Ortho-directed lithiation of ω-phenoxy alcohols

Article abstract of DOI:10.1021/jo990443p

ω-Phenoxy alcohols, PhO(CH₂)(n)OH (n = 2-7), have been subjected to metalation with 2 equiv of n-butyllithium in tetrahydrofuran/methylcyclohexane solvent. Reaction of the resulting lithiated compounds with carbon dioxide (n = 2-7), benzaldehyde (n = 2-6), benzophenone (n = 2, 3), dimethylformamide (n = 2), ethyl formate (n = 2), and chlorodiphenylphosphine (n = 3) afforded the corresponding ortho- substituted hydroxyalkoxybenzenes in yields ranging from 45 to 83%. The synthesis is also reported of five new bis[o-(ω-hydroxyalkoxy)phenyl]mercury compounds (n = 2-6), four crystal structures of which have been determined.

Full text of DOI:10.1021/jo990443p

J . Org. Chem. 1999, 64, 5589-5592
5589
Or th o-Dir ected Lith ia tion of ω-P h en oxy Alcoh ols
Constantinos S. Salteris, Ioannis D. Kostas, Maria Micha-Screttas, George A. Heropoulos, and
Constantinos G. Screttas*
National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry,
4
8, Vas. Constantinou Avenue, 116 35 Athens, Greece
Aris Terzis
Institute of Materials Science, NCSR “Democritos”, 153 10 Aghia Paraskevi Attikis, Greece
Received March 11, 1999
2 n
ω-Phenoxy alcohols, PhO(CH ) OH (n ) 2-7), have been subjected to metalation with 2 equiv of
n-butyllithium in tetrahydrofuran/methylcyclohexane solvent. Reaction of the resulting lithiated
compounds with carbon dioxide (n ) 2-7), benzaldehyde (n ) 2-6), benzophenone (n ) 2, 3),
dimethylformamide (n ) 2), ethyl formate (n ) 2), and chlorodiphenylphosphine (n ) 3) afforded
the corresponding ortho-substituted hydroxyalkoxybenzenes in yields ranging from 45 to 83%. The
synthesis is also reported of five new bis[o-(ω-hydroxyalkoxy)phenyl]mercury compounds (n ) 2-6),
four crystal structures of which have been determined.
In tr od u ction
via “intramolecular metalation” by an initially formed
reactive side-chain metalated species.1 Still another
mode of coordination between the aromatic substrate and
the alkyllithium reagent leading to directed metalation
b,3
Aryllithium reagents resulting from ortho-directed
metalation have found considerable synthetic application
in organic and organometallic synthesis. The mechanism
1
7
is via mixed alkoxide-alkyllithium complex formation.
of this important reaction has been addressed in a
Indeed, there is ample evidence for the formation of such
2
number of recent publications. The preparation of these
complexes.8 Recently, directed lithiations have been
reagents relies on the ability of certain functional groups
to facilitate deprotonation of the aromatic compound in
a regiospecific manner. The number of these functional
groups is considerable, and new ones are continuously
being added to the list.3 It has been recognized that
these groups share the following two properties: first,
they are capable of forming complexes with alkyllithium
reagents, and second, they are devoid of electrophilic sites
that could provide alternative pathways in the reaction
with the alkyllithium reagent.1b Since alkyllithium re-
agents are electron deficient, they function as Lewis
reported from this laboratory for aromatic substrates
possessing both a heteroatom and an alkoxide functional-
ity.4 Attempts have been made to assess the relative
directing aptitude of the DMGs, and comparisons have
,4
been made by referring to the directing ability of the
methoxy group.9
In this paper, we demonstrate the ability of the
ω-lithiooxyalkoxy group to function as an ortho-directing
substituent in the lithiation of aromatics. The synthetic
utility of these new aryllithium reagents has been
demonstated by reacting them with a series of electro-
philes. In addition, we report the crystal structures of
four members of a new class of organomercurials, those
of bis[o-(ω-hydroxyalkoxy)phenyl]mercury compounds.
5
acids, and as such they can form complexes with Lewis
6
bases. Therefore, the existence of an atom in the directed
metalation group (DMG) bearing a lone pair of electrons,
i.e., a heteroatom, is almost a general requirement.1b In
addition, the ortho-directing group renders stabilization
to the aryllithium product by intramolecular interactions.1
In certain instances, however, directed lithiation occurs
a
Resu lts a n d Discu ssion
Lith ia tion of ω-P h en oxy Alcoh ols. Metalation of
ω-phenoxy alcohols was performed using 2 equiv of
n-butyllithium in THF/methylcyclohexane solvent. The
resulting substituted phenyllithiums were derivatized by
reaction with a series of ordinary electrophiles, yielding
the corresponding ortho-disubstituted benzenes in yields
ranging from 45 to 83%; see Scheme 1 and Table 1. The
results from the derivatization of 2 (n ) 2-6) with the
three electrophiles, carbon dioxide, benzaldehyde, and
*
To whom correspondence should be addressed.
1) Selected reviews: (a) Klumpp, G. W. Recl. Trav. Chim. Pays-
Bas 1986, 105, 1. (b) Snieckus, V. Chem. Rev. 1990, 90, 879.
2) (a) Coiti n˜ o, E. L.; Ciuffarin, E.; Floris, F. M.; Tomasi, J . J . Phys.
(
(
Chem. A 1998, 102, 8369. (b) Rennels, R. A.; Maliakal, A. J .; Collum,
D. B. J . Am. Chem. Soc. 1998, 120, 421. (c) Stratakis, M. J . Org. Chem.
1
997, 62, 3024. (d) Faigl, F.; Fogassy, K.; Thurner, A.; T o´ ke, L.
Tetrahedron 1997, 53, 4883. (e) Beak, P.; Basu, A.; Gallagher, D. J .;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. (f) Sa a´ ,
J . M.; Martorell, G.; Frontera, A. J . Org. Chem. 1996, 61, 5194. (g)
Beak, P.; Kerrick, S. T.; Gallagher, D. J . J . Am. Chem. Soc. 1993, 115,
1
0628. (h) Collum, D. B. Acc. Chem. Res. 1992, 25, 448.
3) (a) Mortier, J .; Moyroud, J . J . Org. Chem. 1994, 59, 4042 and
(7) (a) Meyer, N.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1978,
17, 521. (b) Meyer, N.; Seebach, D. Chem. Ber. 1980, 113, 1304.
(8) Screttas, C. G.; Micha-Screttas, M. Organometallics 1984, 3, 904.
(b) Screttas, C. G.; Micha-Screttas, M. J . Organomet. Chem. 1985, 290,
1. (c) Screttas, C. G.; Micha-Screttas, M. J . Organomet. Chem. 1986,
316, 1.
(9) (a) Slocum, D. W.; J ennings, C. A. J . Org. Chem. 1976, 41, 3653.
(b) Winkle, M. R.; Ronald. R. C. J . Org. Chem. 1982, 47, 2101. (c) Wada,
A.; Kanatomo, S.; Nagai, S. Chem. Pharm. Bull. 1985, 33, 1016.
(
references therein. (b) Moyroud, J .; Guesnet, J .-L.; Bennetau, B.;
Mortier, J . Bull. Soc. Chim. Fr. 1996, 133, 133.
(4) (a) Kostas, I. D.; Screttas, C. G.; Raptopoulou, C. P.; Terzis, A.
Tetrahedron Lett. 1997, 38, 8761. (b) Andrieu, J .; Steele, B. R.; Screttas,
C. G.; Cardin, C. J .; Fornies, J . Organometallics 1998, 17, 839.
(
5) Longuet-Higgins, H. C. Quart. Rev. 1957, 11, 121.
(6) Screttas, C. G.; Eastham, J . F. J . Am. Chem. Soc. 1965, 87, 3276.
1
0.1021/jo990443p CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5
590 J . Org. Chem., Vol. 64, No. 15, 1999
Salteris et al.
Sch em e 1
Ta ble 1. Rea ction s of Or ga n olith iu m s 2 w ith
Electr op h iles
group attached to benzene has two available sites for
coordination with the lithiating organolithium, namely
the phenoxy oxygen and the lithioxyalkyl groups, it
appears to us that the lithioxyalkyl moiety is the site of
attachment of the organolithium reagent, whereas the
role of the phenoxy oxygen facilitates considerably the
observed directed lithiation. This is born out from the
organo-
lithium
electro-
phile
pro- yielda
mp/bp °C
(solv recr/mmHg)
duct
(%)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
a : n ) 2 CO2
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
5a
5b
55
63
57
79
80
83
64
75
79
80
83
59
83
51
59
65
45
78
70
64
72
oil
b: n ) 3 CO2
112-114 (PhCH3)b
56-58 (hexane)
c: n ) 4 CO2
d : n ) 5 CO2
oil
7
reported case of directed metalation of 2-phenylethanol,
e: n ) 6 CO2
66-67.5 (PhCH3)
62-63 (PhCH3)
which, although lacking a phenoxy oxygen, undergoes
ortho-metalation albeit under much more vigorous condi-
tions, and this could be ascribed to the higher electro-
f: n ) 7 CO2
a : n ) 2 PhCHO
b: n ) 3 PhCHO
c: n ) 4 PhCHO
d : n ) 5 PhCHO
e: n ) 6 PhCHO
a : n ) 2 Ph2CO
b: n ) 3 Ph2CO
70-71 (PhCH3/hexane)
116-118 (PhCH3)
92-93.5 (PhCH3)
101-105 (PhCH3/hexane)
79-81 (PhCH3/hexane)
134-136 (PhCH3)
113-114 (PhCH3)
132-134 °C (1)c
negativity of the -OCH
that of -CH CH OLi.
2 2
CH OLi group as compared to
2
2
It is appropriate to refer to the synthetic potential of
the ortho-substituted phenyllithiums reported in this
work. Carboxylation and subsequent acidic hydrolysis of
a : n ) 2 HCONMe2 6a
a : n ) 2 HCO2Et
b: n ) 3 Ph2PCl
a : n ) 2 HgCl2
b: n ) 3 HgCl2
c: n ) 4 HgCl2
d : n ) 5 HgCl2
e: n ) 6 HgCl2
7a
8b
9a
9b
9c
9d
9e
127-128.5 (i-PrOH)
94-96 (EtOH/hexane)
104.5-106 (i-PrOH)
85-86.5 (EtOH)
80-82 (EtOH)
53-55 (EtOH/hexane)
72-74 (EtOH)
2
presents simple and efficient one-pot syntheses of o-(ω-
hydroxyalkoxy)benzoic acids 3. Such acids are of interest
as precursors to heterocyclic analogues of ortho-fused
metabolites.12 The derivatization of 2 with benzaldehyde,
benzophenone, and ethyl formate yielded 4, 5, and 7,
respectively, which contain various types of diols and
triols, primary-secondary or a primary-tertiary. These
compounds could serve as starting materials for the
synthesis of heterocyclic compounds. Organolithiums 2
are also useful for the introduction of the formyl group
to the ortho position of the aromatic ring of the ω-phenoxy
alcohols. Thus, reaction of 2a with DMF yielded the
functionalized aldehyde 6a , potential precursor for the
synthesis of “capped porphyrins”, some complexes of
which serve as models for the active site of the oxygen-
binding haemoproteins.13
a
Isolated yields. b Lit.12 mp 107.5-109 °C. c Lit.13 mp 46-46.5
°
C.
mercuric chloride, allow the assessment of the reproduc-
ibility of the metalation step, provided that the reaction
with all three electrophiles is quantitative. We notice,
however, that the yields of a given lithio derivative, e.g.,
that with n ) 2, vary considerably and that the yields
with benzaldehyde are consistently higher in almost
every case. Therefore, taking the metalation yield to be
equivalent to the yield of the derivative with benzalde-
hyde, we notice a 10-15% jump in yield on going from n
In addition to C-C bond formation, dilithiated species
were applied also to C-heteroatom bond formation.
2
)
2 to n ) 3 and higher and, as n in 1 increases, a
Thus, reaction of organolithium 2b with chlorodiphenyl-
phosphine yielded phosphine 8b, which is of interest as
a potential hemilabile P,O,O-ligand in transition-metal
homogeneous catalysis.14
Syn th esis a n d Cr ysta l Str u ctu r e of Bis[o-(ω-h y-
d r oxya lk oxy)p h en yl]m er cu r y Com p ou n d s 9. The
tendency for the yield to level off around 80%. The
consistently lower yields in the lithiation of the phenoxy
alcohol with n ) 2 implies a lower reactivity than those
with n > 2 and that the THF cleavage reaction with BuLi
becomes more competitive to the metalation reaction. The
reason for the lower reactivity of 2-phenoxyethanol is not
understood.10 The reaction leading to 2 may be considered
as another example of the complex-induced proximity
(11) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(12) J ones, P. R.; Malmberg, C. E.; McGrattan, C. J . Pharm. Sci.
effect process (CIPE).11 Although the ω-lithioxyalkoxy
1
975, 64, 1240.
13) Almog, J .; Baldwin, J . E.; Crossley, M. J .; Debernardis, J . F.;
(
(
10) One of the reviewers suggested that possibly a bis chelation of
Dyer, R. L.; Huff, J . R.; Peters, M. K. Tetrahedron 1981, 37, 3589.
(14) Review: Bader, A.; Lindner, E. Coord. Chem. Rev. 1991, 108,
the n-BuLi by the substrate is occurring, leading to a less active
complex in the solvent system utilized.
27.

Ortho-Directed Lithiation of ω-Phenoxy Alcohols
J . Org. Chem., Vol. 64, No. 15, 1999 5591
the lithium-assisted cleavage of 4-phenoxybutyl benzyl ether,18
which in turn was prepared by the reaction of 4-phenoxybutyl
bromide with sodium salt of benzyl alcohol. 7-Phenoxyheptan-
1
-ol (1f) was synthesized by the reduction of 7-phenoxyhep-
1
9
tanoic acid, which in turn was prepared from 5-phenoxypen-
tyl bromide by malonic ester synthesis. The analytical data
2
0
of alcohols 1 were in accordance with those previously re-
ported.1
9,21
4-Phenoxybutyl bromide and 5-phenoxypentyl bro-
mide were prepared by the reaction of the corresponding R,ω-
dibromoalkanes with sodium phenoxide.20 ω-Halo alcohols
were commercially available or prepared by a known proce-
dure.22 Lithiation reactions were performed in standard glass-
ware with ground joints under argon. THF was distilled from
LiAlH
in methylcyclohexane. The organic extracts of all compounds
prepared in this paper were dried over Mg SO . NMR spectra
were recorded at 300 or 80 MHz ( H NMR). In this paper, only
selected NMR and MS data are given for the presented
compounds. Melting points were not corrected. Elemental
analyses were carried out at the National Hellenic Research
Foundation.
4
. n-BuLi was prepared from lithium metal and n-BuCl
F igu r e 1. ORTEP drawing of 9b at the 50% probability level.
The hydrogen atoms are omitted for clarity.
2
4
1
synthetic value of organolithiums 2 in organometallic
synthesis was demonstrated by their reaction with 0.5
equiv of mercury dichloride, yielding novel hydroxy-
substituted organomercurials 9. Suitable crystals for
X-ray crystal structure determination were obtained by
recrystallization of 9a and 9b,c,e from i-PrOH and EtOH,
respectively. Because of the similar conformations in the
crystal structures for compounds 9a-c,e, only one ORTEP
drawing, that of 9b, is shown here (Figure 1).
In all structures, the Hg atom occupies a crystal-
lographic center of symmetry; therefore, the two phenyl
groups are coplanar, the two hydroxyalkoxy groups are
trans to each other, and the C(1)-Hg-C(1) fragment is
linear. In the ortho-substituted diarylmercury com-
pounds, deviations from the coplanarity of the phenyl
groups have been observed in exceptional cases, as in the
structure of bis(o-tolyl)mercury, in which the two phenyl
groups are twisted relative to one another by an angle
of 58.9°, with the methyl groups on the same side of the
molecule.15 The C(1)-Hg distances in molecules 9 of
about 2.06 Å are normal. The nonbonded distances
between mercury and the ethereal oxygens of about 3 Å
are shorter than the sum of the van der Waals radii of
about 4 Å and suggest a rather weak interaction.
Lith ia tion of ω-P h en oxy Alcoh ols 1 a n d Ca r boxyla tion
of Lith iu m or th o-Lith ioa lk oxid es 2. Syn th esis of o-(ω-
Hyd r oxya lk oxy)ben zoic Acid s 3. Typ ica l P r oced u r e.
23
o-(2-Hyd r oxyeth oxy)ben zoic Acid (3a ). To a solution of
1
a (2.76 g, 20 mmol) in THF (15 mL) under argon was added
slowly n-butyllithium (20.5 mL of 1.96 M solution in methyl-
cyclohexane, 40.2 mmol) at -65 °C and stirred for 1 h. The
temperature was then increased to 0 °C and maintained for 2
h, after which time the reaction mixture was stirred at room
temperature overnight, yielding a white suspension. The
suspension of 2a was cooled to -65 °C and poured rapidly into
a beaker containing a slurry of crushed dry ice and anhydrous
diethyl ether. When the carboxylation mixture had reached
room temperature, water was added and the volatile materials
were removed by evaporation. The aqueous phase was washed
2 4
with toluene and hexane and acidified with 20% H SO . The
product was extracted with dichloromethane (5 × 50 mL) and
dried. After filtration, the solvent was evaporated, yielding 3a
(
2 g, 55%) as an oil. The NMR data were in accordance to those
23
previously reported.
o-(3-H yd r oxyp r op oxy)b en zoic a cid (3b ):12 1H NMR
(CDCl ) δ 6.10 (brs, 2H, OH and COOH), 4.35 (t, J ) 5.9 Hz,
3
1
3
2H), 3.95 (t, J ) 5.5 Hz, 2H); C NMR (CDCl
0.56. Anal. Calcd for C10
1.23; H, 6.25.
3
) δ 166.79, 68.37,
6
6
H
12
O
4
: C, 61.22; H, 6.16. Found: C,
1
o-(4-Hyd r oxybu toxy)ben zoic a cid (3c): H NMR (CDCl
3
)
Con clu sion s
δ 5.64 (brs, 2H, OH and COOH), 4.26 (t, J ) 6.1 Hz, 2H), 3.73
1
3
(
t, J ) 5.8 Hz, 2H); C NMR (CDCl ) δ 166.91, 69.21, 61.0.
3
It has been demonstrated that the ω-lithioxyalkoxy
group is ortho-directing in the lithiation of ω-phenoxy
alcohols. The synthetic utility of these novel aryllithium
compounds has been demonstrated by a number of a
carbon-carbon, carbon-heteroatom, and carbon-metal
bond forming reactions.
Anal. Calcd for C11
H, 6.76.
H
14
O
4
: C, 62.85; H, 6.71. Found: C, 62.95;
1
o-(5-Hydr oxypen toxy)ben zoic acid (3d): H NMR (CDCl
3
)
δ 5.40 (brs, 2H, OH and COOH), 4.22 (t, J ) 6.2 Hz, 2H), 3.66
1
3
(
t, J ) 5.85 Hz, 2H); C NMR (CDCl ) δ 166.90, 69.83, 61.86.
3
Anal. Calcd for C12
H, 7.30.
H
16
O
4
: C, 64.27; H, 7.19. Found: C, 64.48;
1
o-(6-Hyd r oxyh exoxy)ben zoic a cid (3e): H NMR (CDCl
3
)
Exp er im en ta l Section
δ 5.63 (brs, 2H, OH and COOH), 4.25 (t, J ) 6.2 Hz, 2H), 3.66
t, J ) 5.9 Hz); 13C NMR (CDCl
) δ 167.66, 68.37, 60.89; ESI-
MS m/z (rel intesity) 261 ([M + Na] , 100). Anal. Calcd for
: C, 65.53; H, 7.61. Found: C, 65.33; H, 7.37.
o-(7-Hydr oxyh eptoxy)ben zoic acid (3f): H NMR (CDCl )
3
δ 5.89 (brs, 2H, OH and COOH), 4.20 (t, J ) 6.3 Hz, 2H), 3.61
(
3
+
Gen er a l Com m en ts. 2-Phenoxyethanol (1a ) was com-
mercially available. ω-Phenoxy alcohols 1b, 1d , and 1e (n )
, 5, and 6) were synthesized by the reaction of sodium
phenoxide, prepared from phenol and aqueous NaOH, with
the appropriate ω-halo alcohol, according to a known proce-
dure. The application of this procedure to the synthesis of
-phenoxybutan-1-ol (1c), either in water or glycol as solvent,
led almost exclusively to THF as the cyclization product of
-chlorobutan-1-ol.17 For this reason, 1c was synthesized by
13 18 4
C H O
1
3
1
6
1
(
18) Selected analytical data: bp 159-165 °C (0.3 mmHg); H NMR
4
(
CDCl
3
) δ 4.67 (s, 2H), 4.11 (t, J ) 6.0 Hz, 2H), 3.70 (t, J ) 6.0 Hz,
2H); 13C NMR (CDCl ) δ 72.47, 69.59, 67.11, 26.08, 25.87; GC-MS (EI)
3
+
4
m/z (rel intesity) 257 ([M + H] , 10).
(
19) Diekman, J .; Thomson, J . B.; Djerassi, C. J . Org. Chem. 1968,
3
3, 2271.
(15) Liptak, D.; Ilsley, W. H.; Glick, M. D.; Oliver, J . P. J . Organo-
(20) Dobrowolska, E.; Eckstein, Z. Przemysl Chem. 1963, 42, 556;
met. Chem. 1980, 191, 339.
Chem. Abstr. 1964, 60, 1637e-f.
(
16) Barner, R.; Schmid, H. Helv. Chim. Acta 1960, 43, 1393.
(21) David, S.; Thieffry, A. J . Org. Chem. 1983, 48, 441.
(22) Dorn, H. In Preparative Organic Chemistry, 4th ed.; Hilgetag,
G., Martini, A., Eds.; J ohn Wiley & Sons: New York, 1972; p 218.
(23) J ones, P. R.; Rothenberger, S. D. J . Org. Chem. 1986, 51, 3016.
(17) Similarly, the attempted conversion of tetramethylene chloro-
hydrin into ethyl hydroxybutyl ether resulted in cyclization to tet-
rahydrofuran: Frearson, P. M.; Stern, E. S. J . Chem. Soc. 1958, 3062.

5
592 J . Org. Chem., Vol. 64, No. 15, 1999
Salteris et al.
(
t, J ) 6.1 Hz, 2H); 13C NMR (CDCl
3
) δ 167.46, 68.46, 61.02;
4a , yielding the crude product, which was recrystallized from
hexane, yielding 7a (1.8 g, 59%). Repeated recrystallization
+
ESI-MS m/z (rel intesity) 275 ([M + Na] , 100). Anal. Calcd
for C14 : C, 66.65; H, 7.99. Found: C, 66.65; H, 7.89.
1
H
20
O
4
from i-PrOH afforded a solid. 7a : mp 127-128.5 °C; H NMR
Rea ction of 2 w ith Ben za ld eh yd e or Ben zop h en on e.
Syn th esis of Ca r bin ols 4 a n d 5. Typ ica l P r oced u r e.
P h en yl-[o-(2-h yd r oxyeth oxy)p h en yl]m eth a n ol (4a ). To a
suspenion of 2a in THF (15 mL)/methylcyclohexane (23.5 mL),
prepared from 1a (2.76 g, 20 mmol) as described above, was
added benzaldehyde (1.9 mL, 18.7 mmol), with ice-water bath
cooling, after which time the reaction mixture was stirred at
room temperature for 1 h. Water was then added, the volatile
materials were removed by evaporation, the residue was
extracted with dichloromethane, and the organic layer was
washed with water and dried. After filtration, the solvent was
evaporated, yielding 4.5 g of the crude product as a viscous
oil, which was solidified and recrystallized from methylcyclo-
hexane, yielding 4a (3.1 g, 64%). Repeated recrystallization
(CDCl ) δ 6.42 (s, 1H), 2.20 (brs, 3H, OH); 13C NMR (CD OD)
3
3
δ 69.23, 64.54, 59.75. Anal. Calcd for C17
H
20
O
5
: C, 67.09; H,
6
.62. Found: C, 67.35; H, 6.78.
Rea ction of 2b w ith Ch lor od ip h en ylp h osp h in e. Syn -
t h esis of [o-(3-H yd r oxyp r op oxy)p h en yl]d ip h en ylp h os-
p h in e (8b). To a suspension of 2b in THF (15 mL)/methyl-
cyclohexane (23 mL), prepared from 1b (3.05 g, 20 mmol), was
added dropwise a solution of chlorodiphenylphosphine (4.2 g,
1
9 mmol) in THF (15 mL), with dry ice-acetone bath cooling,
and then stirred at room temperature overnight. The workup
procedure was as described for 4a , yielding the crude product.
Purification was carried out by recrystallization from EtOH/
hexane, yielding 8b (4.4 g, 65%) as a white solid. 8b: mp 94-
1
from toluene/hexane afforded a white solid. 4a : mp 70-71 °C;
96 °C; H NMR (CDCl
3
) δ 7.34-6.66 (m, 14H), 4.06 (t, J ) 5.7
1
H NMR (CDCl
3
) δ 6.00 (s, 1H,), 3.96 (t, J ) 4.39 Hz, 2H),
Hz, 2H), 3.49 (t, J ) 5.7 Hz, 2H), 1.94 (s, 1H, OH), 1.80 (m,
.81 (s, 1H, OH), 3.72 (m, 2H), 2.81 (s, 1H, OH); 13C NMR
CDCl ) δ 72.37, 69.76, 60.89; GC-MS (EI): m/z (rel intesity)
13
3
(
2
2H); C NMR (CDCl ) δ 160.16-111.07, 66.00, 59.89, 31.51;
3
31P NMR (CDCl ) δ -16.62 (ref to external H PO 85% in D O);
3
3
3
4
2
•
+
44 (M , 59). Anal. Calcd for C15
H
16
O
3
: C, 73.75; H, 6.60.
•+
GC-MS (EI) m/z (rel intesity) 336 (M , 24), 278 (100). Anal.
Calcd for C21 P: C, 74.99; H, 6.29. Found: C, 75.19; H,
.37.
Rea ction of 2 w ith Mer cu r y Ch lor id e. Syn th esis of
Found: C, 73.58; H, 6.66.
P h en yl[o-(3-h yd r oxyp r op oxy)p h en yl]m eth a n ol (4b):
21 2
H O
6
1
H NMR (CDCl
3
) δ 6.05 (s, 1H), 4.50 (s, 2H, 2 × OH), 3.98 (t,
13
3
J ) 5.9 Hz), 3.65 (t, J ) 5.8 Hz, 2H); C NMR (CDCl
6
) δ 72.66,
•+
Bis[o-(ω-h yd r oxya lk oxy)p h en yl]m er cu r y Com p ou n d s 9.
Typ ica l P r oced u r e. Bis[o-(2-h yd r oxyet h oxy)p h en yl]-
m er cu r y (9a ). To a suspension of 2a in THF (50 mL)/
methylcyclohexane (75 mL), prepared from 1a (8.3 g, 60.1
mmol), was added dropwise a solution of mercury chloride (6.8
g, 25 mmol) in THF (20 mL), with ice-water bath cooling, and
then stirred at room temperature overnight. The workup
procedure was as described for 4a except that the solvent used
for extraction of the product being toluene. Purification of the
crude was carried out by recrystallization fom i-PrOH, yielding
5.79, 60.12; GC-MS (EI) m/z (rel intesity) 258 (M , 17). Anal.
Calcd for C16
.02.
H
18
O
3
: C, 74.39; H, 7.02. Found: C, 74.36; H,
7
1
P h en yl[o-(4-h yd r oxybu toxy)p h en yl]m eth a n ol (4c): H
NMR (CDCl
5
6
3
) δ 6.20 (s, 1H), 4.81 (s, 2H, 2 × OH), 4.02 (t, J )
13
3
.7 Hz, 2H), 3.65 (t, J ) 6.1 Hz, 2H); C NMR (CDCl ) δ 72.30,
+•
7.92, 62.23; GC-MS (EI): m/z (rel intesity) 272 (M , 12). Anal.
Calcd for C17
.35.
H
20
O
3
: C, 74.97; H, 7.40. Found: C, 74.95; H,
7
1
P h en yl[o-(5-h ydr oxypen toxy)ph en yl]m eth an ol (4d): H
1
NMR (CDCl
J ) 5.8 Hz, 2H); C NMR (CDCl
MS (EI) m/z (rel intesity) 286 (M , 15). Anal. Calcd for
: C, 75.49; H, 7.74. Found: C, 75.36; H, 7.66.
P h en yl[o-(6-h yd r oxyh exoxy)p h en yl]m eth a n ol (4e): H
NMR (CDCl ) δ 6.03 (s, 1H), 3.93 (m, 2H), 3.58 (t, J ) 6.5 Hz,
3
) δ 6.03 (s, 1H), 4.03 (t, J ) 5.9 Hz, 2H), 3.72 (t,
9a (5.3 g, 45%) as a white solid. 9a : mp 104.5-106 °C; H
1
3
3
) δ 72.33, 68.00, 62.55; GC-
NMR (CDCl ) δ 4.09 (m, 4H), 3.90 (m, 4H), 3.21 (m, 2H, 2 ×
3
•
+
13
OH); C NMR (CDCl
4
3
) δ 70.37, 61.38; ESI-MS m/z (rel intesity)
C
18
H
22
O
3
+
99 ([M + Na] , 100). Anal. Calcd for C16
H, 3.82. Found: C, 40.32; H, 3.89.
H
18HgO
4
: C, 40.47;
1
3
1
Bis[o-(3-h ydr oxypr opoxy)ph en yl]m er cu r y (9b): H NMR
2
7
1
7
H), 3.35 (s, 1H, OH), 2.36 (s, 1H, OH); 13C NMR (CDCl
3
) δ
,
2.37, 67.79, 62.57; GC-MS (EI): m/z (rel intesity) 300 (M+•
3
(CDCl ) δ 4.12 (t, J ) 5.9 Hz, 4H), 3.83 (m, 4H), 2.53 (s, 2H, 2
×
OH); 13C NMR (CDCl
intesity) 527 ([M + Na] , 100). Anal. Calcd for C18
3
) δ 65.15, 59.88; ESI-MS m/z (rel
3). Anal. Calcd for C19
5.71; H, 8.02.
24 3
H O : C, 75.97; H, 8.05. Found: C,
+
H
22HgO
4
:
C, 42.99; H, 4.41. Found: C, 42.97; H, 4.51.
Dip h en yl[o-(2-h yd r oxyeth oxy)p h en yl]m eth a n ol (5a ):
1
1
H NMR (CDCl
.55 (m, 2H), 1.19 (s, 1H, OH); C NMR (CDCl
3
) δ 5.11 (s, 1H, OH), 3.96 (t, J ) 4.1 Hz, 2H),
Bis[o-(4-h yd r oxybu toxy)p h en yl]m er cu r y (9c): H NMR
1
3
3
6
3
•
) δ 81.60, 69.85,
(CDCl
3
) δ 4.03 (t, J ) 5.7 Hz, 4H), 3.67 (t, J ) 5.7 Hz, 4H),
+
13
0.82; GC-MS (EI): m/z (rel intesity) 320 (M , 5). Anal. Calcd
: C, 78.73; H, 6.29. Found: C, 79.04; H, 6.39.
Dip h en yl[o-(3-h yd r oxyp r op oxy)p h en yl]m eth a n ol (5b):
2.66 (brs, 2H, 2 × OH); C NMR (CDCl ) δ 68.07, 62.59; ESI-
3
+
for C21
H
20
O
3
MS m/z (rel intesity) 555 ([M + Na] , 100). Anal. Calcd for
C H HgO : C, 45.24; H, 4.93. Found: C, 45.27; H, 5.03.
2
0
26
4
1
H NMR (CDCl
3
) δ 5.33 (s, 1H, OH), 3.99 (t, J ) 5.9 Hz, 2H),
1
Bis[o-(5-h ydr oxypen toxy)ph en yl]m er cu r y (9d): H NMR
CDCl ) δ 3.99 (t, J ) 5.9 Hz, 4H), 3.62 (t, J ) 5.8 Hz, 4H),
3
8
2
7
.28 (t, J ) 5.9 Hz, 2H), 1.45 (s, 1H, OH); 13C NMR (CDCl
3
) δ
(
3
•
+
2.03, 65.67, 59.34; GC-MS (EI) m/z (rel intesity) 334 (M
). Anal. Calcd for C22
9.18; H, 6.73.
,
1
3
2
6
.15-1.62 (m, 14H, including 2 × OH); C NMR (CDCl
3
) δ
22 3
H O : C, 79.02; H, 6.63. Found: C,
8.17, 62.65. Anal. Calcd for C22 : C, 47.26; H, 5.41.
H
30HgO
4
Found: C, 47.43; H, 5.50.
Bis[o-(6-h yd r oxyh exoxy)p h en yl]m er cu r y (9e):
(CDCl ) δ 3.98 (t, J ) 6.3 Hz, 4H), 3.55 (m, 4H), 1.28 (s, 2H, 2
Rea ction of 2a w ith DMF . Syn th esis of o-(2-Hyd r oxy-
1
3
1
H NMR
eth oxy)ben za ld eh yd e (6a ). To a suspension of 2a in THF
55 mL)/methylcyclohexane (55 mL), prepared from 1a (6.9 g,
0 mmol), was added a solution of DMF (3.6 g, 50 mmol) in
(
5
3
1
3
× OH); C NMR (CDCl
3
) δ 67.87, 62.74; ESI-MS m/z (rel
+
THF (15 mL), with ice-water bath cooling, and then stirred
at room temperature for 2 h. The workup procedure was as
described for 4a , yielding the crude product. Purification was
carried out by distillation, yielding 6a (4.2 g, 51%). 6a : bp
1
(
intesity) 611 ([M + Na] , 100). Anal. Calcd for C24
C, 49.10; H, 5.84. Found: C, 48.92; H, 5.91.
H
34HgO
4
:
Ack n ow led gm en t. The investigation was supported
by the National Hellenic Research Foundation.
32-134 °C (1 mmHg) (lit.13 mp 46-46.5 °C); the 1H NMR
CDCl
3
) spectrum was in accordance with that previously
1
3 13
reported;
C NMR (CDCl ) δ 190.43, 70.22, 60.72.
3
Rea ction of 2a w ith Eth yl F or m a te. Syn th esis of Bis-
Su p p or tin g In for m a tion Ava ila ble: Full details of spec-
tral data for compounds 3-9, experimental section for the
X-ray structure determinations, X-ray tables for compounds
[
o-(2-h yd r oxyeth oxy)p h en yl]m eth a n ol (7a ). To a suspen-
sion of 2a in THF (15 mL)/methylcyclohexane (23 mL),
prepared from 1a (2.76 g, 20 mmol), was added dropwise a
solution of ethyl formate (0.74 g, 10 mmol) in THF (10 mL),
with ice-water bath cooling, and then stirred at room tem-
perature for 1 h. The workup procedure was as described for
9
a -c,e, and ORTEP drawings of 9a ,c,e. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O990443P