, 4H, OCH2CH2O). 1H NMR (CDCl3) (Z
isomer): d 9.05 (s, 2H, NH), 8.96 (s, 2H, NH), 8.40 (m, 2H),
8.35 (d, 2H, JZ7.6 Hz), 7.02 (m, 10H), 6.86 (d, 2H, JZ
8.2 Hz), 5.70 (t, 2H, JZ3.9 Hz, CH]), 4.76 (s, 4H,
OCH2CO), 4.19 (d, 4H, JZ3.9 Hz, OCH2CH]), 4.05 (m,
8H, OCH2CH2, OCH2CO), 3.59 (t, 4H, JZ4.3 Hz,
OCH2CH2), 3.49 (s, 4H, OCH2CH2O). Anal. Calcd for
C42H46N4O12(798.9): C 63.15; H 5.80; N 7.01. Found: C
63.32; H 5.85; N 7.60.
OCH2CH2), 3.86 (t, 4H, JZ4.9 Hz, OCH2CH2). 13C NMR
(CDCl3) (Z isomer): d 163.3, 156.7, 147.9, 133.0, 132.5,
129.4, 128.7, 123.9, 123.0, 122.0, 121.8, 121.6, 113.8,
112.4, 69.7, 69.2, 68.4, 68.0, 66.7. Anal. Calcd for
C38H40N2O9 (668.7): C 68.25; H 6.03; N 4.19. Found: C
68.56; H 5.92; N 4.31.
3.1.11.10. Compound 3d. (E and Z): Yield 140 mg
(99%), colorless oil, purified using column chromatography
with eluent DCM/pet. ether (40–60)/EtOAc, RfZ0.4
[DCM/pet. ether (40–60)/EtOAc 6:4:2]. LCMS; m/zZ713
(MC1). IR: 3340, 2924, 2872, 1659, 1598, 1533, 1480,
1
1454, 1292, 1234, 1119, 1048, 753. H NMR (CDCl3) (E
isomer): d 10.27 (s, 2H, NH), 8.58 (d, 2H, JZ7.2 Hz), 8.28
(dd, 2H, JZ8.0, 1.6 Hz), 7.48 (t, 2H, JZ7.8 Hz), 7.15 (t,
2H, JZ7.6 Hz), 7.10–7.02 (m, 6H), 6.95 (m, 2H), 5.74 (s,
2H, CH]), 4.42 (t, 4H, JZ5.3 Hz, OCH2), 4.25 (t, 4H, JZ
5.0 Hz, OCH2), 3.99 (br, 4H, OCH2CH]), 3.87 (m, 8H,
OCH2), 3.67 (s, 4H, OCH2). 13C NMR (CDCl3) (E isomer):
d 163.3, 156.6, 148.0, 132.9, 133.2, 129.2, 128.7, 123.8,
123.1, 121.9, 121.6, 121.5, 113.7, 112.1, 71.0, 70.6, 69.6,
3.1.11.8. Compound 3b. (E and Z): Yield 0.127 g (99%),
colorless crystals (EtOH), mp 79–80 8C, purified using
column chromatography with eluent DCM/pet. ether (40–
60)/EtOAc, RfZ0.7 [DCM/pet. ether (40–60)/EtOAc
6:4:2]. LCMS; m/zZ639 (MC1). IR: 3346, 2928, 2862,
1
1
69.0, 68.3, 67.9. H NMR (CDCl3) (Z isomer): d 10.31 (s,
1659, 1598, 1531, 1480, 1453, 1291, 1233, 1047, 752. H
2H, NH), 8.58 (d, 2H, JZ7.2 Hz), 8.28 (dd, 2H, JZ8.0,
1.6 Hz), 7.48 (t, 2H, C), 7.15 (t, 2H, JZ7.6 Hz), 7.10–7.02
(m, 6H), 6.95 (m, 2H), 5.55 (t, 2H, JZ4.0 Hz, CH]), 4.41
(t, 4H, JZ5.3 Hz, OCH2), 4.26 (t, 4H, JZ4.8 Hz, OCH2),
4.08 (d, 4H, JZ4.0 Hz, OCH2CH]), 3.87 (m, 8H, OCH2),
3.67 (s, 4H, OCH2). 13C NMR (CDCl3) (Z isomer): d 163.3,
156.6, 147.9, 133.0, 133.2, 129.3, 128.7, 123.8, 123.0,
121.9, 121.7, 121.6, 113.7, 112.1, 70.6, 69.7, 69.1, 68.4,
68.1, 66.8. Anal. Calcd for C40H44N2O10 (712.8): C 67.40;
H 6.22; N 3.93. Found: C 67.55; H 6.49; N 3.98.
NMR (CDCl3) (E isomer): d 10.11 (s, 2H, NH), 8.47 (d, 2H,
JZ7.8 Hz), 8.30 (dd, 2H, JZ7.8, 1.4 Hz), 7.51 (dt, 2H, JZ
7.6, 1.6 Hz), 7.18 (t, 2H, JZ7.6 Hz), 6.99 (m, 6H), 6.88 (d,
2H, JZ8.0 Hz), 5.58 (s, 2H, CH]), 4.34 (m, 8H,
OCH2CH2), 3.87 (br, 4H, OCH2CH]), 3.77 (m, 4H,
OCH2), 2.33 (quint, 2H, JZ6 Hz, OCH2CH2CH2O). 13C
NMR (CDCl3) (E isomer): d 163.4, 156.5, 148.2, 132.9,
132.6, 129.2, 128.3, 124.1, 123.2, 122.2, 122.0, 121.2,
113.8, 111.7, 71.1, 69.3, 67.8, 65.4, 28.8. 1H NMR (CDCl3)
(Z isomer): d 10.09 (s, 2H, NH), 8.51 (d, 2H, JZ7.9 Hz),
8.30 (dd, 2H, JZ7.8, 1.4 Hz), 7.49 (t, 2H, JZ7.5 Hz), 7.18
(t, 2H, JZ7.6 Hz), 6.99 (m, 6H), 6.89 (d, 2H, JZ8.0 Hz),
5.56 (t, 2H, JZ4.2 Hz, CH]), 4.34 (m, 4H, OCH2), 4.27
(t, 4H, JZ4.5 Hz, OCH2), 4.04 (d, 4H, JZ4.2 Hz,
OCH2CH]), 3.77 (m, 4H, OCH2), 2.41 (quint, 2H, JZ
6.4 Hz, OCH2). 13C NMR (CDCl3) (Z isomer): d 163.4,
156.5, 148.0, 133.0, 132.5, 129.7, 128.2, 124.2, 122.9,
122.1, 121.9, 121.4, 113.6, 111.6, 69.2, 67.7, 66.3, 65.4,
29.1. Anal. Calcd for C37H38N2O8 (638.7): C 69.58; H 6.00;
N 4.39. Found: C 69.56; H 6.13; N 4.25.
3.1.11.11. Compound 3e. (E and Z): Yield 139 mg
(98%), colorless crystals (EtOH), mp 114–115 8C, purified
using column chromatography with eluent DCM/pet. ether
(40–60)/EtOAc, RfZ0.7 [DCM/pet. ether (40–60)/EtOAc
6:4:2]. LCMS; m/zZ701 (MC1). IR: 3350, 2934, 2872,
1
1659, 1599, 1534, 1454, 1293, 1230, 1121, 1023, 751. H
NMR (CDCl3) (E isomer): d 10.51 (s, 2H, NH), 8.59 (d, 2H,
JZ8.0 Hz), 8.36 (d, 2H, JZ7.6 Hz), 7.55 (m, 4H), 7.32 (m,
2H), 7.20 (t, 2H, JZ7.5 Hz), 7.04 (d, 2H, JZ8.3 Hz), 6.95
(t, 2H, JZ7.8 Hz), 6.90 (d, 2H, JZ8.3 Hz), 6.72 (t, 2H, JZ
7.8 Hz), 5.57 (s, 2H, CH]), 5.48 (s, 4H, OCH2Ar), 4.08 (m,
4H, OCH2), 3.82 (br, 4H, OCH2CH]), 3.59 (m, 4H,
OCH2). 1H NMR (CDCl3) (Z isomer): d 10.47 (s, 2H, NH),
8.59 (d, 2H, JZ8.0 Hz), 8.36 (d, 2H, JZ7.6 Hz), 7.55 (m,
4H), 7.36 (m, 2H), 7.20 (t, 2H, JZ7.5 Hz), 7.00 (d, 2H, JZ
8.2 Hz), 6.95 (t, 2H, JZ7.8 Hz), 6.90 (d, 2H, JZ8.3 Hz),
6.84 (t, 2H, JZ7.5 Hz), 5.48 (t, 2H, JZ4.0 Hz, CH]), 5.43
(s, 4H, OCH2Ar), 4.08 (m, 4H, OCH2), 3.89 (d, 4H, JZ
4.0 Hz, OCH2CH]), 3.59 (m, 4H, OCH2). Anal. Calcd for
C42H40N2O8 (700.8): C 71.99; H 5.75; N 4.00. Found: C
71.86; H 5.65; N 3.98.
3.1.11.9. Compound 3c. (E and Z): Yield 110 mg (85%),
colorless oil, purified using column chromatography with
eluent DCM/pet. ether (40–60)/EtOAc, RfZ0.5[DCM/pet.
ether (40–60)/EtOAc 6:4:2]. LCMS; m/zZ669 (MC1). IR:
3343, 2926, 2872, 1658, 1598, 1532, 1480, 1454, 1221,
1
1130, 1092, 1047, 771. H NMR (CDCl3) (E isomer): d
10.21 (s, 2H, NH), 8.55 (m, 2H), 8.29 (m, 2H), 7.51 (dt, 2H,
JZ8.2, 1.1 Hz), 7.17 (t, 2H, JZ7.5 Hz), 7.07 (m, 6H), 6.91
(m, 2H), 5.70 (br, 2H, CH]), 4.41 (t, 4H, JZ4.9 Hz,
OCH2CH2), 4.27 (t, 4H, JZ4.9 Hz, OCH2CH2), 3.96 (br,
4H, OCH2CH]), 3.91 (t, 4H, JZ4.9 Hz, OCH2CH2), 3.86
(t, 4H, JZ4.9 Hz, OCH2CH2). 13C NMR (CDCl3) (E
isomer): d 163.4, 156.6, 148.1, 132.9, 132.5, 129.3, 128.6,
124.0, 123.1, 122.0, 121.8, 121.4, 113.8, 112.2, 71.1, 69.5,
3.1.11.12. Compound 4. (E and Z): Yield 84 mg (96%),
colorless crystals (EtOH), mp 203–204 8C. LCMS; m/zZ
441 (MC1). IR: 3367, 3073, 3018, 2919, 2850, 1650, 1601,
1
69.3, 68.2, 67.8. H NMR (CDCl3) (Z isomer): d 10.26 (s,
1
2H, NH), 8.55 (m, 2H), 8.29 (m, 2H), 7.51 (dt, 2H, JZ8.2,
1.1 Hz), 7.17 (t, 2H, JZ7.5 Hz), 7.07 (m, 6H), 6.91 (m, 2H),
5.55 (t, 2H, JZ4 Hz, CH]), 4.38 (t, 4H, JZ4.9 Hz,
OCH2CH2), 4.27 (t, 4H, JZ4.9 Hz, OCH2CH2), 4.08 (d,
4H, JZ4 Hz, OCH2CH]), 3.91 (t, 4H, JZ4.9 Hz,
1533, 1482, 1450, 1298, 1241, 1117, 910, 738. H NMR
(CDCl3) (E isomer): d 8.37 (br, 2H, NH), 8.25 (dd, 2H, JZ
7.6, 1.3 Hz), 7.44 (m, 2H), 7.12 (t, 2H, JZ7.3 Hz), 6.97 (d,
2H, JZ8.2 Hz), 5.95 (br, 2H, CH]), 4.30 (m, 4H, OCH2),
4.10 (br, 4H, OCH2CH]), 3.88 (m, 4H, OCH2), 3.67

1012
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
(m, 4H, NCH2). 13C NMR (CDCl3) (E isomer): d 165.2,
156.5, 132.5, 132.4, 128.7, 122.6, 121.9, 113.2, 71.0, 68.6,
67.9, 39.1. 1H NMR (CDCl3) (Z isomer): d 8.37 (s, 2H, NH),
8.19 (dd, 2H, JZ7.8, 1.4 Hz), 7.43 (m, 2H), 7.11 (t, 2H, JZ
7.3 Hz), 6.94 (d, 2H, JZ8.2 Hz), 5.80 (t, 2H, JZ3.9 Hz,
CH]), 4.27 (m, 4H, OCH2), 4.18 (d, 2H, JZ3.9 Hz,
3.98 (br, 4H, OCH2CH]), 3.78 (m, 4H, OCH2CH2). 13C
NMR (CDCl3) (E isomer): d 166.5, 148.5, 147.5, 129.1,
127.4, 124.4, 123.8, 121.7, 120.3, 117.6, 112.2, 71.2, 70.5,
69.0, 68.3. Anal. Calcd For C30H32N2O8 (548.6): C 65.68; H
5.88; N 5.11. Found: C 65.92; H 6.02; N 4.99.
OCH2CH]), 3.88 (m, 4H, OCH2), 3.62 (m, 4H, NCH2). 13
C
3.1.11.16. Compound 7a. (E and Z): Yield 116 mg
(91%), colorless crystals (EtOH/CHCl3), mp 271–272 8C.
LCMS; m/zZ637 (MC1). IR: 3392, 3059, 2919, 1687,
NMR (CDCl3) (Z isomer): d 165.3, 156.6, 132.4, 132.3,
128.3, 122.5, 121.7, 11.8, 68.7, 68.1, 67.0, 39.2. Anal. Calcd
for C24H28N2O6 (440.5): C 65.44; H 6.41; N 6.36. Found: C
65.33; H 6.39; N 6.54.
1
1599, 1534, 1456, 1253, 1213, 1054, 1044, 966, 749. H
NMR (CDCl3) (E isomer): d 8.37 (s, 2H, NH), 7.94 (d, 2H,
JZ8.9 Hz), 7.90 (dd, 2H, JZ8.0, 1.6 Hz), 7.74 (m, 2H),
7.48 (d, 2H, JZ8.9 Hz), 7.29 (m, 4H), 7.19 (m, 2H), 7.05
(dt, 2H, JZ7.9, 1.6 Hz), 6.94 (dt, 2H, JZ7.8, 1.1 Hz), 6.82
(dd, 2H, JZ8.2, 1.2 Hz), 5.98 (t, 2H, JZ2.2 Hz, CH]),
4.61 (d, 2H, JZ15.4 Hz, OCH2CO), 4.43 (d, 4H, JZ2.2 Hz,
CH2CH]), 4.37 (d, 2H, JZ15.4 Hz, OCH2CO). 13C NMR
(CDCl3) (E isomer): d 166.3, 153.9, 147.6, 133.6, 130.5,
130.4, 128.0, 127.2, 127.1, 126.2, 125.1, 125.0, 124.6,
121.6, 121.2 (2C), 117.7, 111.3, 71.6, 67.9. 1H NMR
(CDCl3) (Z isomer): d 8.70 (s, 2H, NH), 8.09 (dd, 2H, JZ
7.9, 1.8 Hz), 8.00 (d, 2H, JZ8.8 Hz), 7.74 (m, 2H), 7.49 (d,
2H, JZ8.8 Hz), 7.41 (t, 2H, JZ7.6 Hz), 7.29 (m, 2H), 7.19
(m, 2H), 7.13 (d, 2H, JZ8.6 Hz), 6.98 (dt, 2H, JZ7.8,
1.5 Hz), 6.82 (dd, 2H, JZ8.2, 1.2 Hz), 5.47 (t, 2H, JZ4 Hz,
CH]), 4.52 (d, 2H, JZ15.9 Hz, OCH2CO), 4.49 (d, 4H,
JZ4 Hz, CH2CH]), 4.40 (d, 2H, JZ15.9 Hz, OCH2CO).
13C NMR (CDCl3) (Z isomer): d 166.8, 153.2, 147.8, 133.9,
130.4, 130.1, 128.4, 128.2, 127.1, 127.0, 125.5, 124.8,
124.7, 121.9, 121.5, 120.1, 115.8, 112.9, 69.8, 64.9. Anal.
Calcd for C40H32N2O6 (636.7): C 75.46; H 5.07; N 4.40.
Found: C 75.64; H 5.02; N 4.45.
3.1.11.13. Compound 5. (E and Z): Yield 57 mg (60%),
colorless crystals (CH2Cl2), mp 208–209 8C, purified using
column chromatography with eluent DCM/pet. ether
(40–60)/EtOAc, RfZ0.3 [DCM/pet. ether (40–60)/EtOAc
6:4:2]. 2:1. LCMS; m/zZ489 (MC1). IR: 3303, 3072,
3007, 2931, 2863, 1664, 1600, 1536, 1475, 1454, 1303,
1
1233, 1162, 1124, 1099, 1047, 756. H NMR (CDCl3) (E
isomer): d 9.73 (s, 2H, NH), 8.00 (dd, 2H, JZ7.7, 1.3 Hz),
7.81 (m, 2H), 7.43 (dt, 2H, JZ7.2, 1.7 Hz), 7.28 (m, 2H),
7.11 (t, 2H, JZ7.7 Hz), 6.97 (d, 2H, JZ8.3 Hz), 5.47 (s,
2H, CH]), 4.24 (t, 4H, JZ4.2 Hz, OCH2), 3.92 (m, 4H,
OCH2CH]), 3.71 (t, 4H, JZ4.32 Hz, OCH2). 13C NMR
(CDCl3) (E isomer): d 164.8, 156.5, 132.6, 131.4, 131.2,
129.6, 125.9, 125.1, 121.6, 113.1, 71.0, 69.2, 67.2. 1H NMR
(CDCl3) (Z isomer): d 9.81 (s, 2H, NH), 8.11 (dd, 2H, JZ
7.9, 1.5 Hz), 7.99 (m, 2H), 7.43 (dt, 2H, JZ7.2, 1.7 Hz),
7.28 (m, 2H), 7.11 (t, 2H, JZ7.7 Hz), 6.97 (d, 2H, JZ
8.3 Hz), 5.32 (t, 2H, JZ5.3 Hz, CH]), 4.11 (t, 4H, JZ
4.3 Hz, CH2), 3.96 (d, 4H, JZ5.3 Hz, OCH2CH]), 3.66 (t,
4H, JZ4.3 Hz, OCH2). 13C NMR (CDCl3) (Z isomer): d
164.1, 156.3, 132.8, 132.2, 129.0, 125.7, 124.9, 123.9,
121.9, 113.6, 69.0, 67.7, 66.0. Anal. Calcd for C28H28N2O6
(488.6): C 68.84; H 5.78; N 5.73. Found: C 67.22; H 5.87; N
5.85.
3.1.11.17. Compound 7b. (E and Z): Yield 140 mg
(97%), colorless crystals (EtOH), mp 212–213 8C. LCMS;
m/zZ725 (MC1). IR: 3397, 2922, 1707, 1686, 1535, 1456,
1
1362, 1255, 1219, 1117, 912, 753. H NMR (CDCl3) (E
3.1.11.14. Compound 6a. (E and Z): Yield 846 mg
(92%), colorless crystals (EtOH), mp 203–204 8C. LCMS;
m/zZ461 (MC1). IR: 3393, 3066, 1674, 1599, 1537, 1502,
1488, 1453, 1387, 1335, 1292, 1248, 1204, 1189, 1125,
1044, 961, 752. 1H NMR (CDCl3) (E isomer): 8.98 (s, 2H,
NH), 8.42 (dd, 2H, JZ7.9, 1.3 Hz), 7.12 (dt, 2H, JZ8.0,
1.5 Hz), 7.06 (m, 6H), 6.93 (d, 2H, JZ7.4 Hz), 6.14 (s, 2H,
CH]), 4.71 (s, 4H, OCH2CO), 4.57 (s, 4H, OCH2CH]).
13C NMR (CDCl3) (E isomer): d: 166.5, 147.9, 147.3, 127.0,
126.9, 124.6, 123.5, 121.6, 120.6, 115.5, 111.5, 70.2, 68.1.
1H NMR (CDCl3) (Z isomer): d 9.07 (s, 2H, NH), 8.42 (dd,
2H, JZ7.9, 1.3 Hz), 7.06 (m, 8H), 6.93 (d, 2H, JZ7.4 Hz),
5.94 (t, 2H, JZ4.1 Hz, CH]), 4.69 (s, 4H, OCH2CO), 4.65
(d, 4H, JZ4.1 Hz, OCH2CH]). Anal. Calcd for
C26H24N2O6 (460.5): C 67.82; H 5.25; N 6.08. Found: C
67.53; H 5.37; N 6.13.
isomer): d 8.73 (s, 2H, NH), 8.17 (dd, 2H, JZ7.8, 1.6 Hz),
8.00 (d, 2H, JZ8.9 Hz), 7.88 (d, 2H, JZ8.2 Hz), 7.47 (d,
2H, JZ8.9 Hz), 7.37 (dt, 2H, JZ8.1, 1.1 Hz), 7.27 (dt, 2H,
JZ7.1, 1.2 Hz), 7.16 (d, 2H, JZ8.4 Hz), 7.03 (dt, 2H, JZ
7.8, 1.6 Hz), 6.96 (dt, 2H, JZ7.8, 1.2 Hz), 6.84 (dd, 2H,
JZ8.1, 1.3 Hz), 5.33 (t, 2H, JZ2.8 Hz, CH]), 4.65 (d, 2H,
JZ15.6 Hz, OCH2CO), 4.33 (d, 2H, JZ15.6 Hz,
OCH2CO), 4.00 (m, 4H, OCH2CH2), 3.60 (dd, 2H, JZ
12.2, 2.8 Hz, OCH2CH]), 3.51 (m, 2H, OCH2CH2), 3.40
(dd, 2H, JZ12.2, 2.8 Hz, OCH2CH]), 3.24 (m, 2H,
OCH2CH2). 13C NMR (CDCl3) (E isomer): d 166.9,
153.8, 147.8, 133.8, 130.5, 130.3, 128.9, 128.1, 127.3,
127.1, 125.5, 124.7, 124.3, 121.6, 120.9, 120.5, 117.2,
112.6, 68.3, 69.2, 71.0, 71.1. 1H NMR (CDCl3) (Z isomer): d
8.64 (s, 2H, NH), 8.13 (dd, 2H, JZ8.0, 1.6 Hz), 8.01 (d, 2H,
JZ8.9 Hz), 7.85 (d, 2H, JZ8.2 Hz), 7.49 (d, 2H, JZ
8.9 Hz), 7.38 (dt, 2H, JZ8.1, 1.1 Hz), 7.27 (dt, 2H, JZ6.8,
1.2 Hz), 7.16 (d, 2H, JZ8.4 Hz), 7.03 (dt, 2H, JZ7.8,
1.6 Hz), 6.96 (dt, 2H, JZ7.8, 1.2 Hz), 6.82 (dd, 2H, JZ8.1,
1.3 Hz), 5.43 (t, 2H, JZ3.5 Hz, CH]), 4.63 (d, 2H, JZ
15.6 Hz, OCH2CO), 4.45 (d, 2H, JZ15.6 Hz, OCH2CO),
4.00 (m, 4H, OCH2CH2), 3.67 (dd, 2H, JZ12.2, 3.5 Hz,
OCH2CH]), 3.53 (dd, 2H, JZ12.2, 3.5 Hz, OCH2CH]),
3.51 (m, 2H, OCH2CH2), 3.24 (m, 2H, OCH2CH2).13C
NMR (CDCl3) (Z isomer): d 166.6, 153.8, 147.8, 133.7,
130.3, 130.0, 128.9, 128.1, 127.1, 126.8, 125.3, 124.8,
3.1.11.15. Compound 6b. (E): Yield 80 mg (73%),
colorless crystals, mp 160–161 8C, purified using column
chromatography with eluent DCM/pet. ether (40–60), RfZ
0.3 [DCM/pet. ether (40–60)/EtOAc 2:1:1]. LCMS; m/zZ
549 (MC1). IR: 3577, 3391, 2922, 2846, 1689, 1600, 1533,
1
1499, 1454, 1254, 1117, 1048, 750. H NMR (CDCl3) (E
isomer): d 9.26 (s, 2H, NH), 8.42 (dd, 2H, JZ8.0, 1.5 Hz),
7.17–7.02 (m, 10H), 6.93 (d, 2H, JZ8.0 Hz), 5.81 (s, 2H,
CH]), 4.76 (s, 4H, OCH2CO), 4.25 (m, 4H, OCH2CH2),

Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
1013
124.6, 121.4, 121.3, 120.6, 116.9, 112.0, 70.9, 69.0, 68.0,
66.9. Anal. Calcd for C44H40N2O8 (724.8): C 72.91; H,
5.56; N, 3.86. Found: C 71.97; H 5.49; N 4.05.
OCH2CH]), 4.71 (s, 2H, OCH2CO), 4.62 (d, 2H, JZ5.3 Hz,
OCH2CH]). Anal. Calcd for C25H22N2O5 (430.5): C 69.76;
H 5.15; N 6.51. Found: C 60.86; H 5.18; N 6.55.
3.1.11.18. Compound 8a. (E and Z): Yield 130 mg
(100%), colorless crystals (EtOH), mp 205 8C. LCMS;
m/zZ651 (MC1). IR: 3396, 3351, 3070, 2938, 2867, 1691,
1649, 1601, 1535, 1484, 1454, 1374, 1292, 1249, 1206,
1161, 1116, 1043, 754. 1H NMR (CDCl3) (E isomer): d 9.10
(s, 2H, NH), 8.65 (s, 2H, NH), 8.36 (dd, 2H, JZ8.2, 1.7 Hz),
8.03 (d, 2H, JZ7.6 Hz), 7.30 (m, 2H), 7.03 (m, 4H), 6.93 (d,
2H, JZ8.3 Hz), 6.88–6.75 (m, 4H), 5.60 (s, 2H, CH]),
4.94 (s, 4H, OCH2CO), 4.21 (s, 4H, OCH2CH]), 3.72 (s,
4H, CH2N). 13C NMR (CDCl3) (E isomer): d 165.9, 165.6,
155.2, 147.5, 133.1, 132.4, 127.3, 124.7, 122.2, 121.5,
3.1.11.21. Compound 9b. (E and Z): Yield 78 mg (82%),
colorless crystals (EtOH/CHCl3), mp 215–216 8C. LCMS;
m/zZ475 (MC1). IR: 3342, 2919, 1667, 1599, 1533, 1482,
1
1455, 1294, 1229, 1120, 1092, 1007, 911, 746. H NMR
(CDCl3): (E isomer): 10.55 (s, 1H, NH), 9.04 (s, 1H, NH),
8.63 (dd, 1H, JZ8.6, 0.9 Hz), 8.35 (m, 2H), 7.52 (t, 1H, JZ
7.4 Hz), 7.19–6.96 (m, 8H), 6.21 (m, 1H, CH]), 5.97 (m,
1H, CH]), 4.78 (s, 2H, OCH2CH]), 4.66 (s, 2H,
OCH2CO), 4.24 (br, 2H, OCH2CH2), 4.02 (s, 2H,
1
OCH2CH]), 3.67 (br, 2H, OCH2CH2). H NMR (CDCl3)
(Z isomer): d 10.55 (s, 1H, NH), 8.82 (s, 1H, NH), 8.73 (d,
1H, JZ7.8 Hz), 8.38 (m, 2H), 7.52 (t, 1H, JZ7.3 Hz), 7.19–
6.96 (m, 7H), 6.87 (d, 1H, JZ7.7 Hz), 5.97 (m, 2H, CH]),
4.87 (d, 2H, JZ5.6 Hz, OCH2CH]), 4.80 (s, 2H,
OCH2CO), 4.26 (d, 2H, JZ5.6 Hz, OCH2CH]), 4.08 (br,
2H, OCH2CH2), 3.66 (br, 2H, OCH2CH2). Anal. Calcd for
C27H26N2O6 (474.5): C 68.34; H 5.52; N 5.90. Found: C
67.41; H 5.40; N 6.06.
1
120.4, 112.1, 111.9, 68.5, 68.3, 41.4. H NMR (CDCl3) (Z
isomer): d 8.89 (s, 2H, NH), 8.73 (s, 2H, NH), 8.44 (m, 2H),
8.08 (d, 2H, JZ8.3 Hz), 7.33 (m, 2H), 7.03 (m, 4H), 6.89–
6.77 (m, 2H), 6.66 (m, 2H), 5.75 (t, 2H, JZ3.4 Hz, CH]),
4.94 (s, 4H, OCH2CO), 4.24 (d, 4H, JZ3.4 Hz,
OCH2CH]), 3.84 (s, 4H, CH2N). 13C NMR (CDCl3) (Z
isomer): d 165.9, 165.6, 155.2, 146.8, 133.1, 132.4, 127.3,
124.7, 122.2, 121.5, 120.4, 112.1, 111.9, 68.5, 68.3, 41.4.
Anal. Calcd for C36H34N4O8 (650.7): C 66.45; H 5.27; N
8.61. Found: C 66.19; H 5.45; N 8.34.
Acknowledgements
3.1.11.19. Compound 8b. (E and Z): Yield 118 mg
(80%), colorless crystals [EtOAc/pet. ether (40–60)], mp
174–175 8C. LCMS; m/zZ739 (MC1). IR: 3397, 3353,
2931, 2872, 1687, 1642, 1602, 1539, 1484, 1454, 1299,
The support of the University of Kuwait received through
research grant no. SC10/02 and the facilities of ANALAB
and SAF (grant nos. GS01/01, GS03/01) are gratefully
acknowledged.
1
1255, 1208, 1162, 1118, 1045, 909, 732, 649. H NMR
(CDCl3) (E isomer): d 8.71 (s, 2H, NH), 8.60 (s, 2H, NH),
8.28 (dd, 2H, JZ7.7, 1.2 Hz), 8.04 (d, 2H, JZ7.7 Hz), 7.28
(t, 2H, JZ7.7 Hz), 7.10–6.80 (m, 10H), 5.74 (s, 2H, CH]),
4.83 (s, 4H, OCH2CO), 4.13 (m, 4H, OCH2), 3.89 (s, 4H,
OCH2CH]), 3.82 (m, 4H, OCH2CH2), 3.50 (s, 4H,
OCH2N). 13C NMR (CDCl3) (E isomer): d 166.2, 164.9,
155.5, 147.3, 132.8, 132.0, 128.7 (2C), 127.5, 124.5, 122.3,
References and notes
1. (a) For reviews see (a) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413–4450. (b) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012–3043. (c) Armstrong, S. K. J. Chem. Soc.,
Perkin Trans. 1 1998, 371–388. (d) Yet, L. Chem. Rev. 2000,
100, 2963–3007. (e) Martin, S. F.; Deiter, A. Chem. Rev. 2004,
104, 2199–2238.
1
122.0, 120.8, 113.1, 112.5, 70.9, 68.7, 68.6, 68.5, 40.5. H
NMR (CDCl3) (Z isomer): d 8.83 (s, 2H, NH), 8.51 (s, 2H,
NH), 8.28 (dd, 2H, JZ7.7, 1.2 Hz), 8.04 (d, 2H, JZ7.7 Hz),
7.35 (t, 2H, JZ8.4 Hz), 7.10–6.80 (m, 10H), 5.52 (t, 2H,
JZ4.2 Hz, CH]), 4.85 (s, 4H, OCH2CO), 4.13 (m, 8H,
OCH2CH2, OCH2CH]), 3.82 (m, 4H, OCH2CH2), 3.50 (m,
4H, OCH2N). 13C NMR (CDCl3) (Z isomer): d 166.1, 166.0,
155.7, 147.7, 132.9, 132.1, 129.1, 128.7 (2C), 124.8, 122.5,
122.3, 120.9, 113.1, 112.5, 69.3, 69.0, 68.4, 66.7, 40.8.
Anal. Calcd for C40H42N4O10 (738.8): C 65.03; H 5.73; N
7.58. Found: C 65.45; H 5.54; N 8.37.
2. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995,
28, 446–552, and references therein.
3. Xu, Z.; Johannes, C. W.; Salman, S. S.; Hoyveda, A. H. J. Am.
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3942–3943.
¨
6. (a) Konig, B.; Horn, C. Synlett 1996, 1013–1014. (b) Marsella,
3.1.11.20. Compound 9a. (E and Z): Yield 65 mg (75%),
colorless crystals [EtOAc/pet. ether (40–60)], mp 192 8C.
LCMS; m/zZ431 (MC1). IR: 3398, 1690, 1662, 1599, 1531,
1483, 1455, 1329, 1294, 1254, 1235, 1043, 1002, 966, 750.
1H NMR (CDCl3) (E): d 9.80 (s, 1H, NH), 8.88 (s, 1H, NH),
8.49 (m, 1H), 8.29 (m, 2H), 7.53 (dt, 1H, JZ7.8, 1.2 Hz),
7.18 (t, 1H, JZ7.6 Hz), 7.10–7.04 (m, 5H), 6.96 (m, 1H),
6.90 (dd, 1H, JZ7.8, 1.0 Hz), 6.47 (m, 1H, CH]), 6.17 (m,
1H, CH]), 4.77 (br, 2H, OCH2CH]), 4.76 (s, 2H,
M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int. Ed.
1997, 36, 1101–1103. (c) Maynard, H. D.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 4137–4140. (d) Delgado, M.;
Martin, J. D. Tetrahedron Lett. 1997, 38, 8387–8390. (e)
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602–609.
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E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.;
Horwitz, S. J. Am. Chem. Soc. 1997, 119, 2733–2734.
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1
OCH2CO), 4.60 (br, 2H, OCH2CH]). H NMR (CDCl3)
(Z): d 9.80 (s, 1H, NH), 9.00 (s, 1H, NH), 8.40 (m, 2H), 8.23
(m, 1H), 7.50 (t, 1H, JZ7.8 Hz), 7.18–7.04 (m, 6H), 6.96 (m,
2H), 6.45 (t, 2H, JZ5.3 Hz, CH]), 4.89 (d, 2H, JZ5.3 Hz,

1014
Y. A. Ibrahim, E. John / Tetrahedron 62 (2006) 1001–1014
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