Functionalized organozincates and organocuprates derived from γ-hydroxytellurides in the preparation of 1,4-hydroxyketones

Article abstract of DOI:10.1016/j.tetlet.2009.08.097

A C-O-dianionic zincate was generated by a Te/Li exchange reaction of an alkyltelluride, followed by Li/Zn transmetallation and reaction with methyllithium. The reaction between the enantiomerically pure (99% ee) (R)-dianionic zincate and benzoyl chloride

Full text of DOI:10.1016/j.tetlet.2009.08.097

Tetrahedron Letters 50 (2009) 6368–6371
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Tetrahedron Letters
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Functionalized organozincates and organocuprates derived
from
c-hydroxytellurides in the preparation of 1,4-hydroxyketones
*
Jefferson L. Princival, Alcindo A. Dos Santos , João V. Comasseto
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cx.P. 26077, 05508-900 São Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A C–O-dianionic zincate was generated by a Te/Li exchange reaction of an alkyltelluride, followed by Li/
Zn transmetallation and reaction with methyllithium. The reaction between the enantiomerically pure
(99% ee) (R)-dianionic zincate and benzoyl chloride led to 3-hydroxy-1-phenyl pentanone with total
retention of the carbon configuration (99% ee). Similar results were obtained using the corresponding
Lipshutz cyanocuprates.
Received 31 July 2009
Revised 25 August 2009
Accepted 26 August 2009
Available online 1 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hydroxyltellurides
Organozincates
Organocuprates
1,4-Hydroxyketones
Functionalized non-stabilized organometallics are useful inter-
mediatesfor the constructionof multifunctionalorganicstructures.1
Among the most employed functionalized sp3-hybridized organo-
metallics for this end are the organozinc compounds.2 The prepara-
tion of these species from organolithium reagents by
transmetallation is a common practice.1 The functionalized sp3-
hybridized organolithium precursors have been prepared by halo-
gen-,1b–d,h,i sulfur–,3 tin–1b,4 and more recently, tellurium–lithium5
exchange reactions. In this last case the progress has been slower,
presumably due to the lack of reliable information on the physical
and chemical characteristics of organotellurium compounds. Recent
studies of our group showed that functionalized alkyltellurides are
easily prepared and handled,6 demonstrating stability to air and
light, and exhibiting no bad smell, contrary to what is frequently
reported about organotellurium compounds. Keeping these facts
in mind, and considering the easy access to functionalized alkyltel-
lurides in enantiomerically pure form,6a,b,7 we report in this Letter
a study on their transformation into 4-hydroxyketones, through
the intermediacy of organozinc compounds. The fast tellurium/lith-
ium exchange5 and the inertness of both the starting alkyltelluride
and the by-product dibutyltelluride toward the newly formed sp3-
hybridized organometallics are appealing features of our method
to access these reactive intermediates.
The starting hydroxytelluride 1a used in this study was pre-
pared in 85% yield by hydrotelluration of methyl vinyl ketone, fol-
lowed by carbonyl reduction with sodium borohydride.6c,d,f
Li
Li
O
O
ZnCl
PhCOCl (6)
no reaction
n = 1
3a
4a
O
Li
O
Li
H O
TeBu
n
Zn
2
1/n
ZnCl2
BuLi
6
25%
n = 2
n = 3
Ph
OH
1a
2a
7
6
25%
Li
O
ZnLi
3
5a
Scheme 1. Presumed structures of the organozinc species formed and their reaction with benzoyl chloride (6).
* Corresponding author. Tel.: +55 11 3091 2165; fax: +55 11 3815 5579.
E-mail address: alcindo@iq.usp.br (A. A. Dos Santos).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.097

J. L. Princival et al. / Tetrahedron Letters 50 (2009) 6368–6371
6369
Compound 1a is a yellow oil stable in air and ceiling light, and pre-
sents no bad smell. Enzymatic kinetic resolution of (R,S)-1a gave
(S)-1a in 99% ee7 The transformation of 1a into the corresponding
alkoxy-alkyllithium 2a was performed by adding 2.0 equiv of n-
buthyllithium to 1a in THF at ꢀ78 °C. In a previous work, 2a was
captured with carbonyl compounds leading to the corresponding
1,4-diols.6f
In this Letter, 1.0 equiv of the dianion 2a was reacted with 1.0,
0.5, and 0.33 equiv of ZnCl2 with the aim of preparing the corre-
sponding mono-, di-, and tri-organozinc species. The resulting
organometallic solutions were reacted with benzoyl chloride (6).
The results are shown in Scheme 1.
The intermediate 3a did not react with 6, presumably due to the
intramolecular stabilization of the O–Zn–C chelate with a high
covalent bond character. Intermediates 4a and 5a reacted with 6
only in poor yields.
In view of the reactivity presented by entities 3a–5a, and based
on the works8 concerning the enhancement of the reactivity of
organozinc reagents, we decided to transform the intermediate
4a into the corresponding heterozincate 8a (Scheme 2). For this
end telluride 1a was reacted with 2 equiv of n-butyllithium, fol-
lowed by 0.5 equiv of ZnCl2 and then with 1.0 equiv of methyllith-
ium. The heterozincate 8a was reacted with benzoyl chloride (6)
and the desired product 7 was obtained in 70% isolated yield.9
By using an enantioenriched sample of (S)-1a (99% ee),7 the cor-
responding enantiomerically enriched zincate 8a was obtained,
which on reaction with benzoyl chloride (6) gave (S)-7 with 99% ee.
With these results in hands, we reacted other acyl chlorides
with the heterozincate 8a, and several 3-hydroxyketones were
produced in reasonable to good yields as presented in Table 1.
Compounds 7, 12–14 are analogous to Ipomeanol, a potent lung
anticancer agent.10
1) nBuLi (2 equiv)
H O
TeBu
Li
O
Zn(Me)Li
2
2) ZnCl2 (0.5 equiv)
3) MeLi (1 equiv)
1a
8a
6, 70%
O
Ph
7
OH
Scheme 2. Reaction of the mixed hetero organozincate 8a with 6.
Table 1
Hydroxyketones prepared starting from hydroxytelluride 1a
Entry
Substrate
Producta
Yieldb (%)
In a previous work,6c we observed that the dianion 2a can be
transformed into the corresponding Lipshutz cuprate 3b which re-
acts with 2-cycloexen-1-one as expected. This same cuprate re-
acted with benzoyl chloride (6) leading to 7 in 65% yield11
(Scheme 3).
The generality of the above-commented transformations was
demonstrated by preparing a number of different hydroxytellu-
rides, as shown in Scheme 4, following a protocol similar to the
one used to prepare 1a.6f
The hydroxytellurides 1a–e prepared were submitted to the Te/
Li exchange reaction and the corresponding lithium dianions were
used in the formation of cuprates and zincates, as described above
for 1a. The zincates and cuprates derived from 1a–e were reacted
O
O
O
1
62
Cl
Cl
OH
OH
F
F
F
F
12
O
2
3
4
5
6
67
66
58
72
72
13
14
O
O
Cl
OH
O
O
O
O
OH
Te0
1) nBuLi, THF
Cl
O
O
15
2) 2.4 equiv H2O
O
8
O
8
BuTe
EDG
R2
nBuTeH
1)
EWG
R3
Cl
Cl
2) LiAlH4 or NaBH4
OH
OH
R3
1a-e
R2
16
O
5
EDG = OH
O
5
EWG = COR, CO2R
R = Ph, 2-Th, CH3, H
R2 = H, CH3
(1a) R2 = CH3; R3 = H (85%)
(1b) R2 = Ph; R3 = H (81%)
(1c) R2 = 2-Th; R3 = H (91%)
17
R3 = H, CH3
(1d) R2 = R3 = H
(78%)
a
(1e) R2 = H; R3 = CH3 (83%)
All compounds prepared showed analytical data compatible with the proposed
structures.
b
Isolated yields after column chromatography.
Scheme 4. Preparation of hydroxytellurides 1a–e.
O
0.5 equiv CuCN
THF / -78 oC
Li
O
Li
OLi
6
Cu(CN)Li2
OH
7
65%
2a
2
3b
Scheme 3. Transformation of 2 into a Lipshutz cyanocuprate and its reaction with 6.

6370
J. L. Princival et al. / Tetrahedron Letters 50 (2009) 6368–6371
Table 2
Hydroxyketones prepared starting from hydroxytellurides 1a–e
Entry
Hydroxytelluride
Dianion
Producta
Yieldb (%)
O
TeBu
OH
Li
O
Cu(CN)Li2
2
1
65
OH
1a
7
Li
O
Li
Zn(Me)Li
2
2
3
4
5
1a
7
70
77
68
73
OH TeBu
O
O
Cu(CN)Li2
2
OH
1b
18
Li
O
Zn(Me)Li
2
1b
18
S
O
OH TeBu
Li
O
Cu(CN)Li2
2
OH
S
S
1c
19
Li
O
Zn(Me)Li
2
6
7
1c
19
65
67
S
O
TeBu
1d
OH
Li
Li
O
Cu(CN)Li2
OH
2
20
O
Zn(Me)Li
2
8
9
1d
20
62
63
75
O
OH TeBu
Li
O
Cu(CN)Li2
2
OH
1e
21
Li
O
Zn(Me)Li
2
10
1e
21
a
All compounds prepared showed analytical data compatible with the proposed structures.
Isolated yields after column chromatography.
b
with benzoyl chloride (6) giving the corresponding 4-hydroxyke-
tones shown in Table 2.
Acknowledgments
Finally, it must be pointed out that all the organotellurium com-
pounds described in this paper do not smell badly, and are stable in
air and light.
The authors thank FAPESP, CNPq, and CAPES for financial
support.
In conclusion, hydroxyltellurides can be converted into organo-
zincates and organocuprates by a Te/Li exchange reaction followed,
respectively, by transmetallation with ZnCl2 and reaction with
CuCN. The zincates and cuprates react with acid chlorides giving
4-hydroxyketones.
References and notes
1. (a) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 583; (b)
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2.3 mol Lꢀ1) was added. After 5 min freshly prepared THF solution of ZnCl2
(1 mL, 1 mmol, 1 mol Lꢀ1) was added and the mixture was allowed to warm up
to ꢀ10 °C. The mixture was re-cooled to ꢀ78 °C and methyllithium (1.0 mL,
1 mmol, 1 mol Lꢀ1) was added. The mixture was allowed to warm up to 0 °C.
Then freshly distilled benzoyl chloride (6) was added (1 equiv) and the reaction
mixture was stirred for 2 h, poured into aqueous ammonium chloride solution
(2 mL), extracted with ether, and the ether layer was washed with water, dried
over MgSO4, evaporated and the residue was purified by silica gel (230–
400 mesh) chromatography using ethyl acetate/hexane (1:1) to afford 125 mg
of 7. Oil; yield (70%); CAS NR 27927-59-9. 1H NMR (200 MHz; CDCl3) d 1.24
(3H, d, J = 6.1 Hz), 1.77–2.03 (2H, m), 2.99 (1H, s), 3.12 (2H, t, J = 7.0 Hz), 3.89
(1H, sext, J = 6.1 Hz), 7.40–8.00 (5H, m). 13C NMR (50 MHz; CDCl3) d 23.5; 32.9;
34.7; 67.1; 127.9; 128.4; 132.9; 136.6; 200.8. IR (film) cmꢀ1 3420, 3062, 2967,
2929, 1682, 1597, 1449, 1278, 1208, 1128, 1075, 743, 691. MS m/z (rel int.) 160
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11. General procedure for the cuprate preparation/capture: (R,S)-4-Hydroxy-1-
phenylpentan-1-one (7): A solution of the (R,S)-(1a) (520 mg, 2 mmol) in THF
(10 mL) was cooled to ꢀ78 °C, and n-butyllithium (1.74 mL, 4 mmol,
2.3 mol Lꢀ1
) was added. After 5 min this solution was transferred via a
cannula to a THF (5 mL) and CuCN (0,179 g, 2 mmol) suspension. The resulting
suspension was stirred until a clear, light yellow solution was formed (1 h at
ꢀ78 °C). This solution was then transferred via a cannula to another flask
containing benzoyl chloride (0.28 g, 2 mmol) in THF (4 mL). The resulting
mixture was stirred at ꢀ78 °C for 30 min, warmed to room temperature, and
then diluted with ammonium hydroxide/ammonium chloride solution (10%,
5 mL) and diethyl ether (5 mL). The mixture was maintained under vigorous
stirring for 30 min and the phases were separated. The organic phase was
washed with brine (2 ꢂ 3 mL) and the aqueous phase was extracted with ethyl
acetate (5 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and the solvent was removed under reduced pressure. The
resulting residue was purified by CC over silica gel, eluting with ethyl acetate/
hexane (1:1) giving 116 mg of 7 (65%) as an analytically pure material. The
spectral data are identical to those of the compound obtained above.
7. Dos Santos, A. A.; Da Costa, C. E.; Princival, J. L.; Comasseto, J. V. Tetrahedron:
Asymmetry 2006, 17, 2252.
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Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120,
4934.
9. General procedure for the hetero zincate 8a preparation/capture: (S)-4-Hydroxy-1-
phenylpentan-1-one (7): A solution of the (S)-(1a) (520 mg, 2 mmol) in THF
(10 mL) was cooled to ꢀ78 °C and n-butyllithium (1.74 mL, 4 mmol,