Selective lithiation of 4- and 5-halophthalans

Article abstract of DOI:10.3987/COM-08-S(F)85

The reaction of 4- and 5-halophthalans 5 with lithium and a catalytic amount of DTBB at -78 °C leads to the formation of the corresponding functionalized organolithium intermediates 6 and 11, which by reaction with carbonyl compounds give, after hydrolysis, the expected substituted phthalans 8 and 13, respectively. When after reaction with the carbonyl compound the system is allowed to react at 0 °C, a second lithiation occur: A reductive opening of the heterocycle takes place with some regioselectivity leading to new organolithium intermediates 9 and 14/15 that by reaction with electrophiles lead, after hydrolysis, to polyfunctionalized molecules 10 and 16/17, respectively.

Full text of DOI:10.3987/COM-08-S(F)85

HETEROCYCLES, Vol. 77, No. 2, 2009
991
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 991 - 1005. © The Japan Institute of Heterocyclic Chemistry
Received, 29th July, 2008, Accepted, 26th September, 2008, Published online, 29th September, 2008
DOI: 10.3987/COM-08-S(F)85
SELECTIVE LITHIATION OF 4- AND 5-HALOPHTHALANS
Daniel García, Francisco Foubelo,* and Miguel Yus*
Department of Organic Chemistry, Faculty of Science, and Institut of Organic
Synthesis (ISO), University of Alicante, Apdo. 99, 03080 Alicante, Spain
Abstract – The reaction of 4- and 5-halophthalans 5 with lithium and a catalytic
amount of DTBB at -78 ºC leads to the formation of the corresponding
functionalized organolithium intermediates 6 and 11, which by reaction with
carbonyl compounds give, after hydrolysis, the expected substituted phthalans 8
and 13, respectively. When after reaction with the carbonyl compound the system
is allowed to react at 0 ºC, a second lithiation occur: A reductive opening of the
heterocycle takes place with some regioselectivity leading to new organolithium
intermediates 9 and 14/15 that by reaction with electrophiles lead, after hydrolysis,
to polyfunctionalized molecules 10 and 16/17, respectively.
INTRODUCTION
Functionalized organolithium compounds1 can be prepared following the same methodologies used for
simple organolithium compounds. They are also accessible through the reductive ring opening of
appropriate oxygen-, nitrogen- and sulfur-containing heterocycles,2 such as strained heterocycles (three
and four membered-rings) and heterocycles with activated bonds. In addition, suitable precursors are
compounds bearing allylic3 and benzylic4 carbon-heteroatom bonds, and cyclic aryl ethers5 and
thioethers.6 Among the lithiation reagents, the use of an excess of lithium in the presence of a catalytic
amount of an arene7 [naphthalene and 4,4’-di-tert-butylbiphenyl (DTBB)],8 has shown to be very
effective even at low temperatures for this purpose. More recently, polymer supported naphthalene,
biphenyl9 and also polyphenylene10 have been used as electron transfer reagents in these processes.11 As
an example, phthalan (1; R = R’ = H) can be easily opened with the above mentioned methodology to give
the expected lithiated intermediate 2a/2b (R = R’ = H)12 through a favoured reductive benzylic cleavage
(Scheme 1). When the heterocyclic ring isn phthalan bears substituents (1; R = Me, n-Bu, Ph; R’ = H),
_____________________________________________________________________________________
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
the opening takes place giving the most stable intermediate 2a (R = Ph; R’ = H) or 2b (R = Me, n-Bu; R’ =
H) (Scheme 1).13 In the case of non-symmetrically substituted phthalans possessing different groups
attached to the aromatic ring (1; R = H; R’ = OMe, Ph), the reductive opening leading to intermediates 2
occurs with high regioselectivity and it can be explained taking into account the electron density deduced
by semiempirical PM3 calculations of either the anion or the radical-anion intermediate responsible of the
reductive cleavage (Scheme 1).14
R'
R'
R'
i
OLi
Li
Li
O
and/or
OLi
R
R
R
1
2a
2b
R = H, Me, n-Bu, Ph
R' = H, OMe, Ph
Scheme 1. Reagents and conditions: (i) Li, ArH (DTBB or C10H8), THF, -78, 0 or 20 °C, 4 h.
Continuing with our recent studies on the selective lithiation of substituted phthalans,14 we report here the
selective (chemo- and/or regioselective) lithiation of 4- and 5-halophthalans.
RESULTS AND DISCUSSION
Substituted phthalans 5 were prepared starting from the corresponding commercially available phthalic
anhydrides 3 through a three-step process: first reduction with LAH in the presence of ZnCl2 to give the
corresponding diol 4, followed by Swern oxidation and final cyclization of the resulting dialdehyde by
treatment with Et3SiH in the presence of Me3SiOTf. The expected substituted phthalans 5 were obtained,
in general, in good overall yields (Scheme 2).
X
X
X
O
Y
Y
Y
i
OH
OH
ii-iii
O
O
O
3
4
5a (45%)
5b (75%)
5c (64%)
5d (52%)
5e (82%)
a (X = Cl, Y = H)
b (X = Me, Y = H)
c (X = H, Y = F)
d (X = H, Y = Br)
e (X = H, Y = Me)
Scheme 2. Reagents and conditions: (i) LiAlH4, ZnCl2, THF, 0 to 20 °C, 6 h; (ii) DMSO, (COCl)2, Et3N,
CH2Cl2, -60 to 20 °C, 2 h; (iii) Et3SiH, Me3SiOTf, CH2Cl2, 0 ºC, 4 h, then 20 ºC, 2 h.

HETEROCYCLES, Vol. 77, No. 2, 2009
993
The reaction of 4-chlorophthalan (5a) with an excess of lithium powder (1:10 molar ratio) and a catalytic
amount of DTBB (1:0.13 molar ratio; 7.0 mol %) in THF at -78 ºC for 2 h, led to a solution of the
intermediate 6, which by reaction with different carbonyl compounds as electrophiles [R1R2CO: PhCHO,
(CH2)5CO] at -78 ºC gave, after hydrolysis with water at the same temperature, the corresponding alcohol
8 (Scheme 3, Table 1, entries 1 and 2).
R2
R2
R1
OLi
R1
OH
Cl
Li
i
ii
iii
O
O
O
O
6
7
8
5a
[R1-R2 = (CH2)5] iv
OH
OLi
v,iii
Li
OH
OH
OLi
10
9
Scheme 3. Reagents and conditions: (i) Li, DTBB (7.0 mol %), THF, -78 ºC, 2 h; (ii) R1R2CO: PhCHO,
(CH2)5CO, -78 ºC; (iii) H2O, -78 to 20 ºC; (iv) 0 ºC, 1 h; (v) (CH2)5CO, -78 ºC.
Lithiation of 5-fluorophthalan (5c) and 5-bromophthalan (5d) under the same reaction conditions as for
4-chlorophthalan (5a) in Scheme 3 led to organolithium intermediate 11 which upon reaction with
different carbonyl compounds as electrophiles [R1R2CO: t-BuCHO, Et2CO, (CH2)5CO] at -78 ºC gave,
after hydrolysis with water at the same temperature, the corresponding substituted phthalan 13 (Scheme 4,
Table 1, entries 3-5). In these processes, a chemoselective lithiation occurred: Carbon-halogen bonds are
more reactive towards the lithiation reagent than the benzylic carbon-oxygen bond, so halogen/lithium
exchange took place exclusively instead of the reductive opening of the heterocycle. The presence of a
carbon-lithium bond in intermediates 6 and 11 prevents them for suffering a further reduction (reductive
opening in this case) even if the process is performed at 0 ºC. Yields were considerably higher in the case
of 5-halophthalans 5c,d, due probably to the higher stability of the organolithium intermediate 11
compared to 6.
From a synthetic point of view, an interesting variant of the monolithiation of the halophthalans 5 results
when the second electrophile is introduced in the molecule. It happens when the alcoholates 7 [derived from
4-chlorophthalan (5a), Scheme 3] and 12 [derived from 5-bromophthalan (5d), Scheme 4] were stirred at 0
ºC for 1 h in the presence of the excess of lithium still present in the reaction medium. Under these reaction

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HETEROCYCLES, Vol. 77, No. 2, 2009
OLi
OH
R2
Y
Li
R1
ii
R1
i
iii
O
O
R2
O
O
11
12
13
5c (Y = F)
5d (Y = Br)
iv
OLi
OLi
R2
OH
R2
OH
OH
R2
R1
R1
Li
OLi
R1
OLi
Li
R1
R1
OH
R1
v,iii
+
+
R2
R2
OH
R2
OH
16
15
17
14
Scheme 4. Reagents and conditions: (i) Li, DTBB (7.0 mol %), THF, -78 ºC, 2 h; (ii) R1R2CO: t-BuCHO,
Et2CO, (CH2)5CO, -78 ºC; (iii) H2O, -78 to 20 ºC; (iv) 0 ºC, 1 h; (v) R1R2CO: Et2CO, (CH2)5CO, -78 ºC.
Table 1. Preparation of compounds 8 and 13 through monolithiation of halophthalans 5a, 5c and 5d
Starting
phthalan
Alcohols 8 and 13a
Entry
1
R1R2CO
PhCHO
No.
Structure
Yield (%)b
28
Ph
OH
5a
5a
8a
O
OH
2
(CH2)5CO
8b
37
O
OH
3
4
5
5c
5d
5d
(CH2)5CO
t-BuCHO
Et2CO
13a
13b
13c
42
55
61
O
OH
O
OH
O
a All products were >95% pure (GLC and/or 300 MHz 1H RMN). b Isolated yield based on the starting material 5.
conditions the reductive cleavage of the heterocycle took place and after addition of a new equivalent of
the carbonyl compound as electrophile at -78 ºC, followed by hydrolysis with water, the triols 10
(Scheme 3) and 16/17 (Scheme 4) were obtained, respectively. The structure of these compounds was

HETEROCYCLES, Vol. 77, No. 2, 2009
995
elucidated using NOESY, HSQC and HMBC experiments. The solid triol 17a [R = Ph(CH)2] gave
crystals suitable for single crystal X-ray analysis and the obtained structure (Chart 1)15-18 was in total
agreement with the NMR experiments. Apparently, in the case of alcoholate 7 [R1R2 = (CH2)5] a selective
reductive cleavage took place leading to intermediate 9 exclusively (Scheme 3, Table 2, entry 1).
However, in the case of alcoholates 12 derived from 5-bromophthalan (5d), a mixture of the two possible
organolithium intermediates 14 and 15 were obtained, so leading to a mixture of triols 16 and 17 after
reaction with the electrophile (Scheme 4, Table 2, entries 2 and 3). Yields were low in all cases.
Table 2. Preparation of compounds 10, 16 and 17 through monolithiation of halophthalans 5a and 5d
Starting
phthalan
Alcohols 6 and 11a
Structure
Entry
1
R1R2CO
No.
Yield (%)b
21
OH
5a
(CH2)5CO
10
OH
OH
OH
16a
17a
16b
23
13
OH
OH
2
3
5d
5d
Et2CO
OH
OH
OH
OH
(CH2)5CO
28c
OH
OH
a All products were >95% pure (GLC and/or 300 MHz 1H RMN). b Isolated yield based on the starting material 5. c The other
regioisomer was detected by GL-MS (<5%) but it was not isolated.
Chart 1

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The lithiation of 4-methylphthalan (5b) and 5-methylphthalan (5e) was also studied in order to rationalize
the experimental results of the reductive opening of alcoholates 7 and 12, concerning the regiochemistry
of the process. Lithiation of 4-methylphthalan (5b) under the same reaction conditions as previously
described for other phthalan derivatives, followed by hydrolysis with water, gave a mixture of
regioisomeric alcohols 20 and 21 in a 3:2 ratio. That means that the two possible reductive openings of 5b
took place leading to dianionic intermediates 18 and 19 (Scheme 5). Surprisinly, 2,4-dimethylbenzyl
alcohol (23a) was the only reaction product in the case of starting from 5-methylphthalan (5e) and using
water as electrophile. In the case of using 3-pentanone as electrophile, diol 23b was isolated in 31% yield,
2,4-dimethylbenzyl alcohol (23a) being the major reaction product. So, under these reaction conditions
reductive cleavage in 5e leading to intermediate 22 took place exclusively. Since the regiochemistry of
the reductive opening of 4- and 5-methyl substituted phthalans 5b and 5e was different to that of
alcoholates 7 and 12, it seems that the lithium alkoxide unit plays an important role in this process.
Li
OLi
Li
OH
i
ii
+
+
O
OLi
OH
20 (49%)
5b
18
19
21 (33%)
i
iii,ii
Li
OLi
E
O
OH
5e
22
23a (E = H, 97%)
23b (E = Et2COH, 31%)
Scheme 5. Reagents and conditions: (i) Li, DTBB (7.0 mol %), THF, -78 ºC, 2 h; (ii) H2O, -78 to 20 ºC;
(iii) E+: H2O, Et2CO, -78 ºC.
From the results described in this paper we can conclude that it is possible to lithiate selectively 4- and
5-halophthalans 5 using an excess of lithium in the presence of a catalytic amount of DTBB,
halogen/lithium exchange taking place first. A second lithiation occurs only after the reaction of the
resulting organolithium intermediates 6 and 11 with a carbonyl compound as electrophile. The new
organolithium intermediates result from the reductive opening of the heterocycle that happens with some
regioselectivity. The addition of a carbonyl compound as electrophile yields triols 10, 16 and 17.
EXPERIMENTAL
All reactions were performed in oven dried glassware under argon. All chemicals were commercially
available (Acros, Aldrich). TLC was performed on Merck silica gel 60 F254, using aluminum plates and

HETEROCYCLES, Vol. 77, No. 2, 2009
997
visualized with phosphomolybdic acid (PMA) stain. Chromatographic purification was performed by
flash chromatography using Merck silica gel 60 (0.040-0.063 mm) and hexane/EtOAc as eluent. IR
spectra were measured (film) with a Nicolet Impact 510 P-FT Spectrometer. Melting points were
recorded on an OptiMelt (Stanford Research Systems) apparatus using open glass capillaries and reported
without corrections. NMR spectra were recorded with a Bruker AC-400 using CDCl3 as the solvent and
TMS as internal standard. HRMS (EI) were recorded on a Finnigan MAT 95S.
Preparation of diols 4. General procedure.
To a suspension of LiAlH4 (10 mmol, 380 mg) and ZnCl2 (3 mmol, 408 mg) in THF (20 mL) under
Argon was slowly added a solution of the corresponding phthalic anhydride 3 (5 mmol) in THF (2 mL) at
0 ºC. The resulting reaction mixture was strirred at 20 ºC for 6 h. After that it was hydrolyzed with water
(10 mL) at 0 ºC, acidified with 2M HCl (20 mL), extrated with EtOAc (3 × 20 mL), dried over anhydrous
MgSO4 and evaporated (15 Torr). The residue was purified by column chromatography (silica gel,
hexane/EtOAc) to give products 4 in almost quantitative yield. Physical and spectroscopic data as well as
literature references for known compounds follow.
3-Chloro-2-(hydroxymethyl)benzyl alcohol (4a): White solid; mp 69-70 ºC (pentane/CH2Cl2); Rf = 0.29
(hexane/EtOAc: 1/1); IR ν (KBr) 3425-3455 (OH), 3057, 2971, 2892 cm-1; 1H NMR (400 MHz, CDCl3) δ
4.61 (2H, br s, 2×OH), 4.77 (4H, s, 2×CH2OH), 7.14-7.16 (2H, m, ArH), 7.26-7.27 (1H, m, ArH); 13C
NMR (100 MHz, CDCl3) δ 59.1, 63.9 (CH2), 128.3, 129.4, 129.5, 135.0, 136.1, 141.6 (ArC); LRMS (EI)
m/z 156 (M+-H2O, 32%), 155 (41), 154 (98), 153 (100), 127 (12), 125 (34), 91 (44), 90 (10), 89 (27), 77
(28), 63 (10), 51 (11).
2-(Hydroxymethyl)-3-methylbenzyl alcohol (4b): Colorless oil; Rf = 0.21 (hexane/EtOAc: 1/1); IR ν
(film) 3380-3295 (OH), 3069, 2965, 2897 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.33 (3H, s, CH3), 4.11
(2H, br s, 2×OH), 4.48 (2H, s, CH2OH), 4.53 (2H, s, CH2OH), 7.04-7.11 (3H, m, ArH); 13C NMR (100
MHz, CDCl3) δ 19.3 (CH3), 58.4, 65.8 (CH2), 127.4, 128.0, 130.5, 137.2, 137.5, 139.8 (ArC); LRMS (EI)
m/z 152 (M+, 1%), 135 (10), 134 (100), 133 (82), 132 (16), 119 (12), 106 (37), 105 (88), 103 (29), 91 (73),
79 (24), 78 (18), 77 (43), 65 (11), 51 (18).
4-Fluoro-2-(hydroxymethyl)benzyl alcohol (4c): Colorless oil; Rf = 0.20 (hexane/EtOAC: 1/1); IR ν
(film) 3405-3335 (OH), 2947, 2887 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.43 (2H, s, CH2OH), 4.46 (2H,
13
s, CH2OH), 4.70 (2H, br s, 2×OH), 6.86-6.97 (2H, m, ArH), 7.13-7.18 (1H, m, ArH); C NMR (100
MHz, CDCl3) δ 62.2, 62.3 (CH2), 114.2, 114.4, 115.4, 115.7, 130.1, 134.3, 141.5, 141.6, 160.7, 163.9
(ArC); LRMS (EI) m/z 138 (M+-H2O, 100%), 137 (98), 110 (13), 109 (81), 107 (11), 97 (15), 95 (10), 83
(16), 77 (11).
4-Bromo-2-(hydroxymethyl)benzyl alcohol (4d):19 White solid; mp 69-70 ºC (pentane/CH2Cl2); Rf =

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HETEROCYCLES, Vol. 77, No. 2, 2009
0.20 (hexane/EtOAc: 1/1); IR ν (KBr) 3320-3235 (OH), 2941, 2882 cm-1; 1H NMR (400 MHz, CDCl3) δ
4.22 (2H, br s, 2×OH), 4.62 (2H, s, CH2OH), 4.66 (2H, s, CH2OH), 7.29-7.32 (1H, m, ArH), 7.39-7.43
(1H, m, ArH), 7.59 (1H, s, ArH); 13C NMR (100 MHz, CDCl3) δ 61.9, 62.1 (CH2), 122.3, 130.1, 131.2,
131.3, 139.1, 142.8 (ArC); LRMS (EI) m/z 218 (M+, 2%), 216 (2), 200 (94), 199 (89), 198 (100), 197 (82),
171 (28), 169 (29), 92 (13), 91 (69), 90 (35), 89 (45), 79 (10), 78 (24), 77 (41), 65 (17), 63 (24), 51 (22),
50 (12).
2-(Hydroxymethyl)-4-methylbenzyl alcohol (4e):20 Colorless oil; Rf = 0.25 (hexane/EtOAc: 1/1); IR ν
1
(film) 3355-3280 (OH), 3014, 2917, 2880 cm-1; H NMR (400 MHz, CDCl3) δ 2.29 (3H, s, CH3), 4.16
(2H, br s, 2×OH), 4.48 (4H, s, 2×CH2OH), 7.03-7.06 (2H, m, ArH), 7.12 (1H, d, J = 7.7 Hz, ArH); 13C
NMR (100 MHz, CDCl3) δ 21.0 (CH3), 63.2, 63.5 (CH2), 128.8, 129.6, 130.3, 136.2, 138.1, 139.1 (ArC);
LRMS (EI) m/z 152 (M+, 1%), 135 (10), 134 (100), 133 (97), 106 (11), 105 (49), 103 (13), 93 (11), 91
(53), 79 (17), 78 (11), 77 (37), 65 (11), 51 (11).
Preparation of phthalans 5. General procedure.
To a solution of oxalyl chloride (11.5 mmol, 1.450 g, 1.0 mL) in CH2Cl2 (45 mL) was added
dimethylsulfoxide (25 mmol, 1.750 g, 1.8 mL) at -65 ºC. After 5 min at this temperature, a solution of the
corresponding diol 4 (5 mmol) in CH2Cl2 (45 mL) was added and stirring continued for 15 min prior to
the addition Et3N (52 mmol, 5.252 g, 7.2 mL). After that, the cold bath was removed and stirring was
manteined for 2 h at 20 ºC. The reaction mixture was hydrolyzed with 2M HCl (50 mL) and extrated with
CH2Cl2 (3 × 40 mL). The organic layers were washed with water (3 × 50 mL), dried over anhydrous
MgSO4 and evaporated (15 Torr). The resulting dialdehyde was used without purification in the next step
of the reaction. To a solution of the corresponding dialdehyde (4.50 mmol) in dry CH2Cl2 (15 mL) was
successively added Et3SiH (20 mmol, 2.32 g, 2.58 mL) and Me3SiOTf (0.134 mml, 30 mg, 0.025 mL) at
0 ºC. The reaction mixture was stirred at the same temperature for 4 h and for 2 h at 20 ºC. After that the
solvent was evaporated (15 Torr) and the resulting residue was purified by column chromatography
(silica gel, hexane/EtOAc) to give products 5. Overall yields are given in Scheme 2. Physical, and
spectroscopic data as well as literature references for known compounds follow.
4-Chlorophthalan (5a): Yellow oil; Rf = 0.41 (hexane/EtOAc: 10/1); IR ν (film) 3155, 2917, 2855, 1456
1
cm-1; H NMR (400 MHz, CDCl3) δ 5.12 (2H, s, CH2O), 5.16 (2H, s, CH2O), 7.10 (1H, t, J = 4.1 Hz,
ArH), 7.21 (2H, d, J = 3.85 Hz, ArH); 13C NMR (100 MHz, CDCl3) δ 73.3, 74.5 (CH2), 119.3, 127.4,
128.0, 129.2, 137.8, 141.3 (ArC); LRMS (EI) m/z 156 (M+, 17%), 155 (20), 154 (52), 153 (48), 127 (26),
126 (28), 125 (75), 99 (10), 92 (10), 91 (100), 90 (18), 89 (44), 63 (24), 62 (11); HRMS (EI) calcd for
C8H7ClO 154.0185, found 154.0200.
4-Methylphthalan (5b):21 Yellow oil; Rf = 0.36 (hexane/EtOAc: 10/1); IR ν (film) 3027, 2916, 2855

HETEROCYCLES, Vol. 77, No. 2, 2009
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1
cm-1; H NMR (400 MHz, CDCl3) δ 2.30 (3H, s, CH3), 5.07 (2H, s, CH2O), 5.12 (2H, s, CH2O),
7.02-7.05 (2H, m, ArH), 7.10-7.19 (1H, m, ArH); 13C NMR (100 MHz, CDCl3) δ 18.8 (CH3), 73.1, 74.1
(CH2), 118.2, 127.6, 128.0, 130.3, 138.1, 138.7 (ArC); LRMS (EI) m/z 134 (M+, 63%), 133 (43), 119 (16),
106 (56), 105 (100), 103 (29), 91 (71), 79 (25), 78 (15), 77 (38), 63 (11), 51 (20).
5-Fluorophthalan (5c): Yellowish oil; Rf = 0.32 (hexane/EtOAc: 10/1); IR ν (film) 3024, 1262 cm-1; 1H
NMR (400 MHz, CDCl3) δ 5.06 (4H, s, CH2O), 6.90-6.97 (2H, m, ArH), 7.13-7.17 (1H, m, ArH); 13C
NMR (100 MHz, CDCl3) δ 73.1, 73.4 (CH2), 108.1, 108.5, 114.3, 114.6, 122.1, 122.2, 134.5, 141.4,
141.5, 161.1, 164.3 (ArC); LRMS (EI) m/z 138 (M+, 43%), 137 (49), 110 (57), 109 (100), 107 (19), 83
(27), 57 (10).
5-Bromophthalan (5d): White solid; mp 41-42 ºC (pentane/CH2Cl2); Rf = 0.30 (hexane/EtOAc: 10/1); IR
1
ν (KBr) 3074, 1051 cm-1; H NMR (400 MHz, CDCl3) δ 5.09 (2H, s, CH2O), 5.20 (2H, s, CH2O), 7.15
(2H, d, J = 6.3 Hz, ArH), 7.35 (1H, dd, J = 6.3, 2.3 Hz, ArH); 13C NMR (100 MHz, CDCl3) δ 74.7 (CH2),
115.9, 119.7, 129.2, 130.2, 139.8, 141.0 (ArC); LRMS (EI) m/z 200 (M+, 35%), 199 (31), 198 (36), 197
(29), 172 (14), 171 (37), 170 (15), 169 (38), 118 (10), 91 (100), 89 (42), 88 (41), 63 (24), 62 (11).
5-Methylphthalan (5e):22 Colorless oil; Rf = 0.39 (hexane/EtOAc: 10/1); IR ν (film) 3014, 2953, 2910,
1
2850 cm-1; H NMR (400 MHz, CDCl3) δ 2.31 (3H, s, CH3), 5.00 (4H, s, 2×CH2O), 6.96 (1H, s, ArH),
6.99-7.06 (2H, m, ArH); 13C NMR (100 MHz, CDCl3) δ 21.0 (CH3), 73.2 (CH2), 120.4, 121.3, 127.9,
136.0, 136.7, 139.2 (ArC); LRMS (EI) m/z 134 (M+, 65%), 133 (52), 119 (10), 106 (51), 105 (100), 103
(25), 91 (52), 79 (21), 78 (11), 77 (31), 63 (10), 51 (14).
Monolithiation of phthalans 5. Preparation of compounds 8, 13, 20, 21 and 23. General procedure.
To a blue suspension of lithium powder (72 mg, 10.4 mmol) and a catalytic amount of DTBB (34 mg,
0.13 mmol) in dry THF (3 mL) under argon was added dropwise a solution of the corresponding phthalan
5 (1 mmol) in THF (0.5 mL) at -78 ºC, and the resulting mixture was stirred for 2 h at the same
temperature. Then the corresponding carbonyl compound was added dropwise (1.1 mmol) at -78 ºC and,
after 20 min the reaction mixture was hydrolyzed with water (4 mL), extracted with EtOAc (3 × 15 mL),
dried over anhydrous MgSO4 and evaporated (15 Torr). The residue was purified by column
chromatography (silica gel, hexane/ethyl acetate) to yield pure products 8, 13, 20, 21 and 23. Yields are
given in Table 1 and Scheme 4. Physical, analytical and spectroscopic data as well as literature references
for known compounds follow.
4-(1-Hydroxy1-phenylmethyl)phthalan (8a): Colorless oil; Rf = 0.11 (hexane/EtOAc: 5/1); IR ν (film)
3420-3355 (OH), 3069, 3032, 2928, 2855 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.60 (1H, br s, OH), 4.91
(1H, d, J = 12.9 Hz, CHHO), 4.96 (1H, d, J = 12.9 Hz, CHHO), 5.02 (2H, s, CH2O), 7.13 (1H, d, J = 7.3
Hz, ArH), 5.74 (1H, s, CHOH), 7.24-7.33 (7H, m, ArH); 13C NMR (100 MHz, CDCl3) δ 72.8, 73.3 (CH2),

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75.0 (CH), 120.2, 125.1, 126.8, 127.8, 128.0, 128.7, 136.8, 137.6, 139.9, 142.5 (ArC); LRMS (EI) m/z
226 (M+, 2%), 209 (17), 208 (100), 207 (72), 180 (19), 179 (23), 165 (34), 152 (11), 146 (17), 132 (11),
119 (36), 104 (19), 91 (38), 89 (18), 79 (10), 77 (30), 65 (12), 63 (12), 51 (10); HRMS (EI) calcd for
C15H12O [M+-H2O] 208.0883, found 208.0841.
4-(1-Hydroxycyclohexyl)phthalan (8b): Colorless oil; Rf = 0.14 (hexane/EtOAc: 5/1); IR ν (film)
3430-3365 (OH), 2918, 2849, 1037 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.68-1.80 (10H, m, 5×CH2), 2.45
(1H, br s, OH), 5.06 (2H, s, CH2O), 5.35 (2H, s, CH2O), 7.12 (1H, d, J = 6.1 Hz, ArH), 7.20-7.25 (2H, m,
13
ArH); C NMR (100 MHz, CDCl3) δ 20.3, 24.3, 25.6, 30.8, 35.7, 72.8, 74.5 (CH2), 75.8 (CH), 119.5,
123.8, 127.6, 127.7, 130.5, 140.6 (ArC); LRMS (EI) m/z 218 (M+, 7%), 201 (15), 200 (100), 199 (14),
185 (10), 171 (18), 167 (10), 159 (30), 157 (21), 147 (10), 145 (29), 144 (10), 143 (12), 141 (13), 119
(13), 115 (28), 104 (10), 91 (21); HRMS (EI) calcd for C14H16O [M+-H2O] 200.1201, found 200.1233.
5-(1-Hydroxycyclohexyl)phthalan (13a): Yellow oil; Rf = 0.16 (hexane/EtOAc: 5/1); IR ν (film)
3475-3395(OH), 3069, 2933, 2855, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.70-1.85 (10H, m, 5×CH2),
13
2.63 (1H, br s, OH), 5.10 (4H, br s, CH2O), 7.21 (1H, d, J = 8.6 Hz, ArH), 7.40-7.42 (2H, m, ArH); C
NMR (100 MHz, CDCl3) δ 22.3, 25.6, 39.2, 73.3, 73.5 (CH2), 73.7 (CH), 117.3, 120.8, 124.0, 137.6,
139.3, 149.2 (ArC); LRMS (EI) m/z 218 (M+, 28%), 188 (10), 175 (22), 162 (22), 147 (19), 146 (15), 145
(100), 133 (11), 119 (10), 105 (10), 104 (14), 91 (20), 55 (15); HRMS (EI) calcd for C14H18O2 218.1307,
found 218.1305.
5-(1-Hydroxy-2,2-dimethylpropyl)phthalan (13b):23 Colorless oil; Rf = 0.34 (hexane/EtOAc: 2/1); IR ν
1
(film) 3460-3385 (OH), 3020 (ArH), 2953, 2892, 2867 cm-1; H NMR (400 MHz, CDCl3) δ 0.92 [9H, s,
C(CH3)3], 2.55 (1H, br s, OH), 4.40 (1H, s, CHOH), 5.08 (4H, br s, CH2O), 7.13-7.26 (3H, m, ArH); 13C
NMR (100 MHz, CDCl3) δ 26.0 (CH3), 35.1 (C), 73.5, 73.6 (CH2), 82.4 (CH), 120.0, 120.1, 127.1, 138.1,
138.6, 141.8 (ArC); LRMS (EI) m/z 206 (M+, 6%), 150 (15), 149 (100), 93 (18), 91 (34); HRMS (EI)
calcd for C13H18O2 206.1307, found 206.1292.
5-(1-Ethyl-1-hydroxypropyl)phthalan (13c): Colorless oil; Rf = 0.19 (hexane/EtOAc: 5/1); IR ν (film)
3465-3390 (OH), 2967. 2940, 2855 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.77 (6H, t, J = 7.4 Hz, 2×CH3),
1.79-1.91 (4H, m, 2×CH2CH3), 5.10 (4H, br s, CH2O), 7.19 (1H, d, J = 7.95 Hz, ArH), 7.25-7.29 (2H, m,
13
ArH); C NMR (100 MHz, CDCl3) δ 8.0 (CH3), 35.3, 73.5, 73.7 (CH2), 77.5 (C), 118.2, 120.5, 124.8,
137.1, 139.1, 145.5 (ArC); LRMS (EI) m/z 206 (M+, 1%), 178 (13), 177 (100), 175, 147 (11), 119 (10),
91 (11), 57 (50); HRMS (EI) calcd for C13H18O2 206.1307, found 206.1300.
2,3-Dimethylbenzyl alcohol (20):24 1H NMR (400 MHz, CDCl3) δ 1.75 (1H, br s, OH), 2.24 (3H, s, CH3),
13
2.28 (3H, s, CH3), 4.66 (2H, s, CH2OH), 7.07-7.18 (3H, m, ArH); C NMR (100 MHz, CDCl3) δ 20.4
(CH3), 64.2 (CH2OH), 125.6, 125.8, 129.7, 135.0, 137.5, 138.1 (ArC); LRMS (EI) m/z 136 (M+, 35%),

HETEROCYCLES, Vol. 77, No. 2, 2009
1001
134 (37), 133 (36), 121 (21), 119 (21), 118 (100), 117 (47), 115 (10), 107 (14), 105 (52), 103 (23), 93
(30), 91 (73), 79 (19), 78 (12), 77 (44), 65 (13), 51 (15).
2,6-Dimethylbenzyl alcohol (21):25 1H NMR (400 MHz, CDCl3) δ 1.75 (1H, br s, OH), 2.41 (6H, s,
2×CH3), 4.70 (2H, s, CH2OH), 7.01-7.19 (3H, m, ArH); 13C NMR (100 MHz, CDCl3) δ 19.5 (CH3), 59.4
(CH2OH), 128.1, 128.5, 136.6, 137.3 (ArC); LRMS (EI) m/z 136 (M+, 35%), 134 (37), 133 (36), 121 (21),
119 (21), 118 (100), 117 (47), 115 (10), 107 (14), 105 (52), 103 (23), 93 (30), 91 (74), 79 (19), 78 (12),
77 (45), 65 (13), 51 (16).
2,4-Dimethylbenzyl alcohol (23a): Yellow oil; Rf = 0.27 (hexane/EtOAc: 6/1); IR ν (film) 3395-3320
1
(OH), 3006, 2959, 2917, 2849 cm-1; H NMR (400 MHz, CDCl3) δ 1.85 (1H, br s, OH), 2.30 (6H, br s,
2×CH3), 4.60 (2H, s, CH2OH), 6.99 (2H, br s, ArH), 7.18-7.23 (1H, m, ArH); 13C NMR (100 MHz,
CDCl3) δ 18.7, 21.1 (CH3), 63.4 (CH2), 126.7, 127.9, 131.3, 135.8, 136.2, 137.6 (ArC); LRMS (EI) m/z
136 (M+, 52%), 135 (10), 134 (29), 133 (41), 121 (47), 119 (24), 118 (100), 117 (54), 115 (19), 107 (22),
105 (45), 103 (25), 93 (33), 91 (79), 79 (17), 78 (11), 77 (39), 65 (14), 51 (15).
3-[(2-Hydroxymethyl-5-methyl)phenyl]pentan-3-ol (23b): Yellow oil; Rf = 0.32 (hexane/EtOAc: 2/1);
IR ν (film) 3340-3285 (OH), 2963, 2929, 2879 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.94 (6H, t, J = 7.4
Hz, CH3), 1.52-1.60 (4H, m, CH2CH3), 2.33 (3H, s, ArCH3), 2.82 (2H, s, ArCH2), 4.53 (2H, s, CH2OH),
6.94 (1H, s, ArH), 7.02 (1H, d, J = 7.55 Hz, ArH), 7.21 (1H, d, J = 7.55 Hz, ArH); 13C NMR (100 MHz,
CDCl3) δ 8.2, 21.3 (CH3), 30.9, 40.6, 63.1 (CH2), 74.3 (C), 127.7, 130.8, 132.8, 136.1, 137.3, 137.7
(ArC); LRMS (EI) m/z 204 [(M+-H2O) 2%], 186 (20), 184 (21), 175 (61), 171 (12), 169 (33), 157 (55),
153 (11), 143 (20), 142 (24), 141 (20), 128 (15), 119 (29), 118 (100), 117 (22), 115 (18), 91 (14), 57 (23);
HRMS (EI) calcd for C14H20O [M+-H2O] 204.1514, found 204.1494.
Double lithiation of phthalans 5. Preparation of compounds 10, 16 and 17. General procedure.
To a blue suspension of lithium powder (72 mg, 10.4 mmol) and a catalytic amount of DTBB (34 mg,
0.13 mmol) in dry THF (3 mL) under argon was added dropwise a solution of the corresponding phthalan
5 (1 mmol) in THF (0.5 mL) at -78 ºC, and the resulting mixture was stirred for 2 h at the same
temperature. Then, the corresponding carbonyl compound was added dropwise (1.1 mmol) at -78 ºC and
stirring was continued for 20 min. After that, the reaction mixture was allowed to rise to 0ºC and stirring
was continued for 1 h at this temperature. Then, the reaction mixture was cooled down to -78 ºC and the
carbonyl compound (1.1 mmol) was added dropwise. Finally it was hydrolyzed with water (4 mL),
extracted with EtOAc (3 × 15 mL), dried over anhydrous MgSO4 and evaporated (15 Torr). The residue
was purified by column chromatography (silica gel, hexane/ethyl acetate) to yield pure products 10, 16
and 17. Yields are given in Table 2. Physical, analytical and spectroscopic data follow.
1-[2-(1-Hydroxycyclohexyl)-6-(hydroxymethyl)benzyl]cyclohexanol (10): White solid; mp 206-207 ºC

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(pentane/CH2Cl2); Rf = 0.21 (hexane/EtOAc: 2/1); IR ν (KBr) 3420-3350 (OH), 3063, 3020, 2928, 2853,
1
1034 cm-1; H NMR (400 MHz, CDCl3) δ 1.26-1.37 (4H, m, 2×CH2), 1.38-1.93 (14H, m, 7×CH2),
2.01-2.05 (2H, m, CH2), 2.61 (2H, s, ArCH2), 4.72 (2H, s, CH2OH), 7.18 (1H, t, J = 7.7 Hz, ArH), 7.32
(1H, d, J = 7.0 Hz, ArH), 7.72 (1H, d, J = 8.0 Hz, ArH); 13C NMR (100 MHz, CDCl3) δ 16.7, 22.3, 25.6,
37.9, 64.3 (CH2), 74.4, 77.4 (CH), 125.2, 125.6, 126.7, 135.4, 140.9, 146.5 (ArC); LRMS (EI) m/z 220
{M+-[(CH2)5COH], 9%}, 202 (24), 159 (12), 150 (13), 149 (100), 147 (46), 143 (11), 129 (15), 128 (13),
114 (13), 91 (14), 77 (11), 55 (14); HRMS (EI) calcd for C14H20O2 [M+-(CH2)5COH] 220.1463, found
220.1457.
3-[3-(2-Ethyl-2-hydroxybutyl)-4-(hydroxymethyl)phenyl]pentan-3-ol (16a): White solid; mp 90-91 ºC
(pentane/CH2Cl2); Rf = 0.37 (hexane/EtOAc: 1/1); IR ν (KBr) 3375-3300 (OH), 2964, 2937, 2878 cm-1;
1H NMR (400 MHz, CDCl3) δ 0.76 (6H, t, J = 7.4 Hz, 2×CH2CH3), 0.94 (6H, t, J = 7.5 Hz, 2×CH2CH3),
1.43-1.62 (4H, m, 2×CH2CH3), 1.73-1.89 (4H, m, 2×CH2CH3), 2.88 (2H, s, ArCH2), 4.57 (2H, s, CH2OH),
13
7.15 (1H, d, J = 1.7 Hz, ArH), 7.21 (1H, dd, J = 8.4, 1.9 Hz, ArH), 7.30 (1H, d, J = 1.9 Hz, ArH); C
NMR (100 MHz, CDCl3) δ 7.9, 8.2 (CH3), 31.1, 35.0, 41.1, 63.1 (CH2), 75.0, 77.3 (C), 124.2, 129.5,
130.5, 135.7, 138.5, 145.3 (ArC); LRMS (EI) m/z 247 [(M+-Et-H2O), 20%], 191 (15), 190 (85), 179 (12),
161 (57), 159 (12), 134 (15), 133 (34), 105 (10), 91 (11), 87 (16), 57 (100); HRMS (EI) calcd for
C16H23O2 [M+-Et-H2O] 247.1693, found 247.1702.
3-[4-(2-Ethyl-2-hydroxybutyl)-3-(hydroxymethyl)phenyl]pentan-3-ol (17a): White solid; mp 119-120
ºC (pentane/CH2Cl2); Rf = 0.27 (hexane/EtOAc: 1/1); IR ν (KBr) 3390-3310 (OH), 3027, 2966, 2938,
1
2879 cm-1; H NMR (400 MHz, CDCl3) δ 0.76 (6H, t, J = 7.4 Hz, 2×CH3), 0.95 (6H, t, J = 7.4 Hz,
2×CH3), 1.50-1.64 (4H, m, 2×CH2CH3), 1.79-1.86 (4H, m, 2×CH2CH3), 2.86 (2H, s, ArCH2), 4.60 (2H, s,
CH2OH), 7.11 (1H, d, J = 8.05 Hz, ArH), 7.24-7.26 (1H, m, ArH), 7.35-7.37 (1H, m, ArH); 13C NMR
(100 MHz, CDCl3) δ 8.1, 8.2 (CH3), 31.1, 34.8, 40.3, 63.9 (CH2), 75.0, 77.4 (C), 125.0, 128.0, 131.9,
134.0, 140.2, 144.8 (ArC); LRMS (EI) m/z 247 [(M+-Et-H2O), 29%], 191 (15), 190 (100), 179 (24), 172
(11), 162 (12), 161 (84), 148 (10), 134 (18), 133 (41), 105 (14), 91 (13), 87 (22), 57 (98); HRMS (EI)
calcd for C16H23O2 [M+-Et-H2O] 247.1693, found 247.1689.
1-[5-(1-Hydroxycyclohexyl)-2-(hydroxymethyl)benzyl]cyclohexanol (16b): White solid; mp 166-167
ºC (pentane/CH2Cl2); Rf = 0.27 (hexane/EtOAc: 1/1); IR ν (KBr) 3390-3315 (OH), 2931, 2854, 1022
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.31-1.57 (10H, m, 5×CH2), 1.71-1.85 (10H, m, 5×CH2), 2.88 (2H, s,
ArCH2), 4.64 (2H, s, CH2OH), 7.29-7.34 (3H, m, ArH); 13C NMR (100 MHz, CDCl3) δ 23.2, 26.7, 27.0,
38.7, 39.7, 63.5 (CH2), 72.4, 73.8 (CO), 123.9, 129.8, 130.2, 136.9, 139.4, 150.0 (ArC); LRMS (EI) m/z
282 [(M+-2H2O), 22%], 264 (10), 202 (19), 185 (18), 184 (100), 155 (11), 141 (20), 129 (10), 128 (11);
HRMS (EI) calcd for C20H26O [M+-2H2O] 282.1984, found 282.1951.

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ACKNOWLEDGEMENTS
This work was generously supported by the Spanish Ministerio de Educación y Ciencia (MEC; grants no.
Consolider Ingenio 2010-CSD2007-00006 and CTQ-2007-65218). D. G. thanks the University of
Alicante for a predoctoral fellowship. We also thank MEDALCHEMY S.L. for a gift of chemicals.
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15. Crystal data (excluding structure factors) deposited at the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 696182: C18H30O3, M = 294.42; orthorhombic, a =
15.3894(8) Å, b = 10.1191(5) Å, c = 22.8872(12) Å; V = 3564.2(3) Å3; space group Pca2(1); Z = 8; Dc

HETEROCYCLES, Vol. 77, No. 2, 2009
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= 1.097 Mg m-3; λ = 0.71073 Å; μ = 0.073 mm-1; F(000) = 1296; T = 23±1 °C. Data collection was
performed on a Bruker Smart CCD diffractometer, based on three ω-scan runs (starting = -34°) at
values φ =0°, 120°, 240° with the detector at 2θ =-32°. For each of these runs, 606 frames were
collected at 0.3° intervals and 10 s per frame. An additional run at φ =0° of 100 frames was collected to
improve redundancy. The diffraction frames were integrated using the program SAINT16 and the
integrated intensities were corrected for Lorentz-polarization effects with SADABS.17 The structure
2
was solved by direct methods18 and refined to all 3247 unique Fo by full matrix least squares.18 All the
hydrogen atoms were placed at idealized positions and refined as rigid atoms. Final wR2=0.1194 for
all data and 393 parameters; R1=0.0436 for 2493 Fo>4σ(Fo).
16. SAINT Version 6.02A: Area-Detector Integration Software; Siemens Industrial Automation, Inc.:
Madison, WI, 1995.
17. G. M. Sheldrick, SADABS: Area-Detector Absorption Correction, Göttingen University, 1996.
18. G. M. Sheldrick, Acta Cryst., 2008, A64, 112.
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