Reductive deoxygenation of ortho-hydroxyaromatic aldehydes to 1,2-bis(hydroxyaryl)ethanes: application to the synthesis of ethylene bridged calixarene-analogous metacyclophanes

Article abstract of DOI:10.1016/j.tetlet.2009.07.156

A novel and convenient protocol for the synthesis of hexahydroxy[2.1.2.1.2.1]- and octahydroxy[2.1.2.1.2.1.2.1]metacyclophanes from 4-substituted phenol in four steps has been developed. The synthetic route involved the preparation of the key intermediate 1,2-bis(5-substituted-2-hydroxyphenyl)ethanes in good yields via (i) formylation of 4-substituted phenol, (ii) reductive deoxygenation of 5-substituted 2-hydroxy aromatic aldehydes with low-valent titanium reagent and (iii) catalytic hydrogenation. The metacyclophanes were prepared by base-catalyzed macrocyclization of the above intermediates with formaldehyde in refluxing xylene in high yields.

Full text of DOI:10.1016/j.tetlet.2009.07.156

Tetrahedron Letters 50 (2009) 5823–5826
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Tetrahedron Letters
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Reductive deoxygenation of ortho-hydroxyaromatic aldehydes to
1,2-bis(hydroxyaryl)ethanes: application to the synthesis of ethylene bridged
calixarene-analogous metacyclophanes
*
Suchitra Bhatt, Sandip K. Nayak
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel and convenient protocol for the synthesis of hexahydroxy[2.1.2.1.2.1]- and octahydr-
Received 22 June 2009
Revised 29 July 2009
Accepted 31 July 2009
Available online 8 August 2009
oxy[2.1.2.1.2.1.2.1]metacyclophanes from 4-substituted phenol in four steps has been developed. The
synthetic route involved the preparation of the key intermediate 1,2-bis(5-substituted-2-hydroxy-
phenyl)ethanes in good yields via (i) formylation of 4-substituted phenol, (ii) reductive deoxygenation
of 5-substituted 2-hydroxy aromatic aldehydes with low-valent titanium reagent and (iii) catalytic
hydrogenation. The metacyclophanes were prepared by base-catalyzed macrocyclization of the above
intermediates with formaldehyde in refluxing xylene in high yields.
Keywords:
ortho-Hydroxy aromatic aldehyde
McMurry coupling
Ó 2009 Elsevier Ltd. All rights reserved.
1,2-Bis(2-hydroxyaryl)ethanes
Macrocyclization
Metacyclophanes
Calix[n]arenes (n = 4–20), which are phenolic [1n] metacyclo-
phanes and have a basket-like shape,1 have attracted great atten-
tion in the recent years. This is due to their ability to include
other entities such as metal ions,2 anions,3 and neutral molecules4
within their cavities. They have also been used as potential enzyme
mimics in host–guest chemistry.1 In calixarenes, the aromatic rings
are connected by methylene units and the phenolic hydroxyl
groups are ordered in a well-shaped cyclic array due to strong
intramolecular hydrogen bonding. The cavity size of calixarenes
can be changed by varying the number of phenolic units. A large
number of calixarene derivatives containing pendant ether, amide,
ketone, and ester groups have been examined for selective recogni-
tion, sensing and separation of various alkali, alkaline earth, and
transition metal ions. Calixarenes synthesized with bridges other
than methylene groups (homocalixarenes) are likely to have a big-
ger cavity size, and characterization of their hydrogen bonding net-
work and ionophoric properties with larger guests remains an
important area in supramolecular chemistry.
the synthesis of [(2.1)n](n = 3,4)-metacyclophanes in reasonably
good yields via low-valent titanium (LVT) reagent-mediated reduc-
tive deoxygenation of ortho-hydroxy aromatic aldehydes as the key
step.
So far there has been only one report on the synthesis of hexa-
hydroxy[2.1.2.1.2.1.]- and octahydroxy[2.1.2.1.2.1.2.1]metacyclo-
phanes by Yamato et al.6 using anisole as the starting material.
The synthetic strategy involved the preparation of the key interme-
diate, 1,2-bis(5-tert-butyl-2-hydroxyphenyl)ethane (3a) in four
steps which remains too long to be practical for large scale
synthesis of metacyclophanes. In continuation of our work on
supramolecular chemistry of calixarenes,7 it was of interest to
develop a simple and shorter route for the large scale synthesis
of [(2.1)n]-metacyclophanes without the use of sophisticated
reagents.
Synthesis of 3a, in principle, can be accomplished via the
metathesis reaction of 4-tert-butyl-2-vinylphenol with Grubb’s
catalyst to 1,2-bis(5-tert-butyl-2-hydroxyphenyl)ethylene (2a) fol-
lowed by catalytic reduction of the double bond. However, synthe-
sis of 5-tert-butyl-2-vinylphenol from commercially available 4-
tert-butylphenol itself involves several synthetic steps including
Wittig olefination. As an alternative, we felt that LVTreagent-med-
iated reductive deoxygenation of 5-tert-butyl-2-hydroxybenzalde-
hyde (1a) may be a convenient route for the synthesis of 3a.
Classically, LVT reagent-mediated reductive deoxygenation of
benzaldehyde leads to the formation of (E)-stilbenes (McMurry
coupling). However, we have observed earlier that reductive
In contrast to calixarenes, very few reports are available for the
synthesis of homocalixarenes with a bigger cavity size.5 Literature
reports on the synthesis of homocalixarenes are usually low yield-
ing and too long for large scale synthesis and therefore it remained
difficult to obtain a sufficient amount of homocalixarenes to inves-
tigate their chemical behavior. We report herein a short route for
* Corresponding author. Tel: +91 22 25592410; fax: +91 22 25505151.
E-mail address: sknayak@barc.gov.in (S.K. Nayak).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.156

5824
S. Bhatt, S. K. Nayak / Tetrahedron Letters 50 (2009) 5823–5826
deoxgenation of 2-hydroxybenzaldehyde with LVT leads to the
formation of 1,2-bis(2-hydroxyphenyl)ethane (reduced stilbene)
as a sole product instead of the expected 1,2-bis(2-hydroxy-
phenyl)ethylene.8 Under identical reaction conditions, however,
3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde yielded 1,2-
bis(3-hydroxyphenyl)ethylene and 1,2-bis(4-hydroxyphenyl)eth-
ylene, respectively, as the sole products without the formation of
their reduced products.
Keeping this in view, we envisaged that 1,2-bis(5-substituted-
2-hydroxyphenyl)ethanes, which are key intermediates in the syn-
thesis of [(2.1)n]-metacyclophanes, can be achieved by the reduc-
tive deoxygenation of 5-substituted-2-hydroxybenzaldehydes
OH
OH
MgCl2 (3.1 equiv)
R
CHO
(CH2O)n/ACN/
NEt3/reflux/8h
R
1a (96%)
1b (81%)
1c (62%)
1d (82%)
a: CMe3
b: Me
c: Ph
d: Br
e: H
TiCl4/Zn/dioxane/
reflux/5 h
HO
OH
OH
HO
+
R
R
R
R
2a (50%)
2b (53%)
2c (88%)
2d (83%)
3a (29%)
3b (30%)
3c (2%)
10% Pd-C/H2/EtOH
2a
2b
2c
3a (78%)
3b (79%)
3c (74%)
-do-
3d (<1%)
-do-
-do-
2d
3e
3e (90%)
3d (82%)
CuBr2/ACN
(CH2O)n/MOH/xylene/reflux/18 h
OH HO
OH HO
OH
OH
3a
HO
OH
OH
HO
HO
+
(M = Li, Na, K, Rb, Cs)
OH HO
OH
5a
4a
-do-
K2CO3/BrCH2CO2Et/acetone
reflux/24 h
OH
OR
3b
OH
HO
OR
RO
OH HO
OH
OR RO
OR
R = CH2CO2Et
4b
6
Scheme 1.

S. Bhatt, S. K. Nayak / Tetrahedron Letters 50 (2009) 5823–5826
5825
Table 2
with LVT reagent. Thus, formylation of 4-tert-butylphenol with
9a
MgCl2/(HCHO)n afforded 5-tert-butyl-2-hydroxybenzaldehyde9b
Condensation of 3b with paraformaldehye in the presence of different alkali metal
hydroxides followed by alkylation with ethyl bromoacetate
(1a) in 96% yield.10 Reductive deoxygenation of 1a with LVT re-
agent (prepared from TiCl4/Zn/dioxane) furnished a mixture of
(E)-2a11 and 3a6 in 50% and 29% yields, respectively, which were
separated by column chromatography (Scheme 1). The reaction
was carried out on 0.1 M scale without any appreciable change in
the yield and composition of the products. Compound 2a was
smoothly converted to 3a in 78% yield by catalytic hydrogenation.
Thus, synthesis of 3a from 4-tert-butylphenol was accomplished in
three steps with 65% overall yield. It is important to mention that
the overall yield in the reported synthesis of 3a from anisole was
only 38%.6
Metal hydroxide
6a,b (yield %)
LiOH
NaOH
KOH
RbOH
CsOH
29
34
42
57
73
a
Isolated yield after column chromatography.
Due to its insolubility, the intermediate 4b was alkylated to 6. Thus, the yield of
b
6 refers to the overall yield in two steps.
Condensation of 3a with paraformaldehyde and aqueous NaOH
in xylene, following the procedure for the synthesis of calix[6]ar-
ene by Gutsche et al.,12 yielded a mixture of hexa-tert-butyl-hexa-
hydroxy[2.1.2.1.2.1]metacyclophane (4a, 32%) and octa-tert-
butyloctahydroxy[2.1.2.1.2.1.2.1]metacyclophane (5a, 40%), which
were separated by column chromatography.13
The template effect of different alkaline metal ions in the mac-
rocyclization reaction of 3a with formaldehyde was also investi-
gated. As outlined in Table 1, use of bases with larger alkali
metal ions such as KOH, RbOH, and CsOH afforded smaller cavity
macrocycle 4a as the major product, while LiOH and NaOH affor-
ded larger cavity metacyclophane 5a as the predominant product.
Among the different bases used, CsOH afforded the highest total
yield of the metacyclophanes. Thus the synthesis of metacyclo-
phanes 4a and 5a was accomplished from 4-tert-butylphenol in
four steps in overall yields of 40% and 14%, respectively, using
CsOH in the macrocyclization step.
To see the scope and generality of the above protocol, 2-hydroxy-
5-methyl-benzaldehyde14 (1b) (prepared from 4-methylphenol)
was subjected to LVT-induced reductive deoxygenation to yield a
mixture of (E)-1,2-bis(2-hydroxy-5-methylphenyl)ethylene15 (2b)
and 1,2-bis(2-hydroxy-5-methylphenyl)ethane (3b).11 As before,
the compound 2b on catalytic hydrogenation yielded 3b which
was subjected to NaOH-induced macrocyclization with formalde-
hyde. However, inspite of several attempts the metacyclophane
formed could not be purified because of its poor solubility in
commonly used organic solvents. To overcome this, the phenolic
OH groups were alkylated with K2CO3/ethyl bromoacetate to
afford hexa-methyl-hexakis [(ethoxycarbonyl)methoxy][2.1.2.1.
2.1]metacyclophane 6 as the sole product.16 This indirectly shows
the formation of hexamer 4b as the sole product in the macrocycli-
zation reaction of 3b.
such as 2-hydroxy-5-phenylbenzaldehyde17 (1c) were converted
to 1,2-bis(5-phenyl-2-hydroxyphenyl)ethane11 (3c) by a similar se-
quence of reactions as mentioned earlier for 3a and 3b. However, all
attempts to macrocyclize 3c with formaldehyde and base remained
unsuccessful. This is possibly due to the electron-withdrawing ef-
fect of the phenyl group para to phenol, thus deactivating the aro-
matic ring for electrophilic reaction. Similarly, reductive
deoxygenation of 5-bromo-2-hydroxybenzaldehyde18 (1d) yielded
(E)-1,2-bis(5-bromo-2-hydroxyphenyl)ethylene19 (2d) as the sole
product with
a trace amount of 1,2-bis(5-bromo-2-hydroxy-
phenyl)ethane11 (3d). Interestingly, catalytic hydrogenation of 2d
led to the reduction of stilbene double bond with concomitant aro-
matic debromination to afford 1,2-bis(2-hydroxyphenyl)ethane8
(3e) in 90% yield. Compound 3e was further brominated exclusively
at the para-position of the phenolic group using the protocol
(CuBr2/CH3CN) developed earlier in our laboratory20 to yield 3d in
82% yield. However, like 3c, all attempts to base-induce macrocyc-
lization of 3d with formaldehyde remained unsuccessful, and the
starting material was quantitatively recovered. All the compounds
were crystallized and characterized by their spectral (IR, 1H NMR,
13C NMR, and MS) and analytical data.
In conclusion, we have developed an easy and convenient route
for the synthesis of [(2.1)n] (n = 3, 4)-metacyclophanes. The only
report6 so far on the synthesis of this class of macrocycles involved
the preparation of the key intermediate 3a from anisole in four
steps in 38% overall yield while in the present methodology, 3a
was prepared from commercially available 4-tert-butyl phenol in
three steps with much higher yield (65%). The studies on the iono-
phoric properties of synthesized metacyclophanes are currently
underway.
Acknowledgment
As in the case of 3a, different alkali metal bases were screened
to optimize the yields and composition in the macrocyclization
reaction of 3b. In all cases hexamer 6 was obtained as the sole
product (Table 2) and no octamer was detected. The best yield of
6 was achieved using CsOH as base followed by alkylation.
The difference in product composition from the reactions of 3a
and 3b with HCHO/alkali prompted us to explore the role of substit-
uents para- to phenolic-OH group in the macrocyclization reaction
of 3. Thus phenols with electron-withdrawing para-substituent
One of the authors (S.B.) is thankful to the Department of Atom-
ic Energy, Government of India, for the financial support in the
form of a senior research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.156.
References and notes
Table 1
Condensation of 3a with paraformaldehye in the presence of different alkali metal
hydroxides
1. For reviews in calixarene chemistry, see: (a) Gutsche, C. D. Calixarenes; Royal
Society of Chemistry: Cambridge, 1989; (b) Gutsche, C. D. Calixarenes Revisted;
Royal Society of Chemistry: Cambridge, 1998; (c) Ikeda, A.; Shinkai, S. Chem.
Rev. 1997, 97, 1713–1734; (d) Takeshita, M.; Shinkai, S. Bull. Chem. Soc. Jpn.
1995, 68, 1088–1097; (e) Böhmer, V. Angew. Chem., Int. Ed. 1995, 34, 713–745.
2. (a) Arnaud-Neu, F.; Collins, E. M.; Deasy, M.; Ferguson, G.; Harris, S. J.; Kaitne-r,
B.; Lough, A. J.; McKervey, M. A.; Marques, E.; Ruhl, B. L.; Schwing-Weill, M. J.;
Seward, E. M. J. Am. Chem. Soc. 1989, 111, 8681–8691; (b) Zetta, L.; Wolf-f, A.;
Vogt, W.; Platt, K.-L.; Bohmer, V. Tetrahedron 1991, 47, 1911–1924; (c)
McKervey, M. A.; Seward, E. M.; Ferguson, G.; Ruhl, B. L. J. Org. Chem. 1986,
51, 3581–3584; (d) Murakami, H.; Shinkai, S. J. Chem. Soc., Chem. Commun.
Metal hydroxide
4aa (yield %)
5aa (yield %)
LiOH
NaOH
KOH
RbOH
CsOH
19
32
50
54
61
43
40
29
24
22
a
Isolated yield after column chromatography.

5826
S. Bhatt, S. K. Nayak / Tetrahedron Letters 50 (2009) 5823–5826
1603 cmÀ1
1993, 1533–1535; (e) Iwamoto, K.; Shinkai, S. J. Org. Chem. 1992, 57, 7066–
7073.
;
1H NMR (200 MHz, C5D5N): d 7.28–7.58 (m, 10H), 7.71 (d, 4H,
J = 7.4 Hz), 8.30 (s, 2H), 8.46 (s, 2H), 12.2 (br s, 2H, OH); 13C NMR (50 MHz,
C5D5N): d 117.1, 124.7, 125.6, 126.7, 126.8, 126.9, 127.5, 129.2, 132.8, 141.6,
3. Scheerder, J.; Fochi, M.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Org. Chem. 1994,
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K.; Thiemann, T.; Sawada, T.; Mataka, S. Tetrahedron 1999, 55, 2573–2580; (c)
Yamato, T.; Saruwatari, Y.; Yasumatsu, M. J. Chem. Soc., Perkin Trans 1 1997,
1725–1737; (d) Yamato, T.; Saruwatari, Y.; Nagayama, S.; Maeda, K.; Tashiro,
M. J. Chem. Soc., Chem. Commun. 1992, 861–862; (e) Tashiro, M.; Yamato, T. J.
Am. Chem. Soc. 1982, 104, 3701–3710.
156.4; EIMS: m/z = 364. Compound 3c: solid; mp 165–166 °C; IR (KBr):
m 3313,
3019, 2399, 2363 cmÀ1 1H NMR (200 MHz, acetone-d6): d 3.08 (s, 4H), 6.98 (d,
;
2H, J = 8.2 Hz), 7.18–7.54 (m, 14H), 8.60 (s, 2H, OH); 13C NMR (50 MHz,
acetone-d6): d 30.5, 115.5, 125.5, 126.3, 126.4, 128.7, 128.9, 132.4, 141.3,
155.0; EIMS: m/z = 366. 3d: solid mp 168–170 °C; IR (KBr): m ;
3392, 3019 cmÀ1
1H NMR (200 MHz, acetone-d6): d 2.87(s, 4H), 6.80 (d, 2H, J = 8.4 Hz), 7.18 (m,
4H), 8.78 (s, 2H, OH); 13C NMR (50 MHz, acetone-d6): d 29.4, 110.5 116.5, 129.2,
130.5, 132.0, 154.0; EIMS: m/z = 374.
12. Gutsche, C. D.; Dhawan, B.; No, K. H.; Muthukrishnan, R. J. Am. Chem. Soc. 1981,
103, 3782–3792.
13. Typical procedure for the synthesis of 5,12,20,27,35,42-hexa-tert-butyl-8,15,23,
30,38,45-hexahydroxy[2.1.2.1.2.1]metacyclophane (4a) and 5,12,20,27, 35,42,50,
57-octa-tert-butyl-8,15,23,30,38,45,53,60-octahydroxy
6. Yamato, T.; Saruwatari, Y.; Doamekpor, L. K.; Hasegawa, K.; Koike, M. Chem. Ber.
1993, 126, 2501–2504.
7. (a) Bhattacharya, S.; Nayak, S. K.; Semwal, A.; Chattopadhyay, S.; Banerjee, M. J.
Phys. Chem. A 2004, 108, 9064–9068; (b) Mohanty, J.; Pal, H.; Nayak, S. K.;
Chattopadhyay, S.; Sapre, A. V. J. Chem. Phys. 2002, 117, 10744–10751.
8. Nayak, S. K.; Banerji, A. Indian J. Chem. 1991, 30B, 286–287.
9. (a) Chen, Y.; Steinmetz, M. G. J. Org. Chem. 2006, 71, 6053–6060; (b) Shao, N.;
Zhang, Y.; Cheung, S.; Yang, R.; Chan, W.; Mo, T.; Li, K.; Liu, F. Anal. Chem. 2005,
77, 7294–7303.
[2.1.2.1.2.1.2.1]metacyclophane (5a): a dry argon-filled three-necked round-
bottomed flask was charged with 3a (2.0 g, 6.13 mmol), paraformaldehyde
(0.72 g, 24.0 mmol), xylene (50 mL), and 10 N aqueous NaOH (1.2 mL). The
reaction mixture was refluxed for 12 h (until an insoluble solid separated out),
cooled, acidified with dilute 3 N aqueous HCl solution, extracted with
chloroform, and dried (MgSO4). The solvent was evaporated to yield a crude
product which was purified by column chromatography over silica gel to yield
4a (0.66 g, 32% yield) and 5a (0.83 g, 40% yield). 4a: colorless solid (crystallized
10. Typical procedure for the synthesis of 5-tert-butyl-2-hydroxybenzaldehyde (1a)
from 4-tert-butylphenol: dry paraformaldehyde (3.5 g) was added in portions to
from CHCl3-hexane); mp >300 °C; IR (KBr):
m ;
3290, 2958, 2901, 2869 cmÀ1 1H
a
mixture of 4-tert-butylphenol (5.0 g, 33.3 mmol), triethylamine (13 mL,
NMR (200 MHz, CDCl3): d 1.32 (s, 54H), 2.97 (s, 12H), 4.03 (s, 6H), 7.03(s, 6 H),
7.25 (s, 6H), 8.94 (brs, 6H, OH); 13C NMR (50 MHz, CDCl3): d 31.5, 32.1, 32.5,
34.0, 125.6, 125.7, 127.1, 127.5, 143.8, 148.6; EIMS: m/z = 1014; Anal. Calcd for
C69H90O6: C 81.61, H 8.93. Found: C 81.42, H 8.78; 5a: solid (crystallized from
93.3 mmol), and anhydrous MgCl2 (9.8 g, 103 mmol) in acetonitrile (300 mL).
The mixture was refluxed for 8 h, cooled to room temperature, acidified with
aqueous 3 N HCl solution, and extracted with ether. The ether layer was
washed with water, and brine, and dried (MgSO4). Removal of solvent yielded a
crude material which was purified by column chromatography (SiO2) to yield
CHCl3–hexane); mp 240–241 °C; IR (KBr):
m ;
3365, 2963, 2901, 2868 cmÀ1 1H
NMR (200 MHz, CDCl3): d 1.29 (s, 72H), 2.76 (br s, 16H), 3.62 (br s, 4H), 4.46 (br
s, 4H), 7.01 (d, 8 H, J = 2.1 Hz), 7.24 (d, 8H, J = 2.1 Hz), 9.82 (s, 8H, OH); 13C
NMR(50 MHz, CDCl3): d 31.6, 32.1, 33.0, 34.0, 125.2, 125.6, 127.0, 127.7, 143.5,
148.7; EIMS: m/z = 1353; Anal. Calcd for C92H120O8: C 81.61, H 8.93. Found: C
81.73, H 8.81.
1a (5.69 g, 96% yield); oil; IR (neat):
m ;
3418, 2964, 1660, 1486, 1265 cmÀ1 1H
NMR (200 MHz, CDCl3): d 1.32 (s, 9H), 6.93 (d, 1H, J = 10 Hz), 7.51 (d, 1H,
J = 2 Hz), 7.58 (dd, 1H, J = 2, 10 Hz), 9.88 (s, 1H, OH), 10.86 (s, 1H, CHO); 13C
NMR (50 MHz, CDCl3): d 31.1, 34.0, 117.1, 119.9, 129.6, 134.6, 142.6, 159.4,
196.7; EIMS: m/z = 178.
14. Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283–10286.
15. Masutani, K.; Irie, R.; Katsuki, T. Chem. Lett. 2002, 36–37.
11. Typical procedure for the synthesis of (E)-1,2-bis-(5-tert-butyl-2-hydroxy-
phenyl)ethene (2a) and 1,2-bis-(5-tert-butyl-2-hydroxyphenyl)ethane (3a): a dry
argon-filled three-necked round-bottomed flask was charged with dry dioxane
(350 mL), titanium(IV) chloride (10.5 mL, 96 mmol), and zinc dust (12.6 g,
192 mmol), and the mixture was refluxed for 3 h. The black slurry thus
obtained was cooled to 0 °C and then a solution of 1a (5.69 g, 32 mmol) in
dioxane (20 mL) was added to it. The mixture was further refluxed for 2 h and
cooled to room temperature, diluted with diethyl ether, quenched with 10%
aqueous K2CO3 solution (5 mL), and passed through a small bed of Celite. The
Celite bed was thoroughly washed with ether and the filtrate was dried
(MgSO4). Removal of the solvent and subsequent column chromatography over
silica gel yielded 2a (2.59 g, 50% yield) and 3a (1.51 g, 29% yield), respectively.
Catalytic hydrogenation [Pd–C(10%)–EtOH] of 2a afforded 3a in 78% yield.
Compounds 3b, 3c, and 3e were synthesized following a similar procedure
used for 3a. Spectral data for selected compounds: 2a: solid; mp 210–211 °C;
16. Typical procedure for the synthesis of 5,12,20,27,35,42-hexamethyl-8,15,23,
30,38,45-hexakis[(ethoxycarbonyl)methoxy][2.1.2.1.2.1]metacyclophane (6) from
3b in two steps: the crude macrocyclic mixture obtained from the condensation
of 3b (0.88 g, 3.64 mmol) with formaldehyde (following the same procedure
described for the synthesis of 4a/5a from 3a) was added to a mixture of
anhydrous K2CO3 (1.66 g, 12 mmol) and ethyl bromoacetate (3.6 mL, 32 mmol)
in dry acetone (20 mL). The mixture was refluxed for 16 h, cooled to room
temperature, filtered, and the solid residue was washed thoroughly with
methylene chloride. The organic layer was evaporated under reduced pressure.
The excess ethyl bromoacetate was removed in vacuo, leaving a solid residue
which was chromatographed over silica gel to yield 6 (1.14 g, 0.89 mmol, 73%
overall yield in two steps). Colorless solid (crystallized from CHCl3–hexane);
mp 61–64 °C; IR (neat):
m ;
3019, 2927, 1755 cmÀ1 1H NMR (200 MHz, CDCl3): d
1.26 (t, 18H, J = 7.1 Hz), 1.7 (s, 18H), 3.05 (s, 12H), 3.89 (s, 6 H), 4.23 (m, 24H),
6.52 (s, 6H), 6.60 (s, 6H); 13C NMR (50 MHz, CDCl3): d 14.0, 20.2, 28.3, 28.6,
60.9, 70.2, 129.0, 129.1, 132.8, 133.3, 133.8, 152.6, 169.0; EIMS: m/z = 1279.
Anal. Calcd for C75H90O18: C 70.40, H 7.09. Found: C 70.12, H 6.98.
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IR (KBr):
m ;
3424, 2950, 1642 cmÀ1 1H NMR (200 MHz, CDCl3): d 1.32 (s, 18H),
6.84 (d, 2H, J = 8.4 Hz), 7.13 (m, 2H), 7.60 (m, 4H), 8.38 (s, 2H, OH); 13C NMR
(50 MHz, acetone-d6): d 30.9, 33.6, 115.2, 122.9, 123.6, 124.3, 125.0, 141.9,
152.3; EIMS: m/z = 324. Compound 3b: solid; mp 133–134 °C; IR (KBr):
m
= 3252, 2920, 1614, 1505 cmÀ1 1H NMR (200 MHz, CDCl3): d 2.29 (s, 6H),
;
2.80 (s, 4H), 6.71 (br s, 2H, OH), 6.80 (d, 2H, J = 7.8 Hz), 6.96 (m, 4H); 13C NMR
(50 MHz, CDCl3): d 20.4, 32.0, 115.3, 127.7, 128.1, 130.1, 130.6, 151.3; EIMS: m/
z = 242. Compound 2c: solid; mp 265–267 °C; IR (KBr):
m 3331, 3020,