Synthesis of olefinic crown diamides and their conversion into pyrazolino macrocycles: Promising photoluminescent crown compounds

Article abstract of DOI:10.1055/s-2006-942540

Macrocyclic crown diamides with 16- or 24-membered rings containing E- and Z-olefinic double bonds were synthesized either by bisalkylation or by ring-closing metathesis (RCM) techniques. The two methods were evaluated and compared with regard to yield and to product stereochemistry. Isomerization of some Z-olefinic macrocycles to their corresponding E-isomers was achieved using Grubbs' catalyst second generation. Some of the required starting dials, diols and bishalo compounds were prepared by different routes including cross-metathesis (CM). The latter was compared with other investigated methods. Some of the olefinic macrocycles were subjected to cycloaddition reactions with diphenylnitrileimine to give the corresponding pyrazolino macrocycles. The latter showed interesting emission spectra. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942540

PAPER
3261
Synthesis of Olefinic Crown Diamides and their Conversion into Pyrazolino
Macrocycles: Promising Photoluminescent Crown Compounds
Synthesis of
Olef
a
inic Crown
n
D
iamides an
a
d
their Conversio
N
nto Pyrazolino
M
.
acrocycle
s
Malhas, Yehia A. Ibrahim*
Chemistry Department, Faculty of Science, Kuwait University, P. O. Box 5969, Safat 13060, Kuwait
Fax +9654816482; E-mail: yehiaai@kuc01.kuniv.edu.kw
Received 16 May 2006; revised 19 June 2006
PCy3
Abstract: Macrocyclic crown diamides with 16- or 24-membered
rings containing E- and Z-olefinic double bonds were synthesized
either by bisalkylation or by ring-closing metathesis (RCM) tech-
niques. The two methods were evaluated and compared with regard
to yield and to product stereochemistry. Isomerization of some Z-
olefinic macrocycles to their corresponding E-isomers was
achieved using Grubbs’ catalyst second generation. Some of the re-
quired starting dials, diols and bishalo compounds were prepared by
different routes including cross-metathesis (CM). The latter was
compared with other investigated methods. Some of the olefinic
macrocycles were subjected to cycloaddition reactions with diphe-
nylnitrileimine to give the corresponding pyrazolino macrocycles.
The latter showed interesting emission spectra.
N
Mes
Ph
Mes
Cl
N
Cl
Cl
Ru
Ru
Ph
PCy3
Cl
PCy3
I
II
Figure 1 Grubbs’ catalysts
In the present study the effect of Grubbs’ catalysts I and
II on the RCM reactions of 1a–c regarding the yield and
the stereoselectivity of the E- and Z-olefinic macrocyclic
crown diamides was investigated. Thus, RCM of the 1,w-
dienes 1a–c using catalysts I and II (Scheme 1) gave a
mixture of the corresponding isomeric macrocycles 2a–c
and 3a–c, in the yields and E:Z ratios shown in Table 1.
Key words: ring-closing metathesis, E,Z isomerization, macrocy-
clic ether amides, cycloaddition, pyrazolino macrocycles
From Table 1 it is clear that catalyst II is more active and
leads to higher yield of the E-isomer. Thus, 2.5% and
1.25% of catalyst I are needed to accomplish the RCM of
1a and 1b, respectively (entries 1 and 3). However, only
1% of catalyst II is needed to achieve better RCM conver-
sions (entries 2 and 4). On the other hand, RCM of 1c re-
quired 5% of either of the catalyst I or II to achieve 70%
and 93% conversions, respectively (as monitored by
TLC). Table 1 shows also the reported RCM synthesis of
6a,b and 7a,b from the corresponding appropriate 1,w-
dienes 5a,b using catalyst I.4a
Crown compounds and azacrown compounds constitute
important macrocyclic groups in supramolecular chemis-
try. They have been shown to exhibit important applica-
tions including selective ion separation, detection,
molecular recognition, catalysis, biological applications
as well as many other interesting uses in diverse fields of
supramolecular chemistry.1–3 Of particular interest are
crown ethers incorporating amide groups, since such
groups modify the binding properties of the crown com-
pounds in favor of alkaline earth cations over alkali metal
ions. Moreover, the number of ether oxygen atoms, amide
carbonyl groups, ring size, lipophilic groups and other
structural features control the selectivity towards different
ions.2–7
It is also concluded from these results that Grubbs’ cata-
lyst II not only improved the yield of the RCM product
but also increased the selectivity towards the E isomer.
Therefore, in the present study we also investigated the
possibility of Z-to-E isomerization of these olefinic mac-
rocycles. Thus, treatment of 2a and 6a with Grubbs’ cata-
lyst I showed complete recovery of unchanged starting
materials. On the other hand, treatment of 2a, 6a and 6b
with 1% of catalyst II led to 92% conversion of 2a into 3a
(entry 7), 93% conversion of 6a into 7a (entry 10) and
100% conversion of 6b into 7b (entry 11). The Z-to-E
isomerization promoted by Grubbs’ catalyst II is derived
by two factors which are the more thermodynamic stabil-
ity of the E isomer and by the reactivity of this catalyst to-
wards polysubstituted olefins.11
During the past decade, ring-closing metathesis (RCM)
has emerged as a powerful tool for the construction of
small-, medium- and large-ring systems.8 A large part of
the success of this reaction has been due to the availability
of well-defined catalysts such as those developed by
Schrock9 and Grubbs.10
In the present work the synthesis of each of the E and Z
stereoisomers of macrocyclic crown diamides 2a–c, 3a–c,
6a–c and 7a–c with 16- and 24-membered rings was in-
vestigated by bisalkylation and also as E:Z mixtures by
ring-closing metathesis using Grubbs’ catalysts I and II
(Figure 1).
The pure Z macrocycles 2a-c were readily obtained in
42–50% yields via bisalkylation of the dipostassium salts
4a-c with (Z)-1,4-dichloro-2-butene in N,N-dimethyl-
formamide. The pure E isomers 3a-c were similarly ob-
tained in 68-80% yields by treatment of 4a-c with (E)-
1,4-dichloro-2-butene. Similar bisalkylation of 4a–c with
SYNTHESIS 2006, No. 19, pp 3261–3269
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.08.2006
DOI: 10.1055/s-2006-942540; Art ID: T07906SS
© Georg Thieme Verlag Stuttgart · New York

3262
R. N. Malhas, Y. A. Ibrahim
PAPER
Table 1 Catalysts, Yields and Z/E Ratios of Macrocycles
Table 2 Catalysts, Yields and Z/E Ratios of CM Products
Entry
Substrate Catalyst
(conditions)
Product Yield (%) Z/E ratio
Entry
Substrate
Catalyst
Yield (%)
Products
(Z:E ratio)
(conditions)a
1
2
1a
1a
1b
1b
1c
1c
2a
5a
5b
6a
6b
Ia
2a, 3a
2a, 3a
2b, 3b
2b, 3b
2c, 3c
2c, 3c
2a, 3a
6a, 7a
6b, 7b
6a, 7a
7b
604a
85
1:5.7
1:15
1:1.1
1:1.5
1:1.6
1:4
1
2
3
4
5
6
7
11
15
15
16
16
17
17
II
89
13
61
32
34
30
70
11, 12
(1:7.8)
IIb
Ic
I
11, 12
(1:2)
3
1004a
100
70
4
IIb
Id
II
I
11, 12
(1:14)
5
13, 14
(1:2)
6
IId
IIb
Ia
93
7
92
1:11
1:7
II
I
13, 14
(1:5)
8
1004a
984a
93
8, 9
(1:1.6)
9
Ia
1:2.3
1:15
10
11
IIb
IIb
II
8, 9
(1:7)
100
a Substrate (1 mM), catalysts I or II (1%), CH2Cl2 (10 mL), reflux, 2
h.
a Substrate (1 mM), Grubbs’ catalyst (2.5%), CH2Cl2 (10 mL), reflux,
2 h.
b Substrate (1 mM), Grubbs’ catalyst (1%), CH2Cl2 (10 mL), reflux,
2 h.
c Substrate (1 mM), Grubbs’ catalyst (1.25%), CH2Cl2 (10 mL), re-
flux, 2 h.
ucts from the reaction of allylbenzene with o-
allyloxybenzaldehyde using Grubbs’ catalyst I.12
d Substrate (1 M), Grubbs’ catalyst (5%), CH2Cl2 (10 mL), reflux, 2 h.
The E/Z selectivity and isomerization in RCM reactions
and practical solutions to this problem have been ad-
dressed in many reviews; e.g., the Prunet review13a as well
as other papers.13b–d The problem has also been discussed
in Blechert’s review on cross-metathesis13e and in
Schmidt’s review on olefin metathesis.13f
(Z)-1,4-bis(o-chloromethylphenoxy)-2-butene 8 and its E
isomer 9 gave the corresponding Z macrocycles 6a–c (11–
49%) and their E isomers 7a–c (39–56%), respectively.
The starting materials 8 and 9 required for the synthesis of
the macrocycles 6 and 7 were obtained as outlined in
Scheme 2 using two synthetic approaches.
Cycloaddition of the olefinic crown diamides 2a,b and
3a,b with diphenylnitrileimine gave the corresponding
condensed pyrazolino macrocycles 18a,b and 19a,b, re-
spectively (Scheme 3). The latter exhibited absorption
and interesting emission spectra in the UV-Vis region.
The first synthetic approach (Scheme 2) starts with the re-
action of the potassium salt of salicylaldehyde 10 with
(Z)-1,4-dichloro-2-butene and (E)-1,4-dichloro-2-butene
to give (Z)-1,4-bis(o-formylphenoxy)-2-butene 11 and the
corresponding E isomer 12, respectively. Reduction of 11
and 12 with sodium borohydride in methanol gave the
corresponding diols 13 and 14, respectively. Reaction of
compounds 13 and 14 with thionyl chloride in chloroform
gave the corresponding bischloro compounds 8 and 9, re-
spectively, in 95% yield.
Compounds 18, 19 showed absorption bands at lmax
284–360 nm and emission bands at lmax = 436–463 nm.
=
In conclusion, RCM and CM techniques have shown to
give efficient access to macrocycles and the required pre-
cursor bisolefinic compounds. The application of Grubbs’
catalysts of 1st and 2nd generation showed different behav-
ior towards their efficiency and E:Z ratios. Comparison
with other synthetic methods illustrates the synthetic po-
tentialities of these novel catalytic techniques. The con-
version of these olefinic macrocycles to photoluminescent
pyrazolino derivatives paves the path for future applica-
tions.
The second synthetic method (Scheme 2) attempted was
the CM of o-allyloxybenzaldehyde (15), o-allyloxybenzyl
alcohol (16) and o-allyloxybenzyl chloride (17) using
Grubbs’ catalysts I and II. Results of CM are shown in
Table 2. From Table 2 it is clear that the CM reactions can
convert 15, 16 and 17 to the required product; however, as
a mixture of E and Z isomers. It is also clear that Grubbs’
catalyst II gave better yield with better E selectivity com-
pared to the same percent of catalyst I. Also, compound
11 was isomerized to the E isomer 12 with 89% conver-
sion. Compounds 11 and 12 were also obtained as byprod-
Melting points are uncorrected. IR spectra were recorded in KBr
disks on a 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 at 400 MHz and 100
MHz, respectively. 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/
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

PAPER
Synthesis of Olefinic Crown Diamides and their Conversion to Pyrazolino Macrocycles
3263
O
O
O
O
O
O
RCM
+
O
O
O
O
O
O
catalyst I or II
NH
NH
HN
HN
NH
HN
Y
Y
Y
1a–c
2a–c
3a–c
Cl
Br
Cl
Cl
68–80%
Cl
42–50%
HO
KO
NH
OH
O
OK
O
O
O
KOH/MeOH
NH
HN
HN
Y
Y
4a–c
O
O
O
O
O
Cl
Cl
Cl
Cl
Cl
8
9
11–49%
39–56%
O
O
O
O
O
O
O
O
RCM
+
O
O
O
O
O
catalyst I or II
O
O
O
O
O
NH
HN
NH
HN
NH
HN
Y
Y
Y
5a,b
6a–c
7a–c
a: Y = (CH2)2; b: Y = 1,2-C6H4; c: Y = 1,2-C6H10
Scheme 1
APCI ionization mode. The UV–Vis spectra were recorded on a
Cary-5/Varian spectrophotometer and the emission spectra were re-
corded using a SIM AMINCO.BOWMAN series Luminescence
spectrometer. Microanalyses were performed on a LECO CHNS-
932 Elemental Analyzer. The UV-Vis absorption spectra of com-
pounds 18a,b, 19a,b were scanned in chloroform at concentrations
1.0 × 10–4 M, 9.4 × 10–5 M, 1.4 × 10–4 M, 3.7 × 10–5 M, respectively,
in the wavelength range 250–450 nm using a dry, clean, quartz cu-
vette of 1.0 cm path length. From the spectra obtained, absorbance
values at lmax were used to calculate the extinction coefficient. The
emission spectra of compounds 18a,b, 19a,b in chloroform at the
above-mentioned concentrations were obtained after excitation at
l = 294, 285, 360, 284 nm, respectively.
1,2-Bis(2-hydroxybenzamido)cyclohexane
A mixture of 1,2-cyclohexanediamine (cis and trans isomers; 5.0 g,
43.8 mmol) and methyl salicylate (11.3 g, 87.4 mmol) was heated
on a steam bath for 5 h. After cooling, the mixture was recrystallized
from EtOH to give colorless crystals; yield: 8.4 g (54%); mp 238–
239 °C.
IR: 3380, 3319, 3077, 2943, 2856, 2772, 1635, 1595, 1547, 1488,
1444, 1344, 1250, 1220, 1145, 815, 756 cm–1.
1H NMR (DMSO): d = 1.33 (d, J = 9.7 Hz, 2 H), 1.51 (d, J = 9.7 Hz,
2 H), 1.74 (d, J = 7.9 Hz, 2 H), 1.94 (d, J = 12.0 Hz, 2 H), 4.02 (br,
2 H), 6.82 (m, 4 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.76 (d, J = 7.5 Hz, 2
H), 8.71 (br, 2 H, NH), 12.21 (br, 2 H, OH).
13C NMR (CDCl3): d = 22.6, 29.6, 50.2, 113.3, 115.3, 116.3, 125.9,
131.4, 158.1, 166.6.
MS: m/z = 354 [M+].
The starting compounds 1a,14 1,2-bis(2-hydroxybenzami-
do)ethane15 and 1,2-bis(2-hydroxybenzamido)benzene15 were pre-
pared as reported.
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

3264
R. N. Malhas, Y. A. Ibrahim
PAPER
OK
O
10
i
ii
87%
86%
Br
O
O
O
O
O
O
O
CM
I or II
+
O
O
O
11
12
15
iii 66%
iii 68%
iii
O
O
O
O
O
CM
I or II
+
OH
OH
OH
OH
OH
13
14
16
iv 95%
iv 95%
iv
O
CM
9
8
+
I or II
Cl
17
Scheme 2 Reagents and conditions: i) (Z)-1,4-dichloro-2-butene, DMF, 15 min reflux; ii) (E)-1,4-dichloro-2-butene, DMF, 15 min reflux; iii)
NaBH4, MeOH, stirring, 0–5 °C; iv) SOCl2, CHCl3, stirring, 2 h.
Anal. Calcd for C20H22N2O4 (354.41): C, 67.78; H, 6.26; N, 7.95.
Found: C, 67.52; H, 6.48; N, 8.22.
2a,b
3a,b
PhCClNNHPh
TEA, CHCl3
reflux, 24 h
PhCClNNHPh
TEA, CHCl3
1,2-Bis(2-allyloxybenzamido)benzene (1b)
A solution of 1,2-bis(2-hydroxybenzamido)benzene15 (0.35 g, 1
mmol) and KOH (0.12 g, 2 mmol) in MeOH (5 mL) was stirred for
5 min and the solvent was then removed in vacuo to give the corre-
sponding potassium salt. To the latter were added DMF (10 mL)
and allyl bromide (2 mmol). The reaction mixture was then heated
under reflux for 15 min. The mixture was diluted with ice-water (20
mL). The precipitate was collected, washed with cold H2O and fi-
nally crystallized from EtOH to give colorless crystals; yield: 0.28
g (66%); mp 120–122 °C.4a
reflux, 24 h
N
N
N
H
N
H
H
O
H
O
O
O
O
O
O
O
1H NMR (CDCl3): d = 4.64 (d, J = 5.4 Hz, 4 H, OCH2), 5.15 (d, J =
10.5 Hz, 2 H, CH2=), 5.22 (d, J = 17.2 Hz, 2 H, CH2=), 5.88 (m, 2
H, CH=), 6.78 (d, J = 8.3 Hz, 2 H), 7.14 (t, J = 7.5 Hz, 2 H), 7.29
(m, 2 H), 7.46 (dt, J = 1.5, 8.5 Hz, 2 H), 7.81 (m, 2 H), 8.30 (dd,
J = 1.5, 7.8 Hz, 2 H), 9.91 (br, 2 H, NH).
NH
NH
HN
HN
Y
Y
18a: Y = (CH2)2; 53%
18b: Y = C6H4; 54%
19a: Y = (CH2)2; 55%
19b: Y = C6H4; 30%
13C NMR (CDCl3): d = 69.1 (CH2), 112.9, 119.1, 121.5, 121.7,
125.6, 126.0, 131.0, 131.8, 132.7, 133.2, 156.7, 164.1.
Scheme 3
MS: m/z = 428 [M+].
Anal. Calcd for C26H24N2O4 (428.49): C, 72.88; H, 5.65; N, 6.54.
Found: C, 72.58; H, 5.61; N, 6.48.
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

PAPER
Synthesis of Olefinic Crown Diamides and their Conversion to Pyrazolino Macrocycles
3265
1,2-Bis(2-allyloxybenzoylamino)cyclohexane (1c)
13C NMR (CDCl3): d = 40.6, 68.5, 113.0, 122.1, 122.2, 130.3, 132.4,
A solution of 1,2-bis(2-hydroxybenzamido)cyclohexane (0.35 g, 1
mmol) and KOH (0.12 g, 2 mmol) in MeOH (5 mL) was stirred for
5 min and the solvent was then removed in vacuo to give 4c. To the
latter, DMF (10 mL) and the allyl bromide (2 mmol) were added.
The reaction mixture was then heated under reflux for 15 min. The
mixture was diluted with ice-water (20 mL) and the precipitate was
collected, washed with cold H2O and crystallized from EtOH to
give colorless crystals; yield: 0.34 g (79%); mp 118–119 °C.
132.9, 156.5, 165.8.
MS: m/z = 352 [M+].
Anal. Calcd for C20H20N2O4 (352.4): C, 68.17; H, 5.72; N, 7.95.
Found: C, 68.01; H, 5.64; N. 8.05.
(Z)-1,12-Dioxa-5,8-diazatribenzo[b,f,j]cyclohexadec-14-ene-
4,9-dione (2b)
Prepared from 4b and cis-1,4-dichloro-2-butene; colorless crystals
IR: 3377, 3074, 2933, 2858, 1642, 1600, 1531, 1482, 1449, 1300,
1230, 995, 755 cm–1.
(EtOH); yield: 0.16 g (42%); mp 210–212 °C.
IR: 3387, 3312, 3072, 2957, 2890, 1664, 1598, 1537, 1478, 1455,
1294, 1230, 995, 951, 755 cm–1.
1H NMR (CDCl3): d = 4.77 (br, 4 H, OCH2), 6.19 (br, 2 H, CH=),
6.94 (d, J = 8.2 Hz, 2 H), 7.17 (t, J = 7.4 Hz, 2 H), 7.27 (m, 2 H),
7.48 (m, 2 H), 8.12 (m, 2 H), 8.34 (m, 2 H), 9.79 (br, 2 H, NH).
13C NMR (CDCl3): d = 63.8, 112.4, 121.5, 121.9, 124.4, 125.4,
129.4, 129.6, 133.1, 133.2, 155.4, 163.7.
1H NMR (CDCl3): d = 1.43–1.46 (m, 4 H), 1.81 (m, 2 H), 2.28 (d,
J = 12.9 Hz, 2 H), 4.06 (m, 2 H), 4.62–4.73 (m, 4 H), 5.29 (d, J =
10.7 Hz, 2 H), 5.37 (dd, J = 1.0, 17.2 Hz, 2 H), 6.03 (m, 2 H), 6.90
(d, J = 8.3 Hz, 2 H), 7.00 (t, J = 7.6 Hz, 2 H), 7.34–7.38 (dt, J = 1.7,
8.5 Hz, 2 H), 8.07–8.10 (dd, J = 1.7, 7.6 Hz, 2 H), 8.13 (br, 2 H,
NH).
13C NMR (CDCl3): d = 24.8, 32.8, 53.3, 69.8, 112.8, 118.8, 121.1 (2
overlapped signals), 132.0, 132.4, 132.42, 156.6, 165.3.
MS: m/z = 434 [M+].
MS: m/z = 400 [M+].
Anal. Calcd for C24H20N2O4 (400.4): C, 71.99; H, 5.03; N, 7.00.
Found: C, 71.71; H, 5.04; N, 7.10.
Anal. Calcd for C34H32N2O6 (434.54): C, 71.87; H, 6.96; N, 6.45.
Found: C, 71.71; H, 7.22; N, 6.72.
(E)-1,12-Dioxa-5,8-diazatribenzo[b,f,j]cyclohexadec-14-ene-
4,9-dione (3b)
Prepared from 4b and trans-1,4-dichloro-2-butene; colorless crys-
Synthesis of Macrocycles 2a–c, 3a–c, 6a–c, 7a–c via Bisalkyl-
ation; General procedure
tals (EtOH); yield: 0.28 g (68%); mp 280–282 °C.
A solution of each of the appropriate 1,2-bis(2-hydroxybenzoylami-
no) derivatives (1 mmol) and KOH (0.12 g, 2 mmol) in MeOH (5
mL) was stirred for 5 min and the solvent was then removed in vac-
uo to give the corresponding dipotassium salts 4a–c. To the latter
were added DMF (10 mL) and the appropriate dihalo derivatives (1
mmol). The reaction mixture was then heated under reflux for 15
min (during this time the potassium halide precipitated). The mix-
ture was diluted with ice-water (30 mL) and kept for 24 h in the
fridge. The precipitate was collected, washed with cold H2O and
crystallized from the proper solvent to give the corresponding mac-
rocycles 2a–c, 3a–c, 6a–c, 7a–c.
IR: 3333, 3069, 2958, 2878, 1662, 1597, 1532, 1470, 1453, 1309,
1287, 1233, 1089, 994, 974, 759 cm–1.
1H NMR (CDCl3): d = 4.58 (s, 4 H, OCH2), 5.98 (s, 2 H, CH=), 7.04
(d, J = 8.2 Hz, 2 H), 7.19 (t, J = 7.5 Hz, 2 H), 7.29 (m, 2 H), 7.49
(dt, J = 1.8, 7.4 Hz, 2 H), 7.85 (m, 2 H), 8.04 (dd, J = 1.7, 7.8 Hz, 2
H), 9.36 (br, 2 H, NH).
13C NMR (CDCl3): d = 70.9, 116.9, 123.1, 125.4, 126.1, 126.3,
128.3, 130.7, 131.6, 133.0, 155.1, 165.3.
MS: m/z = 400 [M+].
Anal. Calcd for C24H20N2O4 (400.4): C, 71.99; H, 5.03; N, 7.00.
Found: C, 71.77; H, 5.18; N, 7.11.
(Z)-1,12-Dioxa-5,8-diazadibenzo[b,j]cyclohexadec-14-ene-4,9-
dione (2a)
Prepared from 4a and cis-1,4-dichloro-2-butene; colorless crystals
(EtOH); yield: 0.18 g (50%); mp 189–190 °C.
(Z)-1,12-Dioxa-5,8-diazadibenzo[b,j]cyclohexano[f]cyclohexa-
dec-14-ene-4,9-dione (2c)
Prepared from 4c and cis-1,4-dichloro-2-butene; colorless crystals
IR: 3404, 3064, 2941, 2887, 1651, 1639, 1599, 1533, 1482, 1299,
1219, 995, 759 cm–1.
1H NMR (CDCl3): d = 3.72 (br, 4 H, NCH2), 4.80 (d, J = 4.6 Hz, 4
H, OCH2), 6.19 (t, J = 4.6 Hz, 2 H, CH=), 7.05 (d, J = 8.3 Hz, 2 H),
7.14 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 2 H), 8.14 (br, 2 H, NH),
8.22 (d, J = 7.6 Hz, 2 H).
13C NMR (CDCl3): d = 39.5, 63.1, 112.9, 122.1, 122.5, 129.7, 132.4,
132.7, 156.1, 165.3.
MS: m/z = 352 [M+].
(EtOH); yield: 0.19 g (46%); mp 104–106 °C.
IR: 3377, 2991, 2935, 2861, 1641, 1533, 1483, 1300, 1227, 1004,
753 cm–1.
1H NMR (CDCl3): d = 1.31–1.40 (m, 4 H), 1.77 (br, 2 H), 2.25 (m,
2 H), 4.02 (s, 2 H), 4.73–4.81 (m, 4 H), 5.95 (s, 2 H, CH=), 6.84–
6.89 (m, 2 H), 6.93–7.04 (m, 2 H), 7.31 (s, 2 H, NH), 7.99–8.07 (m,
4 H).
13C NMR (CDCl3): d = 24.9, 32.8, 53.1 65.7, 112.6, 122.0, 128.5,
128.6, 131.9, 132.0, 156.3, 165.1.
Anal. Calcd for C20H20N2O4 (352.4): C, 68.17; H, 5.72; N, 7.95.
Found: C, 67.93; H, 5.47; N, 7.81.
LCMS: m/z = 407 [M + 1].
Anal. Calcd for C24H26N2O4 (406.5): C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.74; H, 6.15; N, 6.75.
(E)-1,12-Dioxa-5,8-diazadibenzo[b,j]cyclohexadec-14-ene-4,9-
dione (3a)
Prepared from 4a and trans-1,4-dichloro-2-butene; colorless crys-
tals (EtOH); yield: 0.25 g (70%); mp 210–212 °C.
(E)-1,12-Dioxa-5,8-diazadibenzo[b,j]cyclohexano[f]cyclohexa-
dec-14-ene-4,9-dione (3c)
Prepared from 4c and trans-1,4-dichloro-2-butene; colorless crys-
tals (EtOH–CHCl3); yield: 0.32 g (80%); mp > 330 °C (charred).
IR: 3399, 3104, 3072, 3038, 2933, 2875, 1638, 1599, 1520, 1484,
1295, 1232, 990, 752 cm–1.
1H NMR (CDCl3): d = 3.77 (br, 4 H, NCH2), 4.69 (m, 4 H, OCH2),
6.32 (m, 2 H, CH=), 7.00 (d, J = 8.3 Hz, 2 H), 7.13 (t, J = 7.6 Hz, 2
H), 7.46 (dt, J = 1.5, 7.8 Hz, 2 H), 8.17 (br, 2 H, NH), 8.24 (dd, J =
1.5, 7.8 Hz, 2 H).
IR: 3426, 3362, 3071, 2998, 2961, 2936, 1643, 1598, 1495, 1301,
1231, 1036, 752 cm–1.
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

3266
R. N. Malhas, Y. A. Ibrahim
PAPER
1H NMR (CDCl3): d = 1.39 (m, 2 H), 1.81 (m, 2 H), 1.44 (m, 2 H),
2.40 (m, 2 H), 3.99 (m, 2 H), 4.41 (dt, J = 1.8, 12.2 Hz, 2 H, OCH2),
4.63 (d, J = 12.3 Hz, 2 H, OCH2), 5.80 (t, J = 1.9 Hz, 2 H, CH=),
6.94 (dd, J = 1.0, 8.2 Hz, 2 H), 7.07 (t, J = 7.7 Hz, 2 H), 7.38 (dt, J =
1.2, 8.2 Hz, 2 H), 7.48 (br, 2 H, NH), 7.72 (dd, J = 1.6, 7.7 Hz, 2 H).
13C NMR (CDCl3): d = 24.7, 32.8, 54.3, 71.2, 117.2, 122.6, 127.2,
127.6, 129.7, 131.8, 155.2, 167.4.
MS: m/z = 612 [M+].
Anal. Calcd for C38H32N2O6 (612.7): C, 74.50; H, 5.26; N, 4.57.
Found: C, 74.12; H, 5.16; N, 4.45.
(E)-1,12,16,21-Tetraoxa-5,8-diazapentabenzo[b,f,j,n,v]cyclotet-
racos-18-ene-4,9-dione (7b)
Prepared from 4b and 9; colorless crystals (CHCl3); yield: 0.46 g
(53%); mp 248–250 °C.
MS: m/z = 406 [M+].
IR: 3321, 3068, 3028, 2917, 1650, 1597, 1514, 1477, 1450, 1288,
1243, 1251, 1002, 914, 752 cm–1.
Anal. Calcd for C24H26N2O4 (406.5): C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.64; H, 6.23; N, 6.81.
1H NMR (CDCl3): d = 4.24 (s, 4 H, OCH2CH=), 5.10 (s, 4 H,
OCH2), 5.84 (s, 2 H, CH=), 6.81 (d, J = 8.1 Hz, 2 H), 6.96 (t, J = 7.4
Hz, 2 H), 7.05 (t, J = 7.5 Hz, 2 H), 7.11 (m, 2 H), 7.14 (d, J = 8.3
Hz, 2 H), 7.32–7.37 (m, 4 H), 7.43 (dt, J = 1.7, 7.8 Hz, 2 H), 7.50
(m, 2 H), 8.10 (dd, J = 1.6, 7.9 Hz, 2 H), 9.99 (br, 2 H, NH).
(Z)-1,12,16,21-Tetraoxa-5,8-diazatetrabenzo[b,j,n,v]cyclotetra-
cos-18-ene-4,9-dione (6a)
Prepared from 4a and 8; colorless crystals (EtOH); yield: 0.10 g
(11%); mp 158–160 °C.
IR: 3475, 3522, 3364, 3070, 3035, 2941, 2864, 1649, 1599, 1531,
1484, 1452, 1298, 1245, 1159, 1013, 987, 754 cm–1.
13C NMR (CDCl3): d = 67.6, 67.8, 111.8, 113.3, 120.5, 121.0, 123.5,
123.7, 124.5, 125.3, 128.1, 130.6, 131.2, 131.8, 132.25, 132.28,
155.7, 157.4, 164.6.
1H NMR (CDCl3): d = 3.52 (m, 4 H, NCH2), 4.66 (d, J = 3.6 Hz, 4
H, OCH2CH=), 4.99 (s, 4 H, OCH2Ar), 5.95 (t, J = 3.6 Hz, 2 H,
CH=), 6.68 (d, J = 8.2 Hz, 2 H), 6.79 (t, J = 7.4 Hz, 2 H), 7.01 (m,
4 H), 7.10 (t, J = 7.6 Hz, 2 H), 7.25 (d, J = 7.5 Hz, 2 H), 7.42 (dt, J
= 1.8, 8.4 Hz, 2 H), 8.07 (br, 2 H, NH), 8.21 (dd, J = 1.7, 7.9 Hz, 2
H).
MS: m/z = 612 [M+].
Anal. Calcd for C38H32N2O6 (612.7): C, 74.50; H, 5.26; N, 4.57.
Found: C, 74.32; H, 5.18; N, 4.55.
(Z)-1,12,16,21-Tetraoxa-5,8-diazatetrabenzo[b,j,n,v]cyclohex-
ano[f]cyclotetracos-18-ene-4,9-dione (6c)
Prepared from 4c and 8; colorless crystals (EtOH); yield: 0.28 g
13C NMR (CDCl3): d = 39.8, 64.8, 66.8, 112.0, 113.1, 121.2, 121.3,
121.8, 124.0, 128.8, 129.3, 129.9, 132.2, 130.5, 155.8, 156.9, 165.5.
(32%); mp 120–122 °C.
MS: m/z = 564 [M+].
IR: 3325, 3064, 2930, 2872, 1659, 1598, 1532, 1482, 1456, 1298,
1233, 1005, 753 cm–1.
1H NMR (CDCl3): d = 1.05 (br, 2 H), 1.25 (m, 3 H), 2.01 (m, 2 H),
3.88 (br, 2 H), 4.67–4.74 (m, 5 H), 5.23–5.33 (m, 4 H), 5.87 (m, 2
H), 6.87–6.95 (m, 8 H), 7.25 (m, 4 H), 7.36 (d, J = 7.2 Hz, 2 H), 8.01
(dd, J = 1.4, 7.6 Hz, 2 H), 8.18 (d, J = 6.3 Hz, 2 H, NH).
LCMS: m/z = 565 [M + 1].
Anal. Calcd for C34H32N2O6 (564.6): C, 72.33; H, 5.71; N, 4.96.
Found: C, 72.12; H, 5.56; N, 4.82.
(E)-1,12,16,21-Tetraoxa-5,8-diazatetrabenzo[b,j,n,v]cyclotetra-
cos-18-ene-4,9-dione (7a)
Prepared from 4a and 9; colorless crystals (EtOH); yield: 0.53 g
(56%); mp 158–160 °C.
LCMS: m/z = 619 [M + 1].
Anal. Calcd for C38H38N2O6 (618.7): C, 73.77; H, 6.19; N, 4.53.
Found: C, 73.55; H, 6.17; N, 4.43.
IR: 3375, 3314, 3066, 2936, 1651, 1600, 1529, 1490, 1451, 1297,
1239, 978, 753 cm–1.
(E)-1,12,16,21-Tetraoxa-5,8-diazatetrabenzo[b,j,n,v]cyclohex-
ano[f]cyclotetracos-18-ene-4,9-dione (7c)
Prepared from 4c and 9; colorless crystals (EtOH); yield: 0.34 g
1H NMR (CDCl3): d = 3.44 (m, 4 H, NCH2), 4.50 (s, 4 H,
OCH2CH=), 5.21 (s, 4 H, OCH2), 5.93 (s, 2 H, CH=), 6.89 (d, J =
8.2 Hz, 2 H), 6.96 (t, J = 7.3 Hz, 2 H), 7.06 (t, J = 7.6 Hz, 2 H), 7.11
(d, J = 8.2 Hz, 2 H), 7.29 (t, J = 8.0 Hz, 2 H), 7.37 (dd, J = 1.2, 7.7
Hz, 2 H), 7.43 (m, 2 H), 8.15 (dd, J = 1.7, 7.8 Hz, 2 H), 8.24 (br, 2
H, NH).
(39%); mp 120–122 °C.
IR: 3366, 3064, 2932, 2860, 1639, 1599, 1534, 1489, 1451, 1243,
999, 755 cm–1.
13C NMR (CDCl3): d = 40.0, 67.6, 67.9, 112.1, 112.8, 112.9, 120.9,
1H NMR (CDCl3): d = 1.03 (s, 2 H), 1.27 (m, 4 H), 2.00 (d, J = 9.6
Hz, 2 H), 3.86 (s, 2 H), 4.51 (d, J = 13.2 Hz, 4 H), 5.23–5.33 (m, 4
H), 5.94 (s, 2 H), 6.84–6.92 (m, 8 H), 7.23–7.40 (m, 6 H), 7.99 (d,
J = 7.2 Hz, 2 H), 8.17 (d, J = 6.1 Hz, 2 H, NH).
13C NMR (CDCl3): d = 24.6, 32.1, 53.0, 66.0, 67.4, 111.5, 112.8,
120.8, 120.9, 121.6, 124.5, 127.8, 129.1, 129.3, 131.9, 132.3, 155.7,
156.9, 165.3.
121.1, 121.2, 127.4, 130.0, 132.0, 132.1, 132.6, 156.8, 157.3, 166.0.
MS: m/z = 564 [M+].
Anal. Calcd for C34H32N2O6 (564.6): C, 72.33; H, 5.71; N, 4.96.
Found: C, 72.12; H, 5.63; N, 4.85.
(Z)-1,12,16,21-Tetraoxa-5,8-diazapentabenzo[b,f,j,n,v]cyclotet-
racos-18-ene-4,9-dione (6b)
MS: m/z = 618 [M+].
Prepared from 4b and 8; colorless crystals (CHCl3); yield: 0.43 g
(49%); mp 248–250 °C.
Anal. Calcd for C38H38N2O6 (618.7): C, 73.77; H, 6.19; N, 4.53.
Found: C, 73.55; H, 6.17; N, 4.43.
IR: 3329, 3068, 3036, 2936, 2881, 1699, 1660, 1599, 1535, 1493,
1476, 1455, 1294, 1243, 1123, 999, 753 cm–1.
2-Allyloxybenzaldehyde (15)
To a solution of salicylaldehyde (20 g, 0.16 mol) and KOH (12.5 g)
in EtOH (50 mL) was added allyl bromide (18 mL, 0.24 mol). The
reaction mixture was heated under reflux for 4 h. The solvent was
then removed in vacuo and the remaining oily product was extract-
ed with CH2Cl2 (50 mL) and washed with a KOH solution (50 mL,
10%). The organic layer was separated and dried over Na2SO4 and
the solvent was then removed in vacuo to give 15 (25 g, 94%; Lit.16
bp 85–88 °C, 0.25 mmHg) as a yellow oil which was found to be
1H NMR (acetone-d6): d = 4.67 (m, 4 H, OCH2CH=), 5.18 (s, 4 H,
OCH2), 5.63 (m, 2 H, CH=), 6.89 (t, J = 7.8 Hz, 2 H), 7.04 (m, 4 H),
7.15–7.20 (m, 4 H), 7.28 (t, J = 7.6 Hz, 2 H), 7.42 (m, 4 H), 7.65 (m,
2 H), 8.06 (dd, J = 1.3, 7.7 Hz, 2 H), 9.99 (br, 2 H, NH).
13C NMR (acetone-d6): d = 64.0, 68.3, 113.0, 115.0, 121.8, 122.0,
123.9, 125.2, 126.1, 129.9 (overlapped, 2 × C), 131.2, 131.8, 132.9,
133.2, 133.8, 157.5, 158.0, 164.6.
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

PAPER
Synthesis of Olefinic Crown Diamides and their Conversion to Pyrazolino Macrocycles
3267
pure enough by 1H NMR to be used without further purification in
the next step.
H), 7.57 (t, J = 8.2 Hz, 2 H), 7.87 (d, J = 7.6 Hz, 2 H), 10.51 (s, 2 H,
CHO).
IR: 3351, 3080, 3020, 2989, 2865, 2762, 1687, 1598, 1481, 1457,
1395, 1290, 1240, 1192, 1162, 1104, 998, 931, 841, 760, 658 cm–1.
13C NMR (CDCl3): d = 64.5, 112.5, 121.2, 125.0, 128.5, 128.8,
135.9, 160.5, 189.6.
1H NMR (CDCl3): d = 4.68 (m, 2 H, OCH2), 5.36 (dd, J = 1.3, 10.4
Hz, 1 H, CH2=), 5.47 (dd, J = 1.3, 17.2 Hz, 1 H, CH2=), 6.06 (m, 1
H, CH=), 6.99–7.05 (m, 2 H), 7.55 (m, 1 H), 7.86 (dd, J = 2.0, 8.0
Hz, 1 H), 10.56 (s, 1 H, CHO).
MS: m/z = 296 [M+].
Anal. Calcd for C18H16O4 (296.3): C, 72.96; H, 5.44. Found: C,
72.69; H, 5.67.
MS: m/z = 162 [M+].
(E)-1,4-Bis(o-formylphenoxy)-2-butene (12)
Colorless crystals; yield: 8.4 g (87%); mp 150–152 °C.
2-Allyloxybenzyl Alcohol (16)
IR: 3323, 3101, 3079, 2925, 2867, 2767, 1674, 1599, 1487, 1459,
1391, 1290, 1237, 1167, 1009, 990, 816, 759 cm–1.
1H NMR (CDCl3): d = 4.75 (d, J = 2.0 Hz, 4 H, OCH2), 6.18 (t, J =
2.0 Hz, 2 H, CH=), 7.00 (d, J = 8.4 Hz, 2 H), 7.08 (t, J = 7.6 Hz, 2
H), 7.56 (dt, J = 1.8, 7.8 Hz, 2 H), 7.88 (dd, J = 1.8, 7.7 Hz, 2 H),
10.55 (s, 2 H, CHO).
To a solution of 15 (3.24 g, 20 mmol) in boiling MeOH (25 mL) was
added NaBH4 (1.2 g, 30 mmol) portionwise with stirring over 15
min. The mixture was refluxed for 1 h and then poured over ice-wa-
ter mixture (100 mL). The separated oil was extracted with CHCl3
(50 mL), dried over Na2SO4 and the solvent was removed in vacuo
to give 16 as a yellow oil (3.25 g, almost 100%; Lit.17 bp 83–85 °C,
0.02 mm Hg) which was used without further purification in the
next step.
13C NMR (CDCl3): d = 68.0, 112.7, 121.1, 125.1, 127.8, 128.7,
135.9, 160.6, 189.6.
MS: m/z = 296 [M+].
IR: 3369, 3079, 3041, 2984, 2920, 2871, 1649, 1603, 1590, 1492,
1454, 1423, 1365, 1288, 1239, 1098, 1043, 1020, 999, 929, 754
cm–1.
1H NMR (CDCl3): d = 2.40 (s, 1 H, OH), 4.62 (d, J = 5.1 Hz, 2 H,
OCH2CH=), 4.74 (s, 2 H, CH2OH), 5.34 (dd, J = 1.0, 10.7 Hz, 1 H,
CH2=), 5.44 (dd, J = 1.3, 17.2 Hz, 1 H, CH2=), 6.05 (m, 1 H, CH=),
6.90 (d, 1 H, J = 8.2 Hz), 6.98 (t, J = 7.4 Hz, 1 H), 7.29 (m, 2 H).
Anal. Calcd for C18H16O4 (296.3): C, 72.96; H, 5.44. Found: C,
72.72; H, 5.44.
1,4-Bis(o-hydroxymethylphenoxy)-2-butenes 13, 14; General
Procedure
To a cold (0–5 °C) and stirred solution of bis(carbonyl)ethers 11 or
12 (10 mmol) in MeOH (100 mL) was added dropwise a solution of
NaBH4 (2.57 g, 67 mmol) dissolved in H2O (4.28 mL) and aq NaOH
solution (4.28 mL, 2 N). The reaction mixture was stirred for 2 h (0–
5 °C) and kept in the refrigerator overnight. The insoluble material
was filtered off and the solvent was removed in vacuo. The remain-
ing material was crystallized from EtOH to give the corresponding
diols 13 or 14.
MS: m/z = 164 [M+].
2-Allyloxybenzyl Chloride (17)
To the alcohol 16 (3.25 g, 20 mmol) in CHCl3 (20 mL) was added
SOCl2 (2.5 mL) dropwise with stirring at r.t.. The mixture was
stirred in anhydrous atmosphere at r.t. for 1 h and the solvent was
then removed in vacuo to leave a dark oil in 95% yield (Lit.18) which
was used without further purification in the next step.
(Z)-1,4-Bis(o-hydroxymethylphenoxy)-2-butene (13)
Colorless crystals; yield: 2.0 g (66%); mp 66–68 °C.
IR: 3078, 3024, 2970, 2921, 2867, 1648, 1599, 1494, 1455, 1293,
1251, 1112, 1018, 998, 929, 842, 753, 671 cm–1.
IR: 3366, 3066, 3038, 2924, 2872, 1601, 1491, 1454, 1289, 1233,
1116, 1015, 839, 754 cm–1.
1H NMR (CDCl3): d = 2.72 (s, 2 H, OH), 4.69 (s, 4 H, CH2OH), 4.73
(d, J = 4.0 Hz, 4 H, OCH2), 5.99 (t, J = 4.0 Hz, 2 H, CH=), 6.89 (d,
J = 8.2 Hz, 2 H), 6.99 (t, J = 7.4 Hz, 2 H), 7.28 (dt, J = 1.6, 7.8 Hz,
2 H), 7.33 (dd, J = 1.2, 7.4 Hz, 2 H).
13C NMR (CDCl3): d = 61.6, 64.1, 111.3, 121.1, 128.7, 128.8, 128.9,
129.4, 156.1.
MS: m/z =300 [M+].
1H NMR (CDCl3): d = 4.64 (m, 2 H, OCH2CH=), 4.72 (s, 2 H,
CH2Cl), 5.33 (dd, J = 1.3, 10.6 Hz, 1 H, CH2=), 5.52 (dd, J = 1.3,
17.3 Hz, 1 H, CH2=), 6.09 (m, 1 H, CH=), 6.91 (d, J = 8.3 Hz, 1 H),
6.99 (t, J = 8.1 Hz, 1 H), 7.30 (m, 1 H), 7.39 (dd, J = 1.6, 7.5 Hz, 1
H).
MS: m/z = 182 [M+], 184 [M + 2].
1,4-Bis(o-formylphenoxy)-2-butenes 11 and 12; General Proce-
dure
A solution of salicylaldehyde (7.94 g, 65 mmol) and KOH (3.67 g,
65 mmol) in MeOH (25 mL) was stirred for 5 min and the solvent
was then removed in vacuo to give the corresponding potassium salt
to which DMF (10 mL) and cis-1,4-dichloro-2-butene or trans-1,4-
dichloro-2-butene (31 mmol) was added. The reaction mixture was
then heated under reflux for 15 min (during this time the potassium
halide precipitated). The mixture was then diluted with ice-water
(50 mL) and the precipitate was collected, washed with cold H2O
and finally crystallized from EtOH to give the corresponding deriv-
ative 11 or 12.
Anal. Calcd for C18H20O4 (300.4): C, 71.98; H, 6.71. Found: C,
72.07; H, 6.93.
(E)-1,4-Bis(o-hydroxymethylphenoxy)-2-butene (14)
Colorless crystals; yield: 1.9 g (62%); mp 94–95 °C.
IR: 3326, 3242, 3065, 3025, 2925, 2888, 2849, 1600, 1489, 1453,
1373, 1281, 1227, 1044, 1027, 988, 837, 748 cm–1.
1H NMR (CDCl3): d = 2.32 (s, 2 H, OH), 4.67 (d, J = 2.0 Hz, 4 H,
OCH2), 4.74 (s, 4 H, CH2OH), 6.12 (t, J = 2.0 Hz, 2 H, CH=), 6.89
(d, J = 8.2 Hz, 2 H), 6.99 (t, J = 7.4 Hz, 2 H), 7.26–7.31 (m, 2 H),
7.33 (dd, J = 1.2, 7.3 Hz, 2 H).
13C NMR (CDCl3): d = 62.1, 67.6, 111.5, 121.0, 128.2, 128.9, 128.9,
129.3, 156.2.
MS: m/z = 300 [M+].
(Z)-1,4-Bis(o-formylphenoxy)-2-butene (11)
Colorless crystals; yield: 8.3 g (86%); mp 97–99 °C.
IR: 3424, 3108, 3074, 3040, 2969, 2925, 2875, 2765, 1682, 1598,
1485, 1455, 1393, 1288, 1235, 1163, 1005, 841, 758, 697 cm–1.
1H NMR (CDCl3): d = 4.84 (d, J = 3.4 Hz, 4 H, OCH2), 6.07 (t, J =
3.4 Hz, 2 H, CH=), 6.99 (d, J = 8.4 Hz, 2 H), 7.08 (t, J = 7.5 Hz, 2
Anal. Calcd for C18H20O4 (300.4): C, 71.98; H, 6.71. Found: C,
72.10; H, 6.96.
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

3268
R. N. Malhas, Y. A. Ibrahim
PAPER
1,4-Bis(o-chloromethylphenoxy)-2-butenes 8, 9; General Proce-
dure
pared with the pure Z and pure E NMR signals prepared by the other
methods.
To a cold stirred solution (–10 °C) of diols 13 or 14 (10.9 mmol) in
CHCl3 (100 mL) was added dropwise a solution of SOCl2 (5 mL) in
CHCl3 (5 mL). Stirring was continued for 2 h. The solvent was then
removed in vacuo and the remaining solid was crystallized from
EtOH to give 8 or 9.
Cycloaddition Reactions of 2a,b, 3a,b; General Procedure
To a solution of 2a,b, 3a,b (0.31 mmol) and N-phenylbenzohydra-
zonoyl chloride19 (1.26 mmol) in CHCl3 (15 mL) was added Et3N
(0.5 mL). The reaction mixture was then heated under reflux for 24
h. The solvent was removed in vacuo and the resulting solid was
washed with water and crystallized to give the corresponding deriv-
atives 18a,b, 19a,b.
(Z)-1,4-Bis(o-chloromethylphenoxy)-2-butene (8)
Colorless crystals; yield: 3.2 g (95%); mp 40–42 °C.
IR: 3067, 3035, 2968, 2927, 1688, 1601, 1492, 1456, 1293, 1246,
1108, 1048, 1022, 842, 753, 670, 561 cm–1.
1H NMR (CDCl3): d = 4.69 (s, 4 H, CH2Cl), 4.79 (d, J = 2.3 Hz, 4
H, OCH2), 6.02 (t, J = 2.3 Hz, 2 H, CH=), 6.92 (d, J = 8.3 Hz, 2 H),
6.99 (t, J = 7.5 Hz, 2 H), 7.28–7.32 (m, 2 H), 7.39 (d, J = 7.5 Hz, 2
H).
13C NMR (CDCl3): d = 41.6, 64.6, 111.9, 121.0, 126.1, 128.5, 130.0,
130.7, 156.1.
MS: m/z = 336 [M+], 338 [M + 2], 340 [M + 4].
(Z)-1,3-Diphenyl-1,12-dioxa-5,8-diazadibenzo[b,j]pyrazoli-
no[3,4-n]cyclohexadecane-4,9-dione (18a)
Prepared from 2a; colorless crystals (dilute EtOH); yield: 0.36 g
(53%); mp 152–153 °C.
IR: 3408, 3016, 2926, 2855, 1650, 1600, 1531, 1482, 1455, 1368,
1301, 1216, 993, 758 cm–1.
1H NMR (CDCl3): d = 3.57 (m, 2 H, NCH2), 4.00 (m, 2 H, NCH2),
4.17 (m, 2 H), 4.27 (t, J = 8.2 Hz, 1 H), 4.73 (m, 3 H), 6.27 (d, J =
8.3 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 7.12
(m, 2 H), 7.28–7.48 (m, 9 H), 7.77 (dd, J = 1.1, 7.2 Hz, 2 H), 7.87
(t, J = 6.1 Hz, 1 H, NH), 7.98 (t, J = 5.4 Hz, 1 H, NH), 8.07 (dd, J =
1.6, 7.6 Hz, 1 H), 8.18 (dd, J = 1.6, 7.7 Hz, 1 H).
Anal. Calcd for C18H18Cl2O2 (337.3): C, 64.11; H, 5.38. Found: C,
64.09; H, 5.44.
13C NMR (CDCl3): d = 38.8, 39.6, 47.9, 63.7, 64.1, 67.4, 112.6,
122.1, 122.2, 122.24, 123.2, 124.9, 125.6, 126.3, 128.1, 129.0,
129.6, 129.9, 130.5, 132.2, 132.22, 132.4, 132.8, 146.2, 152.1,
155.1, 156.1, 165.4, 165.5.
(E)-1,4-Bis(o-chloromethylphenoxy)-2-butene (9)
Colorless crystals (EtOH); yield: 3.2 g (95%); mp 96–98 °C.
IR: 3073, 3036, 2971, 2898, 2858, 1778, 1686, 1599, 1498, 1443,
1370, 1302, 1256, 1199, 1159, 1113, 994, 972, 848, 792, 751, 662
cm–1.
MS: m/z = 546 [M+].
1H NMR (CDCl3): d = 4.70 (br, 4 H, OCH2), 4.72 (s, 4 H, CH2Cl),
6.16 (br, 2 H, CH=), 6.90 (d, J = 8.2 Hz, 2 H), 6.98 (t, J = 7.3 Hz, 2
H), 7.29–7.34 (m, 2 H), 7.39 (d, J = 7.5 Hz, 2 H).
UV–Vis (abs): lmax (e) = 294 (10680) nm.
UV–Vis (em): lmax (e) = 463 (61890) nm.
Anal. Calcd for C33H30N4O4 (546.6): C, 72.51; H, 5.53; N, 10.25.
Found: C, 72.21; H, 5.41; N, 10.19.
13C NMR (CDCl3): d = 41.7, 67.8, 112.1, 120.9, 126.1, 127.7, 130.0,
130.6, 156.2.
MS: m/z = 336 [M+], 338 [M + 2], 340 [M + 4].
(Z)-1,3-Diphenyl-1,12-dioxa-5,8-diazatribenzo[b,f,j]pyrazoli-
no[3,4-n]cyclohexadecane-4,9-dione (18b)
Prepared from 2b; yellowish crystals [CH2Cl2–PE (40–60)]; yield:
Anal. Calcd for C18H18Cl2O2 (337.3): C, 64.11; H, 5.38. Found: C,
63.98; H, 5.66.
0.34 g (45%); mp 274–276 °C.
Ring-Closing Metathesis (RCM) of 1a-c: Synthesis of 2a–c and
3a–c; General Procedure
IR: 3455, 3361, 3062, 2928, 2880, 1663, 1598, 1534, 1479, 1294,
1228, 1009, 753, 694 cm–1.
A solution of the substrates 1a–c (1 mmol) in CH2Cl2 (10 mL) and
Grubbs’ catalyst I (1-5 mol% of the substrate as indicated in
Table 1) or II (1 mol% or 5 mol% of the substrate) was heated under
reflux for the time indicated in Table 1. The solvent was then re-
1H NMR (CDCl3): d = 4.64–4.73 (m, 4 H), 4.84 (d, J = 10.8 Hz, 1
H), 4.90 (dd, J = 6.5, 12.2 Hz, 1 H), 6.86 (t, J = 7.3 Hz, 1 H), 6.98–
7.01 (m, 3 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 1 H),
7.18 (t, J = 8.0 Hz, 2 H), 7.27 (d, J = 8.3 Hz, 1 H), 7.30–7.44 (m, 6
H), 7.48–7.55 (m, 2 H), 7.65–7.68 (m, 3 H), 7.76 (dd, J = 1.7, 7.7
Hz, 1 H), 7.85 (dd, J = 1.7, 7.7 Hz, 1 H), 9.54 (s, 1 H, NH), 9.61 (s,
1 H, NH).
13C NMR (DMSO): d = 48.0, 61.7, 65.2, 66.1, 113.8, 114.5, 115.5,
121.2, 121.8, 122.1, 122.7, 125.2, 125.8, 126.4, 126.5, 126.8, 129.1,
129.4, 129.5, 131.26, 131.32, 131.5, 131.8, 132.4, 133.5, 133.8,
134.5, 145.2, 150.3, 156.8, 156.9, 163.6, 163.8.
1
moved in vacuo and the resulting products were analyzed by H
NMR. The yields and Z/E ratios were then determined by 1H NMR
(Table 1) and by comparing their signals with pure-Z and pure-E
NMR signals prepared by bisalkylation method.
Isomerization Experiments of 2a and 6a,b, 11; General Proce-
dure
A solution of 2a or 6a,b (1 mol) in CH2Cl2 (10 mL) and Grubbs’ cat-
alyst I or II (1 mol% of the substrate) was heated under reflux for 2
h. The solvent was then evaporated in vacuo and the resulting reac-
MS: m/z = 594 [M+].
1
UV–Vis (abs): lmax (e) = 285 (26626), 330 (shoulder, 13910) nm.
UV–Vis (em): lmax (e) = 459 (172514) nm.
tion products, yields and Z/E ratios were then determined by H
NMR.
Anal. Calcd for C37H30N4O4 (594.7): C, 74.73; H, 5.08; N, 9.42.
Found: C, 74.53; H, 4.99; N, 9.32.
Cross-Metathesis (CM) of 15-17: Synthesis of 8, 9 and 11-14;
General Procedure
A solution of the substrates 15, 16 or 17 (1 mol) in CH2Cl2 (10 mL)
and Grubbs’ catalyst I or II (1 mol% of the substrate) was heated
under reflux for 2 h. The solvent was then evaporated in vacuo and
(E)-1,3-Diphenyl-1,12-dioxa-5,8-diazadibenzo[b,j]pyrazoli-
no[3,4-n]cyclohexadecane-4,9-dione (19a)
Prepared from 3a; pale yellow crystals (CHCl3); yield: 0.38 g
1
the resulting reaction products were analyzed by H NMR. The
(55%); mp 298–300 °C.
1
yield and Z/E ratios were then determined by H NMR and com-
IR: 3426, 3361, 3068, 2998, 2964, 2938, 1643, 1598, 1532, 1494,
1302, 1231, 1036, 752, 690 cm–1.
Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York

PAPER
Synthesis of Olefinic Crown Diamides and their Conversion to Pyrazolino Macrocycles
3269
1H NMR (DMSO-d6): d = 3.41 (m, 2 H, NCH2), 3.70 (m, 2 H,
NCH2), 3.88 (t, J = 9.6 Hz, 1 H), 4.00 (m, 3 H), 4.55 (dd, J = 5.2,
8.8 Hz, 1 H), 5.40 (dd, J = 3.4, 10.3 Hz, 1 H), 6.85 (t, J = 7.6 Hz, 1
H), 7.00–7.08 (m, 3 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.29–7.42 (m, 7
H), 7.47 (t, J = 7.5 Hz, 2 H), 7.79 (dt, J = 1.6, 7.7 Hz, 2 H), 7.95 (d,
J = 8.1 Hz, 2 H), 8.48 (t, J = 5.6 Hz, 1 H, NH), 8.52 (t, J = 4.8 Hz,
1 H, NH).
13C NMR (DMSO): d = 47.7 (2 × C), 61.1 (2 × C), 63.1, 65.1, 113.2,
113.9 (2 × C), 120.0, 121.4, 121.5, 123.6, 123.7, 126.6 (2 × C),
129.4, 129.6, 129.9, 131.3, 131.9, 132.8 (2 × C), 143.8, 148.4,
156.3, 156.4, 165.9, 165.92.
2127. (f) Konig, B.; Horn, C. Synlett 1996, 1013. (g) Weck,
M.; Mohr, B.; Sauvage, J. P.; Grubbs, R. H. J. Org. Chem.
1999, 64, 5463. (h) Dietrich-Buchecker, C.; Sauvage, J. P.
Chem. Commun. 1999, 615. (i) Kidd, J. T.; Leigh, A. O.;
Wilson, A. J. J. Am. Chem. Soc. 1999, 121, 1599.
(j) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (k) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (l) Kingsbury, J. S.; Harrity, J. P.;
Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 791. (m) Wakamatsu, H.; Blechert, S. Angew. Chem.
Int. Ed. 2002, 41, 2403. (n) Akiyama, R.; Kobayashi, S.
Angew. Chem. Int. Ed. 2002, 41, 2602. (o) Connon, S. J.;
Blechert, S. Top. Organomet. Chem. 2004, 11, 93.
(3) Ibrahim, Y. A.; El Wahy, A. H.; Elkareish, G. J. Chem. Res.,
Synop. 1994, 414.
MS: m/z = 546 [M+].
UV–Vis (abs): lmax (e) = 290 (shoulder, 20000), 360 (37143) nm.
UV–Vis (em): lmax (e) = 450 (41909) nm.
(4) (a) Behbehani, H.; Ibrahim, M. R.; Ibrahim, Y. A.
Tetrahedron Lett. 2002, 43, 6421. (b) Ibrahim, Y. A.;
Behbehani, H.; Ibrahim, M. R.; Malhas, R. N. Tetrahedron
2003, 59, 7273.
Anal. Calcd for C33H30N4O4 (546.6): C, 72.51; H, 5.53; N, 10.25.
Found: C, 72.31; H, 5.35; N, 10.21.
(E)-1,3-Diphenyl-1,12-dioxa-5,8-diazatribenzo[b,f,j]pyrazoli-
no[3,4-n]cyclohexadecane-4,9-dione (19b)
Prepared from 3b; colorless crystals (CHCl3); yield: 0.23 g (30%);
mp 274–276 °C.
(5) Ibrahim, Y. A.; Behbehani, H.; Abrar, N. M. Tetrahedron
2004, 60, 8429.
(6) Ibrahim, Y. A.; Behbehani, H.; Ibrahim, M. R.; Abrar, N. M.
Tetrahedron Lett. 2002, 43, 6971.
(7) Ibrahim, Y. A.; Behbehani, H.; Ibrahim, M. R. Tetrahedron
Lett. 2002, 43, 4207.
(8) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012.
(9) Schrock, R. R.; Murdzed, J. S.; Bazan, G. C.; Robbins, J.;
Dimare, M.; Regan, M. O. J. Am. Chem. Soc. 1990, 112,
3875.
(10) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856.
(11) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543.
IR: 3385, 3053, 3005, 2933, 2880, 1652, 1597, 1494, 1453, 1384,
1317, 1237, 1136, 1028, 758 cm–1.
1H NMR (DMSO): d = 3.78 (m, 2 H), 4.10–4.50 (m, 3 H), 5.14 (m,
1 H), 6.67–6.82 (m, 3 H), 7.07–7.26 (m, 9 H), 7.36–7.87 (m, 10 H),
10.47 (s, 1 H), 10.50 (s, 1 H).
LCMS: m/z = 595 [M + 1].
UV–Vis (abs): lmax (e) = 284 (4478) nm.
UV–Vis (em): lmax (e) = 436 (169784) nm.
Anal. Calcd for C37H30N4O4 (594.7): C, 74.73; H, 5.08; N, 9.42.
Found: C, 74.47; H, 5.33; N, 9.31.
(12) Giger, T.; Wigger, M.; Audétat, S.; Benner, S. A. Synlett
1998, 688.
(13) (a) Prunet, J. Angew. Chem. Int. Ed. 2003, 42, 2826.
(b) Kalesse, M.; Quitschalle, M.; Claus, E.; Gerlach, K.;
Pahl, A.; Meyer, H. H. Eur. J. Org. Chem. 1999, 2817.
(c) Fürstner, A.; Mathes, C.; Grela, K. Chem. Commun.
2001, 1057. (d) Murga, J.; Falomir, E.; Garcia-Fortanet, J.;
Carda, M.; Marco, J. A. Org. Lett. 2002, 4, 3447.
(e) Connon, S. J.; Blechert, S. Angew. Chem. Int. Ed. 2003,
42, 1900. (f) Schmidt, B.; Hermanns, J. Top. Organomet.
Chem. 2004, 13, 223.
Acknowledgment
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, GS02/01, GS03/01) are gratefully acknowledged.
Also, the support of College of Graduate Studies, Kuwait Universi-
ty to the Ph.D. student Rana N. Malhas is highly appreciated.
(14) Ibrahim, Y. A.; Elwahy, A. H. M.; Abbas, A. A.; Kassab, R.
M. J. Chem. Res., Synop. 1999, 522.
References
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Synthesis 2006, No. 19, 3261–3269 © Thieme Stuttgart · New York