Olefination of α-hydroxy or α-aminoaldehyde derivatives via reaction of their arylsulfonylhydrazones with sulfonyl anions

Article abstract of DOI:10.1021/jo0499118

Reaction of tosylhydrazones of O-substituted α-hydroxy or N-substituted α-amino aldehydes (2, 7, 11, 15, 17, and 20) with selected α-magnesio alkyl phenyl sulfones afforded the respective derivatives of allylic alcohols or allylic amines. 2,3-O-Isopropyli

Full text of DOI:10.1021/jo0499118

SCHEME 1
Olefin a tion of r-Hyd r oxy or
r-Am in oa ld eh yd e Der iva tives via Rea ction
of Th eir Ar ylsu lfon ylh yd r a zon es w ith
Su lfon yl An ion s
J erzy Wicha* and Andrzej Zarecki
Institute of Organic Chemistry, Polish Academy of Sciences,
ul. Kasprzaka 44, 01-224 Warsaw, Poland
jwicha@icho.edu.pl
Received J anuary 15, 2004
Abstr a ct: Reaction of tosylhydrazones of O-substituted
R-hydroxy or N-substituted R-amino aldehydes (2, 7, 11, 15,
17, and 20) with selected R-magnesio alkyl phenyl sulfones
afforded the respective derivatives of allylic alcohols or allylic
amines. 2,3-O-Isopropylidene-D-glyceraldehyde (1) was trans-
formed into its tosylhydrazone (2) and then olefins 4a with
retention of optical purity.
Synthesis of olefins by coupling of aldehydes with
alkanes bearing a carbanion-stabilizing group has a
pivotal importance in organic chemistry.1 The classical
Marc J ulia olefination2 applying phenyl- (or tert-butyl)
alkyl sulfones has found numerous applications in target-
oriented synthesis.3 Several modifications of the original
three-step procedure have been developed in order to
improve its efficiency and stereoselectivity. The reductive
elimination step requiring relatively harsh conditions has
received a particular attention.4 Studies on the sulfone-
based olefination reactions culminated in the discovery
by S. A. J ulia and co-workers5 of a new one-step olefi-
nation reaction. The “direct” olefination reaction applies
heterocylic sulfones, such as benzothiazoyl, pyridyl, and
phenyltetrazoyl sulfone. The latter introduced by
Kocienski and co-workers6 offers high E-stereoselectivity.
An indispensable feature of heterocyclic sulfones applied
in the direct J ulia olefination is the presence of a reactive
electrophilic CdN bond. Although the J ulia-Kocienski
olefination reaction proved remarkably successful,7 it
appears that in certain cases application of robust
chemically stable phenyl sulfones may still be of advan-
tage.
A potentially useful variation of olefination of alde-
hydes has been reported by Vedejs et al.8 some time ago.
In this method an aldehyde i, X ) H (Scheme 1) was
initially transformed into its tosylhydrazone ii, X ) H,
and then treated with an excess of R-lithio sulfone.
Exchange of an active proton for metal and addition of
the nucleophile to the tosylhydrazone CdN bond afforded
adduct iii, X ) H. Fragmentation of the intermediate
iii via iv gave olefin v, X ) H. It is noteworthy that no
reducing reagents are involved in the discussed reaction
sequence. Some related coupling reactions involving
aldehyde tosylhydrazones have also been noted.9 We have
recently found10 that replacing R-lithium sulfones used
in the Vedejs procedure by R-magnesium sulfones makes
it possible to evade some side reactions (as the Shapiro
fragmentation11) and to extend significantly the scope of
application of this olefination reaction.
It was thought of interest to determine whether the
tosylhydrazone-mediated olefination may accommodate
aldehydes bearing alkoxy or amino groups (i, X ) OAlkyl
or N(Alk/Aryl) in the R-position. It could be reasoned that
addition of a metalated sulfone (2 equiv) to ii will provide
(1) (a) Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 729.
(b) Preparation of Alkenes: A Practical Approach; Williams, J . M. J .,
Ed.; Oxford University Press: Oxford, 1996.
(2) (a) J ulia, M.; Paris, J .-M. Tetrahedron Lett. 1973, 4833-4836.
(b) Kocienski, P. J .; Lythgoe, B.; Ruston, S. J . Chem. Soc., Perkin Trans.
1 1979, 1290-1293.
(7) Recent works include: (a) Takahashi, T.; Watanabe, H.; Ki-
tahara, T. Tetrahedron Lett. 2003, 44, 9219-9222. (b) Berberich, S.
M.; Cherney, R. J .; Colucci, J .; Courillon, C.; Geraci, L. S.; Kirkland,
T. A.; Marx, M. A.; Schneider, M. F.; Martin, S. F. Tetrahedron 2003,
59, 6819-6832. (c) Kang, S. H.; Choi, H. W.; Kim, C. M.; J un, H. S.;
Kang, S. Y.; J eong, J . W.; Youn, J . H. Tetrahedron Lett. 2003, 44, 6817-
6819. (d) Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron
Lett. 2001, 42, 6619-6624. (e) Charette, A. B.; Berthelette, C.;
St-Martin, D. Tetrahedron Lett. 2001, 42, 5149-5153;
(3) For selected reviews, see: Kocienski, P. Phosphorus Sulphur
1985, 24, 97-127. (b) Simpkins, N. S. Sulphones in Organic Chemistry;
Pergamon Press: Oxford, 1993.
(4) (a) Kende, A. S.; Mendoza, J . S. Tetrahedron Lett. 1990, 31,
7105-7108. (b) Pouilly, P. d.; Chenede, A.; Mallet, J . M.; Sinay, P.
Tetrahedron Lett. 1992, 33, 8065-8068. (c) Satoh, T.; Hanaki, N.;
Yamada, N.; Asano, T. Tetrahedron 2000, 56, 6223-6234. (d) Marko,
I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.; Craig, D.;
Carballares, S.; Dolan, S. Tetrahedron 2001, 57, 2609-2619.
(5) (a) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175-1178. (b) For a review, see: Blakemore, P. R. J .
Chem. Soc., Perkin Trans. 1 2002, 2563-2585.
(8) Vedejs, E.; Dolphin, J . M.; Stolle, W. T. J . Am. Chem. Soc. 1979,
101, 1, 249-251.
(9) (a) Katritzky, A. R.; Tymoshenko, D. O.; Belyakov, S. A. J . Org.
Chem. 1999, 64, 3332-3334. (b) Kabalka, G. W.; Wu, Z.; J u, Y. H.
Tetrahedron Lett. 2001, 42, 4759-4760.
(10) Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J .; Zarecki,
A. J . Org. Chem. 2001, 66, 6994-7001.
(6) Blakemore, P. R.; Cole, W. J .; Kocienski, P. J .; Morley, A. Synlett
1998, 26-28.
(11) Shapiro, R. H. Org. React. (N.Y.) 1976, 23, 405.
10.1021/jo0499118 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/23/2004
5810
J . Org. Chem. 2004, 69, 5810-5812

SCHEME 2
SCHEME 3
magnesium derivative was allowed to react with tosyl-
hydrazone (S)-2 (1 equiv). After completion of the reaction
(2 h) olefin 4a was obtained in 68% yield as a mixture of
E and Z isomers in a ratio of 72:28. Samples of each of
the isomers were separated and found to be enantiomeri-
cally pure (HPLC, Chiralcel OD-H column).
Reaction of the magnesio-derivative of isopropyl phenyl
sulfone 3b with (S)-2 was markedly slower. Olefination
product 4b was obtained in 41% yield along with a side
product (10-15% yield) to which the structure of carbinol
5a was assigned. An analogous reaction using of cyclo-
hexyl phenyl sulfone 3c afforded the respective olefin 4c
in 21% yield and carbinol 5b in 26% yield.
Obviously carbinols 5a and 5b were generated in
reactions of the respective sulfonyl anions with acetone
originating from the acetonide protection group in 2. The
stage of cleavage of the acetal function and its mechanism
are not quite clear. Most likely, acetone is generated from
allylic alcohol derivatives 4b or 4c by Lewis acid cata-
lyzed elimination under the reaction conditions. However,
fragmentation of the intermediate adducts, iv in Scheme
1 (broken-line arrows), cannot be excluded.
3,4:5,6-Di-O-isopropylidene-D-sorbitol19 was oxidized14
to give 2,3:4,5-di-O-isopropylidene-D-arabinose 6 (Scheme
3), and the latter was transformed into tosylhydrazone
7 in the usual way (69% yield). Reaction of 7 with
magnesium derivative of sulfone 3a smoothly afforded
olefin 8, which was isolated in 60% yield, E:Z ) 89:11.
High selectivity of this olefination reaction with respect
to the E-isomer is noteworthy.
intermediate iii, which will fragment to respective
derivatives of allylic alcohols or amines, v, X ) OAlkyl
or N(Alk/Aryl). However, elimination of the X-group may
occur as well, destroying the stereogenic center (if pres-
ent) and affording undesired product vi. It was recently
shown12,13 that tosylhydazones of some O-substituted
R-hydroxy and N-substituted R-amino aldehydes in reac-
tion with organolithium or Grignard reagents afford
olefins viii, as illustrated in Scheme 1. In the present
work we examine olefination of representative R-hydroxy
and R-amino aldehyde derivatives via their tosylhydra-
zones.
2,3-O-Isopropylidene-D-glyceraldehyde (R)-1 (Scheme
2) prepared14 from di-O-isopropylidene-D-mannitol, was
treated with tosylhydrazine in diethyl ether.15 The crude
product was purified by chromatography on silica gel
using a “dry column” technique16 to give tosylhydrazone
(S)-2 (one isomer, semisolid) in 92% yield from di-O-
isopropylidene-D-mannitol. In chloroform-d solution (S)-2
was unstable; however, in DMSO-d6 a satisfactory 1H
NMR spectrum was obtained, and diagnostic signals in
the 13C spectrum were recorded. HPLC analysis (Chiral-
cel OD-H column) indicated that obtained (S)-2 was
virtually enantiomerically pure.
Tosylhydrazone (S)-2 was used routinely in further
reactions immediately after preparation; a sample stored
for a few weeks in a refrigerator recemized almost
completely. Apparently, racemization occurred markedly
faster than decomposition, which may indicate reversible
formation of the respective azoene.17 rac-2 obtained from
rac-1 (prepared18 from 2,3-isopropylideneglycerol) was
crystalline and could be stored for several weeks without
visible decomposition.
Prolinol 9 was oxidized with the Dess-Martin perio-
dinane20 to give aldehyde 10, which was transformed into
its tosylhydrazone 11 without isolation (73% from pro-
linol). Reaction of 11 with magnesio sulfone 3a afforded
olefin 12 in 88% yield (E:Z ) 56:44).
Sulfone 3a (3 equiv) was treated with iPrMgCl in THF
(3.1 equiv) at room temperature, and the resulting
Next, we turned our attention to some acyclic acetal-
dehyde derivatives. Phenoxyacetaldehyde 13 (Scheme 4)
was transformed into tosylhydrazone 15, and the latter
was allowed to react with an anion generated from
sulfone 3a . Labile O-phenyl allylic alcohol derivative 16
was isolated in 45% yield. N-Phenyl-N-tosyl-2-amino-
ethanal 14 in an analogous procedure through tosylhy-
drazone 17 afforded the respective derivative of allylic
(12) (a) Chandrasekhar, S.; Takhi, M.; Yadav, J . S. Tetrahedron Lett.
1995, 36, 307-310. (b) Chandrasekhar, S.; Takhi, M.; Yadav, J . S.
Tetrahedron Lett. 1995, 36, 5071-5074.
(13) For reductive alkylation of aldehydes via tosylhydrazones,
see: Vedejs, E.; Stolle, W. T. Tetraheron Lett. 1977, 135-138.
(14) Elder, J . S.; Mann, J .; Walsh, E. B. Tetrahedron 1985, 41, 3117-
3125.
(15) Bertz, S. H.; Dabbagh, G. J . Org. Chem. 1983, 48, 116-119.
(16) Pedersen, D. S.; Rosenbohm, C. Synthesis 2001, 2431-2434.
(17) For a recent synthetic application of azoenes, see: van Bergen,
M.; Gais, H. J . J . Am. Chem. Soc. 2002, 124, 4321-4328.
(18) De Luca, L.; Giacomelli, G.; Porcheddu, A. J . Org. Chem. 2001,
66, 7907-7909.
(19) J arosz, S.; Zamojski, A. Carbohydr. Chem. 1993, 12, 1223-1228.
(20) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
J . Org. Chem, Vol. 69, No. 17, 2004 5811

(4S)-2,2-Dim et h yl-4-[(1E)-4-p h en ylb u t -1-en yl]-1,3-d iox-
ola n e (E-4a ) a n d (4S)-2,2-Dim eth yl-4-[(1Z)-4-p h en ylbu t-1-
en yl]-1,3-d ioxola n e (Z-4a ). Gen er a l P r oced u r e for Rea c-
tion of R-Ma gn esio Su lfon es w ith Tosylh yd r a zon es. To
sulfone 3a 21 (592 mg, 2.27 mmol, 3 equiv), stirred under argon
at room temperature, was added iPrMgCl (2M in THF, 1.2 mL,
2.4 mmol) (vigorous gas evolution occurred). The mixture was
stirred for 1.5 h, and then tosylhydrazone (S)-2 (227 mg, 0.76
mmol) in THF (10 mL) was added portionwise. After consecutive
2 h, the reaction was quenched with concentrated aqueous
ammonia (0.3 mL). The solid was filtered off and washed with
THF. The combined filtrates were evaporated, and the residue
was chromatographed on silica gel (20 g, hexane/ethyl acetate)
to give 4a (120 mg, 68%) as a colorless oil, Z:E ) 21:79, by HPLC
(hexanes/ethyl acetate, 9:1), tR 4.3 min (Z-) and 4.6 min (E-
isomer). Samples of both isomers were isolated using preparative
HPLC; enantiomeric purity of each of the isomers was confirmed
by analysis on a chiral HPLC column.
SCHEME 4
Da ta for 4a (Z): [R]D -13.2 (c 0.8, hexane). 1H NMR (CDCl3)
δ 1.36 (3H, s), 1.39 (3H, s) 2.3-2.5 (2H, m), 2.5-2.9 (2H, m),
3.35 (1H, t, J 8.1 Hz), 3.76 (1H, dd J 7.1, 6.1 Hz), 4.70 (1H, dd
J 15.5, 8.0 Hz), 5.33-5.48 (1H, m), 5.57-5.75 (1H, m), 7.1-7.4
(5H, m) ppm; on irradiation at δ 2.41 multiplet at δ 5.33-5.48
collapsed to a doublet of doublets, J 10.6, 8,56 Hz, and that at
δ 5.57-5.76 to a doublet, J 10.8 Hz. 13C NMR (CDCl3) δ 26.0
(3), 26.8 (3), 29.7 (2), 35.7 (2), 69.2 (2), 71.9 (1), 109.0 (0), 126.0
(1), 128.0 (1), 128.3 (1), 128.5 (1), 133.5 (1), 141.2 (0) ppm.
Da ta for 4a (E): [R]D + 24.4 (c 3.8, hexane). 1H NMR (CDCl3)
δ 1.38 (3H, br s), 1.42 (3H, s,), 2.30-2.45 (2H, m), 2.60-2.80
(2H, m), 3.53 (1H, t, J 8.0 Hz), 4.04 (1H, dd, J 6.1, 2.0 Hz), 4.35-
4.55 (1H, m), 5.46 (1H, ddt, J 15.3, 7.8, 1.4 Hz), 5.83 (1H dt J
15.3, 6.6 Hz), 7.1-7.4 (5H, m) ppm; on irradiation at δ 2.37
multiplet at δ 5.46 collapsed to a doublet of doublets, J 15.2,
7.9 Hz, and that at δ 5.83 to a doublet, J 15.2 Hz. 13C NMR
(CDCl3) δ 26.0 (3), 26.7 (3), 34.1 (2), 35.3 (2), 69.4 (2), 77.2 (1),
109.0 (0), 125.8 (1), 127.9 (1), 128.28 (1), 128.34 (1), 134.7 (1),
141.5 (0) ppm. 4a (E) HRMS (EI): calcd for C15H20O2, 232.14633,
found 232.14694.
r a c-2,2-Dim et h yl-4-[(1E)-4-p h en ylb u t -1-en yl]-1,3-d iox-
ola n e (E-4a ) a n d r a c-2,2-d im eth yl-4-[(1Z)-4-p h en ylbu t-1-
en yl]-1,3-d ioxola n e (Z-4a ) were prepared in an analogous way
from r a c-1. Pure compounds rac-Z-4a and rac-E-4a were
separated by preparative HPLC and analyzed on chiral analyti-
cal HPLC columns. Resolution of rac-(Z)-4a was achieved on a
Chiralcel OD-H column (hexane/2-propanol, 9:1): tR 10.1 min
(S-enantiomer) and 11.4 min (R)-enantiomer. rac-(E)-4a was
separated on a Chiralcel OJ column (hexane-2-propanol, 9:1):
tR 14.1 min (S)-enantiomer and 16.4 min (R)-enantiomer.
amine 18 in 57% yield. Finally, glyoxal 1,1-dimethyl
acetal 19 gave tosylhydrazone 20 (61% yield, after
chromatography) and then dimethylacetal of R,â-unsat-
urated aldehyde 21 in 57% yield.
In conclusion, representative aldehydes bearing an
alkoxy- or alkylamino group in the R-position in reaction
with R-magnesio sulfones afford the respective deriva-
tives of allylic alcohols or allylic amines. 2,3-O-Isopro-
pylidene-D-glyceraldehyde afforded tosylhydrazone 2 and
the olefination products 4 with virtually complete reten-
tion of optical activity.
Exp er im en ta l Section
N′-{(1E)-[(4S)-2,2-Dim eth yl-1,3-dioxolan -4-yl]m eth ylen e}-
4-m eth ylben zen esu lfon oh yd r a zin e (2). Di-O-isopropylidene-
D-mannitol (1.0 g, 3.81 mmol) was oxidized with sodium perio-
date14 (907 mg) in THF (15 mL) and water (1.7 mL), and the
product was isolated with diethyl ether. The thus obtained
solution of 2,3-O-isopropylidene-D-glyceraldehyde (R)-1 in diethyl
ether/THF was dried over anhydrous MgSO4. After removal of
the drying agent, tosylhydrazine (1.457 g, 7.82 mmol) was added,
and the mixture was stirred at room temperature for 30 min.
The solvent was evaporated, and the residue was chromato-
graphed on silica gel (30 g, hexanes/ethyl acetate, gradient
elution) to give (S)-2 (2.097 g, 92% from di-O-isopropylidene-D-
mannitol) as a colorless semisolid mass, [R]23 ) +18.6 (c 8.3,
D
1
ethyl acetate). H NMR (DMSO-d6) δ 1.26 (6H, s), 2.39 (3H, s),
3.75 (1H, dd, J 8.5, 6.0 Hz), 4.05 (1H, dd J 8.6, 6.6 Hz), 4.42
(1H, dt, J 6.4, 6.2 Hz), 7.14 (1H, d, J 6.4 Hz), 7.41 (2H, apparent
d, J 8.1 Hz), 7.68 (2H, apparent d, J 8.1 Hz), 11.36 (1H, s) ppm.
13C NMR (DMSO-d6) δ 21.0 (3), 25.2 (3), 26.2 (3), 66.3 (2), 74.5
(2), 109.1 (0), 127.0 (1), 129.5 (1), 135.9 (0), 143.3 (0), 147.8 (1)
ppm.
Freshly prepared tosylhydrazone (S)-2 was enantiomerically
pure by HPLC (see the following experiment). However, it
racemized and slowly decomposed on storing; after several weeks
racemization was virtually complete.
r a c-N′-{(1E)-[2,2-Dim eth yl-1,3-d ioxola n -4-yl]m eth ylen e}-
4-m eth ylben zen esu lfon oh yd r a zin e (2). 2,3-Isopropylidene-
glycerol (Solketal, Fluka) (1.00 g) was oxidized using the
modified18 Swern method. The aldehyde was purified by chroma-
tography and treated with tosylhydrazine as described above.
rac-2 was obtained (776 mg, 34% from Solketal), mp 126-127
°C (tert-butyl methyl ether/hexane). HPLC analysis: a Chiralcel
OD-H column, hexane/2-propanol, 4:1, 0.5 mL/min, tR 16.8 and
18.1 min for (R)- and (S)-enantiomers, respectively.
Ack n ow led gm en t. We thank Professor Sławomir
J arosz of our Institute for a gift of 3,4:5,6-di-O-isopro-
pylidene-D-sorbitol. Financial support from the State
Committee for Scientific Research, Grant 3 T09A 134
18 is acknowledged.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal conditions; full experimental procedures for compounds 4b,
4c, 5a , 5b, 7, (E)-8, (Z)-8, 11, (E)-12, (Z)-12, 15, (E)-16, (Z)-
16, 17, (E)-18, (Z)-18, 20, (E)-21, and (Z)-21; and NMR spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0499118
(21) Keck, G. E.; Savin, K. A.; Weglarz, M. A. J . Org. Chem. 1995,
60, 3194-3204.
5812 J . Org. Chem., Vol. 69, No. 17, 2004