Lithiation and reactions of stilbene oxides: Synthetic utility

Article abstract of DOI:10.1021/ol0485013

(Chemical Equation Presented) The lithiation of trans- and cis-stilbene oxides (±)-1 and 8 has been investigated. While with 8, lithiation occurred exclusively at the benzylic position, with the trans isomer (±)-1, ortho-lithiation competed with α-lithiation depending upon the experimental conditions. The configurational stability of the α-lithiated cis- and trans-stilbene oxides (±)-2 and (±)-9, respectively, was proved as well as that of scalemic stilbene oxide (R,R)-2.

Full text of DOI:10.1021/ol0485013

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4191-4194
Lithiation and Reactions of Stilbene
Oxides: Synthetic Utility
Saverio Florio,*,† Varinder Aggarwal,*,‡ and Antonio Salomone†,‡
Dipartimento Farmaco-Chimico, UniVersity of Bari, C.N.R.,
Istituto di Chimica dei Composti Organometallici “ICCOM”,
Sezione di Bari, Via E. Orabona 4, I-70126-Bari, Italy, and
School of Chemistry, UniVersity of Bristol, Cantock’s Close,
Bristol BS8 1TS, UK
florio@farmchim.uniba.it; V.aggarwal@bristol.ac.uk
Received July 29, 2004
ABSTRACT
The lithiation of trans- and cis-stilbene oxides (±)-1 and 8 has been investigated. While with 8, lithiation occurred exclusively at the benzylic
position, with the trans isomer ( )-1, ortho-lithiation competed with
±
r-lithiation depending upon the experimental conditions. The configurational
stability of the
(R,R)-2.
r
-lithiated cis- and trans-stilbene oxides (
±
)-2 and (
±
)-9, respectively, was proved as well as that of scalemic stilbene oxide
Polysubstituted epoxides are often key intermediates in the
construction of structurally complex molecules,1 and as such
their synthesis has been intensively studied.2a-g Among the
numerous routes that have been developed to this end, the
oxiranylanion-based methodology has been exploited in only
a few cases.2h The related enantioselective version has been
pursued even less.2k,3,4
Quite recently, we developed a new stereospecific syn-
thesis of styrene oxide derivatives, which was based on the
oxiranyllithium methodology. Starting from (S)- or (R)-
styrene oxide, it was possible to obtain R-substituted styrene
oxides in high yields and excellent enantiomeric purity.3 The
stereospecificity of the lithiation-trapping sequence of
phenylpropylene oxides has also been shown.4
In continuation of our work on the chemistry of aryl-
stabilized oxiranyllithiums, and to evaluate the substituent
effect on their reactivity and stability, we conducted a
detailed exploration of the lithiation of stilbene oxides and
successive trapping with electrophiles.
(2) (a) Kolb, H. C.; Sharpless, K. B. Transition Met. Org. Synth. 1998,
2, 219. (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal.
2001, 343, 5. (c) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem. 2001, 113, 1479.
(d) Pedragosa-Moreau, S.; Morriseau, C.; Zylber, J.; Archelas, A.; Baratti,
J.; Furstoss, R. J. Org. Chem. 1996, 61, 7402. (e) Abbotto, A.; Capriati,
V.; Degennaro, L.; Florio, S.; Luisi, R.; Pierrot, M.; Salomone. A. J. Org.
Chem. 2001, 66, 3049. For reviews see: (f) Besse, P.; Veschambre, H.
Tetrahedron 1994, 50, 8885. (g) Aggarwal, V. K.; Winn, C. L. Acc. Chem.
Res. 2004, 37, 611-620. (h) Hodgson, D. M.; Gras, E. Synthesis 2002,
1625. (k) Yamauchi, Y.; Katagiri, T.; Uneyama, K. Org. Lett. 2002, 4 (2),
173.
† University of Bari, C.N.R., ICCOM.
‡ University of Bristol.
(1) (a) Lertvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.; Thonyoo,
P. J. Org. Chem. 2001, 66, 4692. (b) Mori, Y.; Yaegashi, K.; Furukawa,
H. J. Am. Chem. Soc. 1997, 119, 4557. (c) Mori, Y.; Yaegashi, K.;
Furukawa, H. Tetrahedron 1997, 53, 12917. (d) Mori, Y.; Yaegashi, K.;
Furukawa, H. J. Org. Chem. 1998, 63, 6200. (e) Mori, Y. Heteroat. Chem.
1997, 17, 183. (f) Agami, C.; Dechoux, L.; Doris, E.; Mioskowski, C.
Tetrahedron Lett. 1997, 38, 4071. (g) Dechoux, L.; Agami, C.; Doris, E.;
Mioskowski, C. Eur. J. Org. Chem. 2001, 4107. (h) Capriati, V.; Degennaro,
L.; Favia, R.; Florio, S.; Luisi, R. Org. Lett. 2002, 4, 1551.
(3) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4,
2445.
(4) Capriati, V.; Florio, S.; Luisi, R.; Nuzzo, I. J. Org. Chem. 2004, 69,
3330.
10.1021/ol0485013 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/19/2004

We made several attempts to increase the regioselectivity
in favor of the ortho-lithiation by using different bases, lower
temperatures (-110 to -98 °C), and different solvents: all
were unsuccessful. The percentage of trans-4a, which was
the minor product at -98 °C when using s-BuLi, increased
with temperature until it became the main product at -60
°C (4a:5a ) 74:26, entry 5). The conversion of starting
material also increased with the temperature. When trans-1
was lithiated (s-BuLi/TMEDA, -98 °C) and then allowed
to warm to rt, PhCH2COPh formed (75% yield) after acidic
quenching. Such an isomerization of 1 has been already
reported.7
We subsequently focused on finding conditions that
favored R-deprotonation. Lithiation of 1 with either 3 or 1.5
equiv of n-BuLi and 3 equiv of TMEDA in THF at -60 °C
for 2 h gave the best conversion of 1 to 2 with high
regioselectivity. Quenching with MeI gave the R-substituted
product 4a in very good yields (81 and 73%) and high
regioselectivity: the 4a:5a ratio ranged from 92:8 to 90:10
(Table 1, entries 9 and 12).
An increase in regioselectivity was also observed (4a:5a
> 98:2) when the deprotonation was performed without
TMEDA, but the conversion of 1 was poor (40%) (Table 1,
entry 14). Good yield and regioselectivity were also noted
in toluene (entry 11). In all cases, the conversion of 1 to 4a
proceeded with complete retention of configuration.
We suspected that the observed temperature dependence
in the regioselective lithiation of 1 could be the result of an
equilibration of the R- and ortho-lithiated species (“anion
translocation”).9 However, three experiments ruled out such
a possibility. In the first, we subjected the o-bromo-trans-
stilbene oxide 610 to a lithiation-methylation sequence under
a variety of experimental conditions. In no case did we
observe R-methylation: only trans-1 and the ortho-methy-
lated compound 5a were obtained (Table 2). The formation
Scheme 1. Lithiation-Methylation of (()-1
Lithiation of racemic trans-stilbene oxide 1 followed by
quenching with MeI gave a mixture of the expected epoxide
trans-4a and the ortho-methylated epoxide 5a, the 4a:5a ratio
being dependent upon the experimental conditions (Scheme
1 and Table 1). s-BuLi (1.5 equiv), TMEDA (1.5 equiv),
Table 1. Lithiation-Methylation of (()-1: Effect of the
Lithiating System and Experimental Conditions on the
Regioselectivitya
T
t
conversion of 1
entry base (equiv)b (°C) (min) 4a:5ac,d,e
(%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
s-BuLi (2) f
s-BuLi (2) f,g
s-BuLi (2) f
s-BuLi (2)
s-BuLi (1.5)h
s-BuLi (1.5)h
s-BuLi (1.1)
s-BuLi (1.5)
n-BuLi (3)
-78
-78
-50
-78
-60
-98
-98
-98
-60 120
-60 180
35
-60 120
-60 60
-60 120
45
45
30
30
60
60
30
10
70:30
66:34
85:15
50:50
74:26
36:64
37:63
36:64
92:8
90:10
85:15
90:10
90:10
>98:2
85:15
>98:2
-
98
98
98
90
82
67
48
36
88
85
85
81
55
40
34
22
-
n-BuLi (1.5)
n-BuLi (1.5)h,i -55
n-BuLi (1.5)
n-BuLi (1.5)
n-BuLi (3)f
n-BuLi (1.5)h,j -55
35
60
35
15
t-BuLi (1.2)f
MeLi (1.5)f
LDA (1.5)f
-78
-55
-98
Table 2. Reaction of Lithiated (()-6 in THF with MeI
-
-
a Reactions performed in THF/TMEDA (3 equiv). b Equivalents with
1
respect to 1. c Determined by H NMR analysis. d For spectroscopic data
of 4a and 5a, see ref 8. e Inseparable mixture. f Reaction without TMEDA.
g Reaction in 2/1 hexane/THF. h Reaction performed with 1.5 equiv of
TMEDA. i Reaction in toluene. j Reaction in DME.
RLi
time (h)
temp (°C)
5a (%)a
1 (%)a
t-BuLi
n-BuLi
n-BuLi
1.5
1.5
0.5b,c
-98
-78
-78
68
77
72
32
23
10
THF, -98 °C, and 1 h as the reaction time represented the
best conditions for the formation of epoxide 5a (4a:5a )
36:64, entry 6). To account for formation of 5a we believe
that there is coordinative assistance of the epoxide oxygen
to the H-Li exchange on the phenyl ring (intermediate 3).
In other words, the epoxide is acting as an ortho-directing
group (DoM methodology).5 This behavior is quite surprising
since benzylic ethers, unlike the related benzylic amines,
usually undergo exclusive R-lithiation rather than ortho-
lithiation.6
a Yield by H NMR analysis on the crude mixture. b Formation of 1 is
lowered by shorter reaction times. c 1H NMR analysis on the crude mixture
showed 18% of unreacted (()-6.
1
of 1 and 5a can be ascribed to Li-Br exchange and hydrogen
trapping by any proton source in the reaction medium and
methylation with MeI, respectively.
(6) Schoolkopf, U. Angew. Chem., Int. Ed. Engl. 1979, 18, 763.
(7) Cope, A. C.; Trumbull, P. A.; Trumbull, E. J. Am. Chem. Soc. 1958,
80, 2844.
(8) Oudeyer, S.; Le´onel, E.; Paugam, J. P.; Ne´de´lec, J. Y. Synthesis 2004,
389.
(5) Organolithiums: SelectiVity for Synthesis; Clayden, J., Ed.; Perga-
mon: Oxford, 2002; Tetrahedron Organic Chemistry Series, Vol. 23, pp
28-73.
4192
Org. Lett., Vol. 6, No. 23, 2004

In the second experiment, trans-1 was first lithiated with
s-BuLi/TMEDA at -98 °C, kept there for 1.5 h, then warmed
to -60 °C for 1 h and quenched with MeI. The 4a:5a ratio
was 57:43, which lies between the 4a:5a ratio of 36:64
measured at -98 °C and 74:26 recorded at -60 °C. This
result confirms that ortho-lithiation is favored at low tem-
perature and R-lithiation at high temperature.11
Table 3. Reaction of Lithiated (()-1 with Electrophiles
12a
In the third experiment, dideutero stilbene oxide 1-d2
entry product electrophile
E
4 (%)a
4:5b
was first deprotonated with s-BuLi/TMEDA at -98 °C,
warmed to -60 °C for 1.5 h, and then quenched with MeI
to give o-methyl stilbene oxide 5a-d2, o,o′-dimethyl stilbene
oxide 7-d212b and R-methyl stilbene oxide 4a-d1 (Scheme 2).
1
2
3
4
4bc
4cc
4de
4ee,f
EtI
AllylBr
PhCHO
Et
Allyl
PhCHOH
57
55
56d
56
97:3
93:7
90:10
>99:1
PhCONMe2 PhCO
a Isolated yields. b Regioisomeric ratio by 1H NMR analysis on the crude
mixture. c For spectroscopic data of 4b and 4c, see refs 8 and 14,
respectively. d Overall yield in both diastereomers (dr ) 60/40). e For
spectroscopic data, see Supporting Information. f s-BuLi was used instead
of n-BuLi to avoid the formation of PhCOBu by the reaction of n-BuLi
with PhCONMe2.
Scheme 2. Reaction of Lithiated (()-1-d2 in THF with MeI
4e (Table 3, entry 4). These results provide further evidence
of the configurational stability of the parent lithiated oxirane
when held at -60 °C for 2 h.
On the basis of results collected in Tables 1-3, the
following conclusions can be drawn. First, the base used
controls the regioselectivity of the deprotonation reaction,
s-BuLi promoting ortho-lithiation, n-BuLi favoring R-lithia-
tion. In all cases, addition of TMEDA promotes ortho-
lithiation but to different extents depending on the base
employed. Second, attempts to lithiate 1 with t-BuLi or LDA
at -78 °C or lower temperature failed. In fact, just traces of
4a and 5a could be observed in the crude reaction mixture
None of these products were ortho-deuterated, thus demon-
strating the absence of ortho-lithiation followed by anion
translocation to the R-lithio species. Interestingly, the regi-
oselectivity (highly shifted toward ortho-lithiation) of the
deprotonation-methylation sequence was highly dependent
on the H/D substituent, thus demonstrating a remarkable
kinetic isotopic effect. The deprotonation-methylation se-
quence carried out on the “light” stilbene oxide 1 led to a
4a:5a ratio ) 57:43, and the o,o′-dimethylated stilbene oxide
7 did not form at all.
Lithiation of 1, carried out under conditions that favor
R-deprotonation, followed by trapping with EtI and allylBr,
afforded epoxides 4b and 4c, respectively, with high regio-
selectivity and complete retention of configuration, together
with small amounts of epoxides 5b and 5c. Trapping with
benzaldehyde, however, furnished epoxy alcohol 4d (almost
1:1 diastereomeric mixture, dr ) 60:40) together with
epoxide 5d (mixture of diastereoisomers, dr ) 60:40) (Table
3).
1
by H NMR analysis after quenching with MeI (Table 1),
although it had been reported that lithiated stilbene oxide 2,
generated upon treatment of 1 with t-BuLi (or LDA), could
be trapped with Me3SiCl (internal quenching).15 Third, the
regioselectivity depends also upon the electrophile, the
addition of PhCONMe2 to a mixture of n-BuLi, TMEDA,
and 1 (Table 3, entry 4) furnishing the R-acyl stilbene oxide
4e in a highly regioselective manner. NMR analysis of the
crude reaction product did not show any trace of the acylated
epoxide on the ortho position. This behavior may be due to
a higher kinetic nucleophilicity of the oxiranyllithium 2
compared with the aryllithium 3. Moreover, under the
experimental conditions that favor the R-lithiation [n-BuLi
(1.5 equiv), TMEDA (3 equiv), PhCONMe2 (1.5 equiv) at
-60 °C], 1-phenylpentanone (formed by addition of the
excess n-BuLi to PhCONMe2) might protonate the lithiated
The configuration of the two diastereoisomers of 4d
(1R*,2S*,3R* and 1R*,2R*,3S*) was deduced by 500 MHz
1H NMR analysis.13a The configuration of 4d-syn was also
confirmed by X-ray analysis.13b Lithiation of 1 followed by
quenching with PhCONMe2 produced exclusively epoxide
(13) (a) According to previous observations on many diastereomeric
epoxy alcohols (See ref 3 and: Adam, W.; Braun, M.; Griesbeck, A.;
Lucchini, V.; Staab, E.; Will, B. J. Am. Chem. Soc. 1989, 111, 203), the
carbinol proton of the syn isomer (in our case corresponding to (1R*,2S*,3R*)-
4d) absorbs at a lower field than the corresponding proton of the anti isomer
(δ 4.81 vs 4.60 for 4d-syn and 4d-anti). (b) CCDC 246147 contains the
supplementary crystallographic data for compound (1R*,2S*,3R*)-4d. These
data can be obtained free of charge via the Internet at www.ccdc.ac.uk/
conts/retrieving.html or from the Cambridge Crystallographic Data Centre,
12, Union Road, Cambridge CB2 1EZ, UK; fax: (int) +44-1223/336-033;
e-mail: deposit@ccdc.cam.ac.uk.
(9) As an example of “anion translocation”, see: Ahmed, A.; Clayden,
J.; Rowley, M. Tetrahedron Lett. 1998, 39, 6103.
(10) For the preparation of 6, see: Akgun, E.; Glinski, M. B.; Dawan,
K. L.; Durst, T. J. Org. Chem. 1981, 46, 2730.
(11) Lithiation at -98 °C was not complete. Therefore, as the mixture
is warmed from -98 to -60 °C, the remaining strarting material is
deprotonated at the higher temperature, which favors R-lithiation.
(12) (a) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.;
Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.;
Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125,
10926. (b) The presence of 7-d2 (not isolated) was ascertained by 1H NMR,
GC-MS analysis on the crude mixture, and comparison with the light
compound 7 (see Supporting Information).
(14) Yano, K.; Hatta, Y.; Baba, A.; Matsuda, H. Synthesis 1992, 693.
(15) Eisch, J. J.; Galle, J. E. J. Org. Chem. 1990, 55, 4835-4840 and
refs cited therein.
Org. Lett., Vol. 6, No. 23, 2004
4193

species 2 and 3: in fact, only 10% of 4e was observed. In
that case, the use of sec-BuLi was necessary to obtain 4e in
56% yield.
We also studied the lithiation of scalemic (R,R)-trans-
stilbene oxide 1 (ee ) 98%)12 (Scheme 3). Treatment of
We next studied the lithiation of cis-stilbene oxide 8. It
was interesting to observe that, in this case, the R-lithiation
Versus ortho-lithiation competition does not take place.
Indeed, when MeI was added to the lithiated cis-stilbene
oxide 9 [generated by deprotonation of 8 (n-BuLi (1.5 equiv)/
TMEDA (3.0 equiv), THF, -98 °C, 30 min)], the R-me-
thylated compound 10a was formed exclusively. The absence
of ortho-lithiation may reflect the reduced steric hindrance
associated with R-lithiation of cis-stilbene oxide compared
to the trans isomer. The higher reactivity of cis-epoxides
toward deprotonation with respect to the trans isomers is well
documented.16 Similarly, treatment of 9 with other electro-
philes (Table 4) produced exclusively the R-functionalized
Scheme 3. Lithiation-Ethylation of (R,R)-1
(R,R)-1 with n-BuLi at -60 °C gave the lithiated derivative
(R,R)-2, which proved to be quite stable and could be kept
for at least 2 h at that temperature. Quenching with EtI
furnished (R,R)-trans-stilbene oxide (+)-4b ([R]D ) + 22
(c 0.93, CHCl3) (45% yield) together with the starting
1
epoxide (R,R)-1 (27%). The H NMR analysis of (+)-4b
showed no signal of the cis epimer.
Table 4. Reaction of Lithiated 8 with Electrophiles
In conclusion, R-lithiated stilbene oxides 2 and 9 proved
to be chemically much more stable than lithiated styrene
oxide.3 Indeed, 2 and (R,R)-2 can be kept at -60 °C for at
least 2 h and 9 at -98 °C for 30 min. Moreover, due to
their configurational stability, it is possible to trap the
R-lithiated stilbene oxides, in a stereospecific manner, by
alkylation, hydroxyalkylation, or acylation of the benzylic
position. We have also observed, for the first time to our
knowledge, the ortho-directing capability of the oxirane
moiety in lithiation of the phenyl ring. Finding experimental
conditions that favor the ortho-lithiation is at present being
pursued in our labs. Further studies are under way to exploit
the configurational stability of lithiated stilbene oxides.
entry
product
electrophile
E
yield (%)a
1
2
3
4
5
10ab
10bb
10cd
10df,g,h
10ef
MeI
EtI
AllylBr
PhCHO
PhCONMe2
Me
Et
Allyl
PhCHOH
PhCO
89c
76
55e
91i
88
a Isolated yields. b For spectroscopic data of 10a and 10b see ref 8.
1
c Yield by H NMR analysis. d For spectroscopic data of 10c, see ref 14.
e 1,2-Diphenyl ethanone was isolated in 40% yield (oxiranyllithium isomer-
ization product). f For spectroscopic data, see Supporting Information.
g Inseparable mixture of diastereoisomers; the separation and subsequent
full characterization was possible only on the O-acetyl derivatives. h Relative
configuration of the two diastereoisomers (syn and anti, respectively,
(1R*,2S*,3S*)-10d and (1R*,2R*,3R*)-10d) was assigned by 1H NMR.13a
i Overall yield in both diastereomers (dr ) 70:30).
Acknowledgment. We thank MIUR (Rome) and the
University of Bari for financial support to National Project
“Stereoselezione in Sintesi Organica, Metodologie ed Ap-
plicazioni” and the FIRB Project. We are also grateful to
Dr. Michel Giorgi of the Faculte´ des Sciences Saint-Jerome,
Marseille, France, for performing X-ray analysis of com-
pound (1R*,2S*,3R*)-4d. We also thank the University of
Bristol for hosting Ph.D. Antonio Salomone.
stilbene oxides 10a-e again with complete retention of
configuration. To understand the fate of lithiated cis-stilbene
oxide 9 at temperatures higher than -98 °C, we deprotonated
8 with n-BuLi/TMEDA in THF at -98 °C and allowed the
reaction mixture to reach room temperature. The major
product was PhCH2COPh (62% yield).
Supporting Information Available: Full experimental
details and characterization data (1H and 13C NMR, physical
data) for compounds 4b, 4d-e, 7, and 10a-e. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Molander, G. A.; Mautner, K. Pure Appl. Chem. 1990, 62, 707.
OL0485013
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