Advantageous syntheses of stilbenes via benzotriazole-stabilized anions

Full text of DOI:10.1021/jo982262d

3332
J . Org. Chem. 1999, 64, 3332-3334
Notes
Sch em e 1
Ad va n ta geou s Syn th eses of Stilben es via
Ben zotr ia zole-Sta bilized An ion s
Alan R. Katritzky,* Dmytro O. Tymoshenko, and
Sergei A. Belyakov
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida, 32611-7200
Received November 13, 1998
In tr od u ction
dicate that the (E/Z)-ratio is not affected by changes in
concentration, mode of addition, or molar ratio of alde-
hyde to ylide, and only to a minor extent by the substitu-
tion in the aldehyde and aralkylidene-triphenylphos-
phorane precursors. Peterson olefinations require multi-
step syntheses of starting arylmethylsilanes, and for
stilbenes show low stereoselectivity.17 Stabilization of the
anion by an arylsulfonyl group in J ulia olefinations
affords high yields of 1,2-diphenyl-2-(phenylsulfonyl)-1-
ethanol intermediates, but high stereoselectivity was
demonstrated only for aliphatic derivatives.18,19 Our
recently reported20a,b addition of benzotriazole-stabilized
anions to carbonyl compounds and subsequent in situ
low-valent titanium dehydroxybenzotriazolylation of the
intermediate diastereoisomeric N-(â-hydroxyalkyl)ben-
zotriazoles gives predominantly trans-alkenes, -dienes,
and -trienes.20b
The use of an aldehyde as its enamine derivative can
limit possible side reactions, give higher yields, and form
selectively E-stilbenes.9 An alternative is the use of
arylsulfonylhydrazones,21 in a process similar to the
Shapiro reaction,22 and we recently23 demonstrated the
utility of R-(1-benzotriazolyl)ketone hydrazones 1 for the
preparation of alkynes 3 via dianion 2 (Scheme 1, Bt )
1-benzotriazolyl) by a Shapiro-like reaction.22,24
Stilbenes are well-known as optical brighteners1 and
synthetic precursors of phenanthrene alkaloids2 and
enantiomerically pure 1,2-diphenylethane-1,2-diamines3
and diols4 via asymmetric dihydroxylation. The growing
interest in diphenylethylene derivatives is connected with
the antileukemic,5 carcinostatic,6 and protein-tyrosine
kinase inhibitory7 activities of some synthetic as well as
naturally occurring8 stilbenes, specifically their trans-
isomers.
Syntheses of stilbenes from aryl aldehydes and stabi-
lized benzyl carbanions have gained increased impor-
tance.9 Frequently, the carbanion is stabilized using octet
enlargement, as by P, Si, and S heteroatoms at the
R-position of the benzyl intermediate in Wittig,10 Peter-
son,11 and J ulia12 reactions, respectively. In the well-
studied Wittig reaction, stilbenes are usually formed in
moderate to high yield as a mixture of (E)- and (Z)-
isomers together with triphenylphosphine as a side
product.9 Although the (E/Z)-ratio can be influenced by
varying some of the reaction conditions (solvent, tem-
perature, base, promotor, etc.),13-15 recent studies16 in-
(1) Zweidler, R.; Heinz, H. In Kirk-Othmer Encyclopedia of Chemical
Technology, 3rd ed.; Mark, H. F., Othmer, D. F., Overberger, C. G.,
Seaborg, G. T., Eds.; J ohn Wiley and Sons: New York, 1978; Vol. 4, p
213.
(2) Estevez, J . C.; Villaverde, M. C.; Estevez, R. J .; Seijas, J . A.;
Castedo, L. Can. J . Chem. 1990, 68, 964.
Resu lts a n d Discu ssion
(3) Pini, D.; Iuliano, A.; Rosini, C.; Salvadori, P. Synthesis 1990,
11, 1023.
(4) Tang, X.-Q.; Harvey, R. G. Tetrahedron Lett. 1995, 36, 6037.
(5) Mannila, E.; Talvitie A.; Kolehmaonen E. Phytochemistry 1993,
33, 813.
(6) Ohsumi K.; Tsuji T.; Morinaga Y.; Ohishi K. Eur. Pat. Appl. EP
641,767; Chem. Abstr. 1995, 122, 265183f.
(7) Thakkar, K.; Geahlen, R. L.; Cushman, M. J . Med. Chem. 1993,
36, 2950.
We have now found that reactions of benzotriazole
derivatives 4 with tosylhydrazones of carbonyl com-
pounds 5 in the presence of strong base provide a smooth
entry to E-stilbenes (Scheme 2, Table 1). The suggested
mechanism of this reaction (Scheme 2) involves the
(8) Si, J . Tianran Chanwu Yanjiu Yu Kaifa 1994, 6, 71; Chem. Abstr.
1995, 122, 213785j.
(9) Becker, K. B. Synthesis 1983, 5, 341.
(16) Yamataka, H.; Nagareda, K.; Ando, K.; Hanafusa, T. J . Org.
Chem. 1992, 57, 2865.
(17) Peterson, D. J . J . Org. Chem. 1968, 33, 780
(18) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Bull. Soc. Chim.
Fr. 1993, 130, 336.
(19) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Lorne, R.; Ruel, O. Bull.
Soc. Chim. Fr. 1993, 130, 856.
(20) (a) Katritzky, A. R.; Li, J . J . Org. Chem. 1997, 62, 238. (b)
Katritzky, A. R.; Cheng, D.; Henderson, S. A.; Li, J . J . Org. Chem.
1998, 63, 6704.
(21) Vedejs, E.; Dolphin, J . M.; Stolle, W. T. J . Am. Chem. Soc. 1979,
101, 249.
(22) Shapiro, R. H. Tetrahedron Lett. 1968, 345.
(23) Katritzky, A. R.; Wang, J .; Karodia, N.; Li, J . J . Org. Chem.
1997, 62, 4142.
(10) Maguire, A. R. In Comprehensive Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon Press: New York, 1995; Vol. 1, p 589.
(11) Gosney, I.; Lloyd, D. In Comprehensive Organic Functional
Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W.,
Eds.; Pergamon Press: New York, 1995; Vol. 1, p 719.
(12) Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: New York, 1991; Vol. 1, p 729.
(13) Drefahl, G.; Lorenz, D.; Schnitt, G. J . Prakt. Chem. 1964, 23,
143.
(14) Bottin-Strzalko, T.; Seyden-Penne, J .; Tchoubar, B. C. R. Acad.
Sci., Ser. C 1971, C272, 778; Chem. Abstr. 1971, 74, 111466d.
(15) J ohnson, A. W.; Kyllingstad, V. L. J . Org. Chem. 1966, 31, 334.
(24) Shapiro, R. H.; Heath, M. J . J . Am. Chem. Soc. 1967, 89, 5734.
10.1021/jo982262d CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/13/1999

Notes
J . Org. Chem., Vol. 64, No. 9, 1999 3333
Ta ble 1. Syn th eses of E-Stilben es 10 via
Sch em e 3
Ben zotr ia zole-Sta bilized An ion s
en-
try
meth-
od
E/ Z yield,a
Ar1
Ar2
base ratio
%
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
A
A
A
A
A
A
B
B
B
B
B
B
B
B
BuLi 92/8 57
BuLi 90/10 48
BuLi 99/1 53
BuLi 98/2 61
p-CH3C6H4
p-CH3OC6H4
Ph
p-ClC6H4
p-CH3C6H4 Ph
p-CH3C6H4 Ph
p-CH3C6H4 Ph
Ph
Ph
BuLi
LDA
-
-
traces
traces
LDA 93/7 65
LDA 99/1 84
LDA 95/5 79
LDA 100/0 73
LDA 94/6 69
LDA 100/0 81
LDA 100/0 64
LDA 99/1 68
Ph
p-CH3C6H4
p-CH3OC6H4
10 p-ClC6H4
11 p-CH3C6H4 p-CH3OC6H4
12 Ph p-ClC6H4
13 p-CH3C6H4 p-CH3C6H4
14 Ph
3,4,5-(CH3O)3C6H2
a
Isolated yield of pure E-isomer.
Sch em e 2
formed separately and then added by cannula to a
solution of preformed N-lithio tosylhydrazone 7 (method
B). This procedure, and the use of LDA instead of BuLi,
minimizes side reactions of tosylhydrazone25 and im-
proves yields of the stilbenes (Table 1). In all cases only
the E-stilbene was isolated after recrystallization or
chromatography. According to GCMS analysis of the
crude reaction mixture, the E/Z-ratio was greater then
10:1. Similar alkene formation via the reaction of tosyl-
hydrazone anions with R-lithio sulfides, sulfones, thio-
acetals, hemithioacetals, and nitriles21 shows E:Z ratios
in the range of 2:1 to 1:2, although the E-isomer was
formed predominantly from â-methylstyrene. The high
stereoselectivity of our novel olefination probably is
connected to the formation of intermediates 11 and 12
in which the lithium is chelated by the neighboring
nitrogen of the benzotriazole substituent (Scheme 3). This
greater stabilization of the intermediate by a benzotri-
azolyl group, as compared to a phenylthio or alkylsulfinyl
group and the strain in syn intermediate 11 being larger
than in 12 makes the formation of the anti isomer more
favorable. Further loss of nitrogen leads to the predomi-
nant formation of the less-strained anion 14, which yields
E-stilbene as the major product.
addition25 of an anion 6 to tosylhydrazone anion 7 with
the formation of dianion 8. Loss of TsLi, nitrogen, and
benzotriazole anion leads to the expected olefins 10 via
9. This pathway is similar to our previous preparation
of alkynes,23 but reflects the lower bond order of the
newly formed C-C bonds in the intermediates.
Con clu sion
P r ep a r a tion of Sta r tin g Ma ter ia ls. Compounds
4a -d were synthesized by reactions of benzotriazole with
the corresponding benzyl chloride,26 and 5a -e as previ-
ously reported.27
Convenient and stereospecific stilbene syntheses start-
ing from tosylhydrazones of benzaldehydes with substi-
tuted N-benzylbenzotriazoles are described. This one-step
method, which includes a Shapiro-type transformation,
offers good stereoselectivity with predominant formation
of E-isomers and compares favorably with the Wittig,
Peterson, and J ulia reactions. It provides an alternative
to the recently described20a,b McMurry type dehydroxy-
benzotriazolylation route to olefins.
P r ep a r a tion of Stilben es. Deprotonation of com-
pounds 4a -d with n-butyllithium (BuLi) or lithium
diisopropylamide (LDA) gave dark-green solutions of the
corresponding anions, which underwent nucleophilic
addition to the tosylhydrazones 5a -e to form the corre-
sponding stilbenes 10, with disappearance of the green
color. While it is convenient to employ a one-pot proce-
dure (method A: i.e. treatment of a solution of tosylhy-
drazone and N-benzylbenzotriazole in THF with BuLi or
LDA), the best results were obtained when anion 6 was
Exp er im en ta l Section
Melting points were determined on a hot stage apparatus
without correction. 1H and 13C NMR spectra were obtained on
a 300 MHz spectrometer (300 and 75 MHz respectively) in
chloroform-d.
THF and DME were distilled under nitrogen immediately
prior to use from a purple solution containing benzophenone/
sodium. Column chromatography was carried out on MCB silica
(25) Vedejs, E.; Stolle, W. T. Tetrahedron Lett. 1977, 18, 135.
(26) Katritzky, A. R.; Toader, D. J . Am. Chem. Soc. 1997, 119, 9321.
(27) Bamford, W. R.; Stevens, T. S. J . Chem. Soc. 1952, 4735.

3334 J . Org. Chem., Vol. 64, No. 9, 1999
Notes
gel (230-400 mesh). Other chemicals were used as obtained from
commercial sources. Reactions were routinely carried out under
nitrogen atmosphere with magnetic stirring.
Meth od B. Compounds 5a -d (2 mmol) were dissolved in THF
(30 mL) in a reaction flask under nitrogen and cooled to -78
°C. BuLi (2.85 mL, 1.4 M, 4 mmol) or LDA (2.7 mL, 1.5 M, 4
mmol) was added in one portion (solution 1). Separately, a
solution of 4a -e (2 mmol) in 20 mL of THF at -78 °C under
nitrogen was treated with BuLi (2.85 mL, 1.4 M, 4 mmol) or
LDA (2.7 mL, 1.5 M, 4 mmol) (solution 2). Solution 2 was added
dropwise to solution 1 by cannula, and the mixture was stirred
for another 12 h while the temperature was allowed to rise to
20 °C. A workup and isolation procedure similar to that in
method A gave stilbenes 10.
Gen er a l Syn th etic P r oced u r e. Meth od A. Compounds
4a -d (2 mmol) and 5a -e (2 mmol) were dissolved in THF (30
mL) in a reaction flask under nitrogen and cooled to -78 °C.
BuLi (2.85 mL, 1.4 M, 4 mmol) or LDA (2.7 mL, 1.5 M, 4 mmol)
was added in one portion. The dark-colored solution was stirred
for 12 h while the temperature was raised to 20 °C. The mixture
was quenched with water. Hexanes (50 mL) were added, and
the organic phase was separated, washed with 10% Na2CO3 (2
× 50 mL) and water (50 mL), and then dried (Mg2SO4 anhy-
drous). Concentration under reduced pressure followed by silica
gel column chromatography with hexanes/ethyl acetate (4:1) as
the eluent gave stilbenes 10.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectral
data of stilbenes 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O982262D