Synthesis of new dihydroxy-dioxygenated ortho-[2,x]cyclophanes

Article abstract of DOI:10.3987/com-00-9022

The synthesis of title compounds (1a-f) by intramolecular reductive coupling is presented. The reaction is carried out in water solution, in the presence of Zn or Al powder, in basic media.

Full text of DOI:10.3987/com-00-9022

HETEROCYCLES, Vol. 53, No.11, 2000, p.2459 - 2470, Received, 26th July, 2000
SYNTHESIS OF NEW DIHYDROXY-DIOXYGENATED ortho-
[2,x]CYCLOPHANES
Cristian Simiona, Alina Simiona, Yoshiharu Mitomaa, Satoko
Nagashimaa, Takatoshi Kawajib, Iwao Hashimotob, and Masashi
Tashiro*a
aTohwa Institute for Science, Tohwa University, 1-1-1 Chikushigaoka, Minami-ku,
b
Fukuoka 815-8510, Japan and Department of Materials Science, Wakayama
National College of Technology, Noshima 77, Nada-cho, Gobo, Wakayama 644-
0023, Japan
Abstract - The synthesis of title compounds (1a-f) by intramolecular reductive
coupling is presented. The reaction is carried out in water solution, in the presence
of Zn or Al powder, in basic media.
INTRODUCTION
The reductive coupling of carbonyl compounds using different catalytic systems (such as metals, low-valent
early transition metal species, salts or complexes) is known as pinacol coupling reaction, and various
reducing agents for this reaction have been developed extensively over the last three decades.1 This
particular method for constructing carbon-carbon bond, subsequently 1,2-diols, by reductive coupling of
carbonyl compounds has received far more attention as an intermolecular process than as an intramolecular
one. Nevertheless, several intramolecular versions of the above reaction were effectively employed as key
steps in the total synthesis of some complex natural and unnatural products. Thus, we can easily classify the
intramolecular reductive coupling processes as: 1) starting from aliphatic dialdehydes;2 2) starting from
thioether dicarbonyl compounds;3 3) starting from biphenyl derivatives;4 4) used in syntheses of natural
products (such as taxoid ring systems,5 trehazoline6 or trehazolamine,7 inositol derivatives,8 cembranoids9 or
other terpenoids10). Furthermore, these syntheses imply the use of sophisticated reagents in carefully chosen
reaction conditions. We developed recently a new method for performing the reductive coupling of carbonyl
or imine compounds that proved to be effective in aqueous conditions, in the presence of cheap,
commercially available metallic powders of Al or Zn, in a basic media (usually 10% aqueous NaOH
solution).11 This method has already been applied to the single-step synthesis of tetrahydroxy[2,2]meta-
cyclophanes via pinacol coupling reaction of 1,3-benzene dicarboxaldehydes.12
We wish to report now the synthesis of a series of bridge-hydroxylated [2,x]ortho-cyclophanes (x=3~8),

with two hydroxyl groups in the first bridge and two or three oxygen atoms in the second bridge, namely
4,5-dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclononane (1a), 4,5-dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclo-
decane (1b), 4,5-dihydroxy-1,8-dioxy-2,3:6,7-dibenzocycloundecane (1c), 4,5-dihydroxy-1,8-dioxy-2,3:6,7-
dibenzocyclododecane (1d), 4,5-dihydroxy-1,8,11-trioxy-2,3:6,7-dibenzo-cyclotridecane (1e) and 4,5-
dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclotetradecane (1f), respectively.
RESULTS AND DISCUSSIONS
Our approach strategy to the target molecules involves the intramolecular reductive coupling of aromatic
aldehydes connected by a dietheric bridge. Such compounds can be readily obtained, using a two-step
synthesis, from salicylaldehyde, as presented in the retrosynthetic scheme:
8
1
X
X
O
O
O
O
OH
O
HO OH
O
O
1a-f
2a-f
3
X = CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)2-O-(CH2)2, (CH2)6
Scheme 1 Retrosynthesis scheme for diols (1a-f)
We have already investigated the behavior of o- and p-anisaldehydes toward pinacol coupling.11c Both
proved to be favorable substrates, yielding consequently the corresponding diols. We decided therefore to
submit some compounds with structures of type (2a-f) to the intramolecular reductive coupling. Moreover, a
scrutinized investigation of the chemical literature showed us no mentions of diols with structures of title
molecules (1a-f).
Previous reports on the synthesis of some dialdehydes of type (2) showed two groups of processes: a) the
transformation of salicylaldehyde into the corresponding sodium alcoxyde and a subsequent Williamson
reaction with a dibrominated compound, in reflux of DMF13 or b) a one-pot reaction among salicylaldehyde,
a dihalogenated compound and NaOH, without isolation of the sodium salt, in boiling alcohol/NaOH
solution14 or boiling THF/HMPA solution.15 We performed the syntheses of compounds (2a-f) as one-pot
reactions, using salicylaldehyde and the corresponding dibrominated compounds, in ethanol and in the
presence of a diluted aqueous NaOH solution. All reactions were carried out by refluxing the reaction
mixture for 72 h. We also found out that nitrogen flow is not necessary (there are no changes concerning the
total yield of the reaction), as it was previously mentioned in literature data.14
X
O
O
OH
NaOH, Br(Cl)-X-Br(Cl)
H2O, EtOH
reflux, 72 h
O
O
O
3
2a-f
Scheme 2 Synthesis of dialdehydes (2a-f)

Table 1. Synthesis of dialdehydes (2a-f)
mp (˚C) (lit.,13a mp)
131 (131-132)
Cpd.
2a
2b
2c
X
Yield (%)
-CH2-
-(CH2)2-
-(CH2)3-
57
45
62
130 (130-131)
98 (97-98)
2d
2e
2f
-(CH2)4-
-(CH2)2-O-(CH2)2-
-(CH2)6-
64
112 (112.5-113.5)
73.5-75 (66-6714a)
77-79 (79.5-80)
56
23a)
a) 1,6-Dichlorohexane was used instead of the corresponding dibrominated compound.
Pinacol intramolecular condensations of compounds (2a-f) were carried out in 10% aqueous NaOH solution
and in the presence of Zn or Al powder. The dialdehyde was dispersed in 10 mL of ethanol, the metallic
powder (Zn or Al) was added and after that the NaOH solution was poured into the reaction flask, in one
portion. The reaction mixture was kept at 60˚C and ultrasonication for 5 h, under mechanical stirring (for
Methods A and B), or at room temperature and magnetical stirring, for 5 h (for Methods C and D). The
results of these processes are summarized in Table 2.
X
X
O
O
O
O
Method A, B, C or D
HO OH
O
O
2a-f
1a-f
Scheme 3 Synthesis of diols (1a-f)
Table 2. Syntheses of diols (1a-f)
Isolated Yield (%) (Recovery of 2a-f (%))
Method
D a)
Cpd.
X
mp (˚C)
A
B
C
1a
1b
1c
1d
1e
1f
-CH2-
-(CH2)2-
-(CH2)3-
85 (5) 32 (36) 73 (9) 40 (40)
55 (11) 74 (24) 41 (20) 64 (27)
166-168
149-151
180-182
216-218
176-180
96-98
62 (4) 77 (6)
60 (6) 59 (26)
-(CH2)4-
53 (8) 50 (29) 50 (27) 42 (48)
39 (2) 41 (10) 47 (7) 49 (18)
46 (11) 65 (21) 52 (8) 73 (17)
-(CH2)2-O-(CH2)2-
-(CH2)6-
a) Method A: Zn, 10% NaOH, ultrasonication, 60˚C, 5 h; Method B: Al, 10% NaOH, ultrasonication, 60˚C,
5 h; Method C: Zn, 10% NaOH, rt, 5 h; Method D: Al, 10% NaOH, rt, 5 h.
Although the use of Al powder seems to be more effective in these processes, Zn powder afforded a higher
purity of desired cyclic diols. Longer reaction time does not affect overall yield in the case of small rings
(1a-c), but the transformations are almost quantitative when 1d-f are obtained in 24 h reactions.
An interesting aspect in the syntheses of diols (1a-f) is represented by the fact that only one isomer was
formed. On the basis of NMR studies we can assume a trans configuration of the central cycle, which is in
agreement with previous stereochemical studies that also emphasized the preferential formation of trans

structures,2a,2c,4 exception being made by reductive coupling reactions of aliphatic dialdehydes catalyzed by
SmI2 or Bu3SnH.2b,2d,2f For example, McMurry2c showed that for titanium-induced intramolecular
pinacolization, the ratio between cis and trans isomers varies from cis as major product to trans as major
product in direct connection with the size of the ring: small rings prefer a cis configuration while larger
cyclic compounds adopt a trans configuration. Furthermore, most of the reductive coupling reactions were
assumed to proceed by the dimerizations of carbonyl radical anions formed by a single electron transfer.2c
The diradicals can dimerize either on the metal surface or when linked to the complex which catalyzes the
reaction (so that steric interactions are minimized):
C
O
C
C
O
C
O
C
HO
C
O
or
HO
Y
cis configuration
Metal
Scheme 4 McMurry’s model for the formation of cis configuration of diols2c
In McMurry’s reductive coupling processes or in other such similar processes, the affinity of Ti for oxygen
or of SmI2 for oxygen, respectively, may offer a possible explanation for the mechanism presented in
Scheme 4. In the case of Zn or Al, the relation between the metal and the oxygen atom or the carbonyl
group is not clearly established, but we can suppose that: 1) if the distance between the two carbonyl groups
is long enough (at least 8 or 9 atoms, as in the case of aliphatic dialdehydes2c), 2) if the molecule presents a
rigid system, similar to aromatic aldehydes, and 3) if the chain connecting the two carbonyl groups offers
few possibilities of rotation of the molecule, then the approach of the two carbonyl moieties will take place
in such a manner that the two carbonyl groups are coming from opposite directions and this will compel the
diradical into a conformation in which the two oxygen atoms are in opposite positions, leading finally to a
trans configuration of the intramolecular reductive coupling product:
X
C
X
X
C
X
X
C
X
O
C
O
C
O
X
X
O
HO
C
C
C
OH
trans configuration
O
O
Metal
Metal
Scheme 5 Proposed model for the formation of trans configurated diols
Thus, it seems very probable that all our compounds assumed a trans configuration due to their aromatic
bridged structures. An illustration of such behaviour is the different ratios between cis and trans isomers
obtained in the case of cyclic aliphatic diols (4, 5 and 6):2c,2h

OH
OH
OH
OH
OH
OH
4
5
6
5 : 95
25 : 75
5 : 95
cis / trans:
Scheme 6 cis/trans Ratios for cyclic aliphatic diols (4-6)
As we can see from Scheme 6, just by introducing a small restrain such as two double bonds in a 12-atoms
chain, the ratio of cis / trans isomers changed from 25 : 75 to 5 : 95.
On the other hand, the 1H-NMR of the diols (1a-f) showed symmetrical aromatic rings (identical signals for
all 4 types of aromatic protons – see EXPERIMENTAL) and a single signal for both the CH(OH) methyne
groups, although it is splitted in two due to coupling with OH groups (on deuteration, the methyne signal
became a sharp singlet). A singlet for both methyne groups means that both groups are equivalent. Getting
identical signals for all the 4 types of aromatic protons requires similar environments and this is possible in a
trans configuration, as suggested also by MM2 and MOPAC calculation and molecule geometry simulation.
In order to establish with great certainty the stereochemistry of each product, we converted the diols into
their acetonides:2h
X
O
O
O
X
O
O
(CH3)2CO, I2
molecular sieves, 4A
reflux, 1h
O
HO OH
H3C CH3
1a-f
7 a-f
Scheme 7 Transformation into acetonides (7a-f) of diols (1a-f)
In all cases, the acetonides showed the -CH(OR)- methine hydrogens as sharp singlet in the range 5.29-5.69
ppm and, most important, the two methyl groups as a singlet between 1.47 and 1.61 ppm. This indicated
clearly a trans configuration.2h In the case of cis acetonide the two methyl groups present two different
signals.18
CONCLUSIONS
We succeeded in the cyclization of dialdehydes by intramolecular reductive coupling processes, in aqueous
media and in convenient reaction conditions. Moreover, the reactions presented a very high stereoselectivity,
the trans isomers being the single reductive coupling products.
ACKNOWLEDGEMENT
The authors thank Ms. Miho Tamura for performing all elemental analyses.

EXPERIMENTAL
Melting points were determined on a Yanaco Micro Melting Point Apparatus and are uncorrected. All NMR
spectra were recorded on a JEOL JNM-LA 300, 300 MHz, in CDCl3 with TMS as internal standard. J values
are given in Hz. Identification of products in reaction mixtures was made by GC (SHIMADZU GC=17A,
carrier gas N2, pressure 135 Kgf/cm2, flow 55 mL/min on a J&W Scientific DB-1 fused silica capillary
column, length 30 m, I.D. 0.32 mm with film of 0.25 mm) and GC-MS (Hewlett-Packard HP6890 GC,
carrier gas He, flow 1.5 mL/min, velocity 48 and pressure 10.3, J&W Scientific DB-1 fused silica capillary
column and Jeol - AUTOMASS system II MS). IR spectra were recorded on a JEOL JIR-WINSPEC50
(KBr).
General Procedure for the Synthesis of Dialdehydes (2a-f)
In a 500 mL 3-necked round bottom flask provided with reflux condenser were introduced 12.2 g (0.1 mol)
salicylaldehyde in 10 mL of EtOH and 200 mL of 2% aqueous NaOH (0.1 mol NaOH) solution. After 15
min of stirring, a solution of 0.05 mol of the corresponding dibrominated compound disolved in 150 mL of
EtOH was added in one portion. The mixture was kept with magnetical stirring, under reflux, for 72 h. The
reaction mixture was cooled and kept for 24 h on ice. The dialdehyde slowly precipitated. After filtration
and drying, the crude dialdehydes were recrystallized from EtOH or i-PrOH.
α,...
X
H3
3
H4
H5
O
O
2
1
4
5
CHO OHC
6
H6
2a-f
α
α
α β
2a: X = -CH2-, 2b: -CH2-CH2-, 2c: -CH2-CH2-CH2-,
α β
β
α
2d: -CH2-CH2-CH2-CH2-, 2e: -CH2-CH2-O-CH2-CH2-
γ
β
α
2f: -CH2-CH2-CH2-CH2-CH2-CH2-
2,2’-Methylenebis(oxy)bisbenzaldehyde (2a).
,14a
This compound was obtained as white needles (i-PrOH), mp 131˚C (lit.,13a
131-2˚C).16 ν (KBr, cm-1):
2863, 2759, 1685, 1596; δH: 6.00 (s, 2Hα), 7.14-7.20 (m, 2H5, 7.7, 7.5, 0.9), 7.34-7.38 (m, 2H3, 7.3, 0.9),
7.57-7.64 (ddd, 2H4, 7.5, 7.3 ,1.9), 7.84-7.88 (dd, 2H6, 7.7, 1.9), 10.46 (s, 2H, CHO); δC: 90.75 (Cα), 114.93
(2C3), 123.03 (2C5), 125.80 (2C1), 128.97 (2C6), 135.96 (2C4), 158.61 (2C2), 188.96 (2CHO); m/z
(intensity): 256 (M+, 1), 135 (M - O-C6H4-CHO, 100), 77 (C6H5, 32). Anal. Calcd for C15H12O4: C, 70.30;
H, 4.72. Found: C, 70.26; H, 4.75.
1,2-Bis(2’-formylphenyl)-1,2-dioxaethane (2b).
This compound was obtained as yellow needles (EtOH), mp 130˚C (lit.,13a 130˚C). ν (KBr, cm-1): 2942,
2865, 1685, 1596; δH: 4.59 (s, 4Hα), 7.04-7.12 (m, 2H5, 2H3, 8.3, 7.7, 6.6, 0.8), 7.53-7.61 (ddd, 2H4, 8.3,

6.6, l.9), 7.83-7.87 (dd, 2H6, 7.7, 1.9), 10.44 (s, 2H, CHO); δC: 67.07 (2Cα), 112.74 (2C3), 121.52 (2C5),
125.29 (2C1), 128.72 (2C6), 135.87 (2C4), 160.72 (2C2), 188.27 (2CHO); m/z (intensity): 270 (M+, 2), 149
(M – -O-C6H4-CHO, 37), 121 (M – -(CH2)2-O-C6H4-CHO, 100), 77 (C6H5, 45). Anal. Calcd for C16H14O4: C,
71.10; H, 5.22. Found: C, 71.12; H, 5.30.
1,3-Bis(2’-formylphenyl)-1,3-dioxapropane (2c).
This compound was obtained as white needles (EtOH), mp 98˚C (lit.,13a 97-98˚C). ν (KBr, cm-1): 2967, 2869,
2763, 1683, 1600; δH: 2.43 (q, 2Hβ, 6.0), 4.33 (t, 4Hα, 6.0), 6.99-7.07 (m, 2H5, 2H3, 8.4, 7.7, 7.5, 0.8), 7.51-
7.57 (ddd, 2H4, 8.4, 7.4, l.6), 7.80-7.85 (dd, 2H6, 7.7, 1.6), 10.50 (s, 2H, CHO); δC: 29.07 (Cβ), 64.64 (2Cα),
112.41 (2C3), 120.95 (2C5), 124.92 (2C1), 128.68 (2C6), 135.96 (2C4), 160.90 (2C2), 189.33 (2CHO); m/z
(intensity): 284 (M+, 2), 163 (M – -O-C6H4-CHO, 11), 121 (M – -(CH2)3-O-C6H4-CHO, 100), 77 (C6H5, 68).
Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found C, 71.72; H, 5.70.
1,4-Bis(2’-formylphenyl)-1,4-dioxabutane (2d).
The compound was obtained as white needles (EtOH), mp 112˚C (lit.,13a 112.5-113.5˚C). ν (KBr, cm-1):
2964, 2877, 1685, 1600; δH: 2.11 (t, 4Hβ, 5.4), 4.19 (t, 4Hα, 5.4), 6.96-7.06 (m, 2H5, 2H3, 9.1, 8.5, 7.7, 0.9),
7.50-7.57 (ddd, 2H4, 9.1, 8.5, l.3), 7.80-7.85 (dd, 2H6, 7.7, 1.3), 10.49 (s, 2H, CHO); δC: 25.90 (2Cβ), 67.88
(2Cα), 112.40 (2C3), 120.75 (2C5), 124.92 (2C1), 128.50 (2C6), 135.91 (2C4), 161.12 (2C2), 189.46 (2CHO);
m/z (intensity) 298 (M+, 1), 177 (M – -O-C6H4-CHO, 5), 158 (M – -(CH2)3-O-C6H4-CHO, 10), 121 (M – -
(CH2)4-O-C6H4-CHO, 63), 77 (C6H5, 50), 55 (100). Anal. Calcd for C18H18O4: C, 72.46; H, 6.07. Found C,
72.41; H, 6.17.
2,2’-Bis(o-formylphenyl)-diethyl ether (2e).
This compound was obtained as white needles (EtOH), mp 73.5–75˚C (lit.,15b 66-7˚C). ν (KBr, cm-1): 2937,
2894, 1685, 1600; δH: 3.98-4.01 (2d, 4Hβ, 4.6, 3.3), 4.25-4.29 (2d, 4Hα, 4.6, 3.3), 6.97-7.07 (m, 2H5, 2H3,
8.3, 7.7, 7.5), 7.50-7.57 (ddd, 2H4, 8.3, 7.5, l.9), 7.80-7.85 (dd, 2H6, 7.7, 1.9), 10.50 (s, 2H, CHO); δC: 68.32
(2Cβ), 68.89 (2Cα), 112.84 (2C3), 121.11 (2C5), 125.13 (2C1), 128.45 (2C6), 135.87 (2C4), 161.06 (2C2),
189.63 (2CHO); m/z (intensity): 314 (M+. 1), 135 (M – -CH2-O-(CH2)2-O-C6H4-CHO, 28), 121 (M  -
(CH2)2-O-(CH2)2-O-C6H4-CHO, 66), 77 (C6H5, 52), 55 (100). Anal. Calcd for C18H18O5: C, 68.78; H, 5.77.
5.77. Found C, 68.63; H, 5.80.
1,6-Bis(2’-formylphenyl)-1,6-dioxahexane (2f).
This compound was obtained as pale yellow needles (EtOH), mp 77-79˚C (lit.,13a 79.5-80˚C). ν (KBr, cm-1):
2931, 2852, 1685, 1675, 1596; δH: 1.59 (t, 4Hγ, 6.4), 1.90 (q, 4Hβ, 6.4), 4.10 (t, 4Hα, 6.4), 6.95-7.05 (m, 2H5,
2H3, 8.4, 7.3, 7.7, 0.8), 7.50-7.57 (ddd, 2H4, 8.4, 7.3, l.8), 7.80-7.85 (dd, 2H6, 7.7, 1.8), 10.51 (s, 2H, CHO);
δC: 25.85 (2Cγ), 29.06 (2Cβ), 68.29 (2Cα), 112.49 (2C3), 120.60 (2C5), 124.94 (2C1), 128.34 (2C6), 135.95
(2C4), 161.46 (2C2), 189.80 (2CHO); m/z (intensity) 326 (M+, 1), 205 (M – -O-C6H4-CHO, 3), 121 (M – -
(CH2)6-O-C6H4-CHO, 31), 77 (C6H5, 29), 55 (100). Anal. Calcd for C20H22O4: C, 73.60; H, 6.79. Found C,
73.57; H, 6.83.

General Procedure for the Synthesis of Cyclic Diols (1a-f)
Methods A and B: In a 100 mL 3-necked round bottom flask provided with reflux condenser and
mechanical stirrer were introduced 2 mmol of dialdehyde in 10 mL of EtOH and 30 mmol of metal (1.95 g
Zn or 0.9 g Al). Aqueous NaOH (10%) solution (20 mL, 4 mmol) was added in one portion. The reaction
mixture was stirred under ultrasonication, at 60˚C, for 5 h. The metallic residue was filtered off, washed
with water and dichloromethane. The filtrate was extracted with dichloromethane (45 mL in 3 portions). The
combined organic layers were dried on MgSO4, the solvent evaporated and the crude residue submitted to
column chromatography on Wakogel C-300 (silica gel, dimension of particle 45-70 µm, eluent hexane-
acetone 100:0 to 70:30).
Methods C and D: In a 100 mL round bottom flask provided with reflux condenser were introduced 2 mmol
of dialdehyde in 10 mL of EtOH and 30 mmol of metal (1.95 g Zn or 0.9 g Al). Aqueous NaOH (10%)
solution (20 mL, 4 mmol) was added in one portion. The reaction mixture was stirred at rt for 5 h. The
metallic residue was filtered off, washed with water and dichloromethane. The filtrate was extracted with
dichloromethane (45 mL in 3 portions). The combined organic layers were dried on MgSO4, the solvent
evaporated and the crude residue submitted to column chromatography on Wakogel C-300 (silica gel,
dimension of particle 45-70 µm, eluent hexane-acetone 100:0 to 70:30).
α,...
X
H3
3
H4
H5
O
O
2
1
4
5
CH
CH
6
H6
OH
OH
1a-f
α
β
α
α
1a: X = -CH2-, 1b: -CH2-CH2-, 1c: -CH2-CH2-CH2-,
α
β
β
α
1d: -CH2-CH2-CH2-CH2-, 1e: -CH2-CH2-O-CH2-CH2-
γ
α
β
1f: -CH2-CH2-CH2-CH2-CH2-CH2-
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclononane (1a).
This compound was obtained as white prisms, mp 166-168˚C. ν (KBr, cm-1): 3471 (OH, sh), 3357, 3299
(OH, br), 3020, 2937, 2886, 1604; δH: 3.07 (d, 2H, OH-exchanges with D2O, 3.5), 5.45 (s, 2Hα), 5.54 (d, 2H,
CH, 3.5), 6.81-6.87 (d, 2H3, 7.7), 6.95-7.03 (dd, 2H5, 7.5, 7.3), 7.07-7.16 (ddd, 2H4, 7.7, 7.3, 1.4), 7.20-7.25
(dd, 2H6, 7.5, 1.4); δC: 76.61 (2-C(OH)-), 101.01 (2Cα), 121.23 (2C3), 125.22 (2C5), 129.07 (2C6), 129.67
(2C4), 134.41 (2C1), 155.61 (2C2); m/z (intensity): 258 (M+, 1), 136 (M – -O-C6H4-CH-OH, 100), 122 (M – -
CH2-O-C6H4-CH-OH, 35), 105 (M – -O-CH2-O-C6H4-CH-OH, 16), 77 (C6H5, 48). Anal. Calcd for
C15H14O4: C, 69.75; H, 5.46. Found C, 69.82; H, 5.51.
4,5-Dihydroxy-1,8-dioxy-2,3:6,7dibenzocyclodecane (1b).
This compound was obtained as white prisms, mp 149-151˚C. ν (KBr, cm-1): 3403 (OH, sh), 3345 (OH,

br), 2939, 2881, 1600; δH: 2.85 (d, 2H, OH-exchanges with D2O, 2.9), 4.21 (d, 2Hα, 7.0), 4.44 (d, 2Hα, 7.0),
5.39 (d, 2H, CH, 2.9), 6.81-6.85 (dd, 2H3, 7.9, 1.1), 6.88-6.94 (ddd, 2H5, 7.7, 7.5, l.1), 7.07-7.13 (ddd, 2H4,
7.9, 7.7, l.8), 7.21-7.44 (dd, 2H6, 7.5, 1.8); δC: 70.59 (2Cα), 75.72 (2C(OH)-), 118.35 (2C3), 123.27 (2C5),
128.82 (2C6), 128.91 (2C4), 133.17 (2C1), 156.04 (2C2); m/z (intensity): 272 (M+, 3), 149 (M – -HO-C6H4-
CHOH, 28), 122 (M – -(CH2)2O-C6H4-CHOH, 100), 105 (M – -O-(CH2)2-O-C6H4-CHOH, 22), 77 (C6H5, 46).
Anal. Calcd for C16H16O4: C, 70.57; H, 5.92. Found C, 70.46; H, 6.09.
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocycloundecane (1c).
This compound was obtained as white prisms, mp 180-182˚C. ν (KBr, cm-1): 3469 (OH, sh), 3261 (OH, br),
2942, 2925, 2863, 1602; δH: 2.18 (2q superposed, 2Hβ, 4.6), 2.75 (d, 2H, OH-exchanges with D2O, 6.7), 4.13
(2t superposed, 2Hα, 4.6), 4.33 (2t superposed, 2Hα, 6.0), 5.27 (d, 2H, CH, 6.7), 7.00-7.10 (m, 2H5, 2H3, 7.8,
7.6, 7.5, 1.1), 7.20-7.27 (ddd, 2H4, 7.8, 7.5, l.6), 7.45-7.50 (dd, 2H6, 7.6, 1.6); δC: 28.93 (Cβ), 69.04 (2Cα),
71.81 (2-C(OH)-), 117.13 (2C3), 122.68 (2C5), 126.64 (2C6), 128.38 (2C4), 134.26 (2C1), 155.59 (2C2); m/z
(intensity): 286 (M+, 4), 165 (M – -O-C6H4-CHOH, 16), 135 (M – -(CH2)2-O-C6H4-CHOH, 36), 121 (M – -
(CH2)3-O-C6H4-CHOH, 100), 105 (M – -O-(CH2)3-O-C6H4-CHOH, 56), 77 (C6H5, 99). Anal. Calcd for
C17H18O4: C, 71.31; H, 6.34. Found C, 71.30; H, 6.47.
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclododecane (1d).
This compound was obtained as white prisms, mp 216-218˚C. ν (KBr, cm-1): 3490 (OH, sh), 3351 (OH, br),
2929, 2892, 2842, 1600; δH: 2.01-2.12 (m, 4Hβ), 2.42 (d, 2H, OH -exchanges with D2O, 6.8), 3.99-4.09 (m,
4Hα), 5.42 (d, 2H, CH, 6.8), 6.82-6.87 (dd, 2H3, 8.1, 0.7), 6.98-7.05 (ddd, 2H5, 7.4, 7.3, 0.7), 7.23-7.30 (ddd,
2H4, 8.1, 7.3, l.6), 7.49-7.54 (dd, 2H6, 7.4, 1.6); δC: 27.37 (2Cβ), 68.24 (2Cα), 70.53 (2-C(OH)-), 110.36
(2C3), 120.19 (2C5), 126.00 (2C6), 128.13 (2C4), 130.99 (2C1), 155.87 (2C2); m/z (intensity): 300 (M+, 5),
179 (M – -O-C6H4-CHOH, 10), 165 (M – -CH2-O-C6H4-CHOH, 8), 135 (M – -(CH2)3-O-C6H4-CHOH, 17),
105 (M – -O-(CH2)4-O-C6H4-CHOH, 22), 77 (C6H5, 69), 55 (100). Anal. Calcd for C18H20O4: C, 71.98; H,
6.71. Found C, 71.77; H, 7.00.
4,5-Dihydroxy-1,8,11-trioxy-2,3:6,7-dibenzocyclotridecane (1e).
This compound was obtained as white prisms, mp 176-180˚C. ν (KBr, cm-1): 3531 (OH, sh), 3397 (OH, br),
2923, 2879, 1600; δH: 2.61 (d, 2H, OH - exchanges with D2O, 5.5), 3.88-4.08 (m, 4Hβ, 2Hα), 4.15-4.22 (m,
2Hα), 5.36 (d, 2H, CH, 5.5), 6.84-6.88 (dd, 2H3, 8.3, 1.0), 6.95-7.02 (ddd, 2H5, 7.5, 7.5, 1.0), 7.19-7.26 (ddd,
2H4, 8.3, 7.5, l.7), 7.44-7.48 (dd, 2H6, 7.5, 1.7); δC: 68.18 (2Cβ), 70.38 (2Cα), 71.46 (2-C(OH)-), 112.42
(2C3), 121.08 (2C5), 127.53 (2C6), 128.32 (2C4), 130.11 (2C1), 155.56 (2C2); m/z (intensity): 316 (M+, 3),
165 (M – -(CH2)2O-C6H4-CHOH, 25), 121 (M – -(CH2)2O(CH2)2O-C6H4-CHOH, 100), 77 (C6H5, 55). Anal.
Calcd. for C18H20O5: C, 68.34; H, 6.37. Found C, 67.96; H, 6.49.
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclotetradecane (1f).
This compound was obtained as white prisms, mp 96-98˚C. ν (KBr, cm-1): 3559 (OH, sh), 3384 (OH, br),
2938, 2862, 2824, 1595; δH: 1.76-1.80 (m, 4Hγ), 1.82-1.92 (m, 4Hβ), 2.18 (d, 2H, OH, exchanges with D2O,
3.8), 4.02-4.08 (m, 4Hα), 5.43 (d, 2H, CH, 3.8), 6.85-6.87 (dd, 2H3, 8.0, 0.8), 6.96-7.03 (ddd, 2H5, 7.7,

7.5, 0.8), 7.22-7.29 (ddd, 2H4, 8.0, 7.5, l.7), 7.56-7.61 (dd, 2H6, 7.7, 1.7); δC: 26.01 (2Cγ), 26.95 (2Cβ), 68.24
(2Cα), 70.32 (2 -C(OH)-), 110.84 (2C3), 120.43 (2C5), 128.11 (2C6), 128.35 (2C1), 128.73 (2C4), 156.00
(2C2); m/z (intensity): 328 (M+, 3), 310 (M+– H2O, 5), 175 (M – -(CH2)2-O-C6H4-CH-OH, 44), 152 (M – -
(CH2)4-O-C6H4-CH-OH, 13), 121 (M – -(CH2)6-O-C6H4-CH-OH, 58), 107 (M – -O-(CH2)6-O-C6H4-CH-OH,
82), 77 (C6H5, 59), 55 (100). Anal. Calcd for C20H24O4: C, 73.15; H, 7.36. Found C, 73.02; H, 7.45.
General Procedure for the Preparation of Acetonides (7a-f) Using Acetone / Iodine / Molecular sieves19
To a solution of diol (0.2 mmol) in acetone (10 mL, pre-dried) placed in a 20 mL two-necked round-bottom
flask provided with reflux condenser were added 1.5 g molecular sieves, 4A, previously activated during 4
h at 100˚C. After being stirred for 5 min, 30 mg (0.12 mmol) iodine was added to the mixture. The mixture
was heated to reflux with stirring for 1 h. After being cooled to rt, ether (20 mL) was added to the resulting
mixture, which was filtered. The filtrate was washed twice with 10% aqueous Na2SO3 sol., twice with water
and with brine. The organic layer was dried over MgSO4 and then concentrated in vacuo. The crude residue
was directly submitted to NMR analysis.
H3
3
α,...
X
H4
H5
O
O
2
1
α
α
β
α
4
5
7a: X = -CH2-, 7b: -CH2-CH2-, 7c: -CH2-CH2-CH2-,
α β
β
α
6
7d: -CH2-CH2-CH2-CH2-, 7e: -CH2-CH2-O-CH2-CH2-
H6
O
O
γ
α β
7f: -CH2-CH2-CH2-CH2-CH2-CH2-
H3C CH3
7a-f
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclononane acetonide (7a).
δH: 1.60 (s, 6H, CH3), 5.17 (s, 2H, CH), 5.45 (s, 2Hα), 6.89-6.92 (m, 2H3), 6.99-7.31 (m, 2H5, 2H4), 7.66-
7.70 (m, 2H6)
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclodecane acetonide (7b).
δH: 1.51 (s, 6H, CH3), 4.16 (d, 2Hα, 7.0), 4.38 (d, 2Hα, 7.0), 5.29 (s, 2H, CH), 6.89-6.92 (m, 2H3), 7.01-7.06
(m, 2H5), 7.16-7.22 (m, 2H4), 7.56-7.59 (m, 2H6)
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocycloundecane acetonide (7c).
δH: 1.47 (s, 6H, CH3), 1.89-1.92 (m, 2Hβ), 4.07-4.15 (m, 2Hα), 4.32-4.38 (m, 2Hα), 5.36 (s, 2H, CH), 6.82-
6.85 (m, 2H5), 6.92-6.97 (m, 2H3), 7.14-7.19 (m, 2H4), 7.53-7.57 (m, 2H6)
4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclododecane acetonide (7d).
δH: 1.55 (s, 6H, CH3), 1.85-2.09 (m, 4Hβ), 3.91-4.08 (m, 4Hα), 5.51 (s, 2H, CH), 6.72-6.95 (m, 2H3, 2H5),
7.08-7.26 (m, 2H4), 7.40-7.45 (m, 2H6)
4,5-Dihydroxy-1,8,11-trioxy-2,3:6,7-dibenzocyclotridecane acetonide (7e).
δH: 1.54 (s, 6H, CH3), 3.65-3.75 (m, 4H), 4.00-4.13 (m, 4H), 5.69 (s, 2H, CH), 6.79-6.90 (m, 2H3, 2H5),
7.11-7.18 (m, 2H4), 7.32-7.35 (m, 2H6)

4,5-Dihydroxy-1,8-dioxy-2,3:6,7-dibenzocyclotetradecane acetonide (7f).
δH: 1.56 (s, 6H, CH3), 1.53-1.80 (m, 4Hγ, 4Hβ), 3.88-4.10 (m, 4Hα), 5.62 (s, 2H, CH), 6.70-6.94 (m, 2H3,
2H5), 7.07-7.53 (m, 2H4, 2H6)
REFERENCES AND FOOTNOTES
1
2
For different reviews see a) T. Wirth, Angew. Chem., Int. Ed. Engl., 1996, 35, 61; b) H. O. House,
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Chem. Soc., 1989, 111, 8236; h) J. E. McMurry and J.G. Rico, Tetrahedron Lett., 1989, 30, 1169
J. Nakayama, R. Hasemi, K. Yoshimura, Y. Sugihara, and S. Yamaoka, J. Org. Chem., 1998, 63, 4912
and ref. cited therein
3
4
a) K. Ohmori, M. Kitamura, and K. Suzuki, Angew. Chem. Int. Ed., 1999, 38, 1226; b) N. Taniguchi, T.
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5
a) K. Takatori, Y. Takeuchi, Y. Shinohara, K. Yamaguchi, M. Nakamura, T. Hirosawa, T. Shimizu, M.
Saito, S. Aizawa, O. Sugiyama, Y. Ohtsuka, and M. Kajiwara, Synlett, 1999, 975; b) I. Shiina, H.
Iwadare, H. Sakoh, M. Hasegawa, Y.-I. Tani, and T. Mukaiyama, Chem. Lett., 1998, 1; c) C. S.
Swindell, M. C. Chander, J. M. Heerding, P. G. Klimko, L. T. Rahman, J. V. Raman, and H.
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Tetrahedron Lett., 1994, 35, 4959; e) S. Arseniyadis, D. V. Yashunsky, R. Pereira de Freitas, M. M.
Dorado, E. Toromanoff, and P. Potier, Tetrahedron Lett., 1993, 34, 1137; f) K. C. Nicolau, Z. Yang, and
E. J. Sorensen, and M. Nakada, Chem. Commun., 1993, 1024
6
7
8
A. Boiron, P. Zillig, D. Faber, and B. Giese, J. Org. Chem., 1998, 63, 5877
I. Storch de Gracia, H. Dietrich, S. Bobo, and J. L. Chiara, J. Org. Chem., 1998, 63, 5883
a) J. L. Chiara and M. Martin-Lomas, Tetrahedron Lett., 1994, 35, 2969; b) J. P. Guidot, T. Le Gall, and
C. Mioskowski, Tetrahedron Lett., 1994, 35, 6671
9
a) J. E. McMurry and R. G. Dushin, J. Am. Chem. Soc., 1990, 112, 5942; b) J. E. McMurry, J. G. Rico,
and Y.-N. Shih, Tetrahedron Lett., 1989, 30, 1173
10 a) J. E. McMurry and N. O. Siemers, Tetrahedron Lett., 1994, 35, 4505; b) C. Anies, A. Pancrazi, and
J.-Y. Lallemand, Tetrahedron Lett., 1994, 35, 7771
11 a) T. Tsukinoki, Y. Mitoma, S. Nagashima, T. Kawaji, I. Hashimoto, and M. Tashiro, Tetrahedron Lett.,
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117; c) T. Tsukinoki, T. Kawaji, I. Hashimoto, S. Mataka, and M. Tashiro, Chem. Lett., 1997, 235
12 a) D. A. Sahade, K.-I. Tsukamoto, T. Thiemann, T. Sawada, and S. Mataka, Tetrahedron, 1999, 55,
2573; b) D. A. Sahade, S. Mataka, T. Sawada, T. Tsukinoki, and M. Tashiro, Tetrahedron Lett., 1997,
38, 3745
13 a) R. Jaunin and J.-P. Magnenat, Helv. Chim. Acta, 1959, 42, 328; b) R. Jaunin and A. Stoll, Helv. Chim.
Acta, 1960, 43, 1864
14 a) D. Baldwin, P. A. Duckworth, G. R. Erickson, L. F. Lindoy, M. McPartlin, G. M. Mockler, W. E.
Moody, and P. A. Tasker, Aust. J. Chem., 1987, 40, 1861; b) L. G. Armstrong and L. F. Lindoy,
Inorganic Chem., 1975, 14, 1322
15 a) J. Tirado-Rives, M. A. Oliver, F. R. Fronczek, and R. D. Gandour, J. Org. Chem., 1984, 49, 1627; b)
J. Tirado-Rives, R. D. Gandour, and F. R. Fronczek, Tetrahedron Lett., 1982, 23, 1639
16 L. F. Lindoy14a reported mp 124˚C, but the dialdehyde seemed to be a crude reaction product; R.
Jaunin13a reported a recrystallized product of mp 131-132˚C.
17 J. Tirado-Rives15b reported a melting point of a crude reaction product.
18 When performing the synthesis of diols (1b and 1e) using SmI2 in dry THF,2b the mixture of cis and trans
configurations for the corresponding diols were obtained. After chromatographic separation and
acetonidation, the cis diol acetonide presented two distinct signals for the two methyl groups at 1.60 and
1.80 ppm – T. Kawaji, unpublished results
19 K. P. R. Kartha, Tetrahedron Lett., 1986, 27, 3415