Simple diastereoselectivity on addition of α-haloalkyl grignard reagents to benzaldehyde

Article abstract of DOI:10.1021/jo034138m

The addition of α-haloalkyl Grignard reagents to benzaldehyde occurs with simple diastereoselectivity substantially higher than that of the corresponding lithium reagents. Reaction in the presence of dimethyl-aluminum chloride suppresses subsequent Oppenauer oxidation of the resulting Mg-alkoxides by excess benzaldehyde.

Full text of DOI:10.1021/jo034138m

SCHEME 1
Sim p le Dia ster eoselectivity on Ad d ition of
r-Ha loa lk yl Gr ign a r d Rea gen ts to
Ben za ld eh yd e
Volker Schulze, Peter G. Nell, Andrew Burton, and
Reinhard W. Hoffmann*
Fachbereich Chemie der Philipps-Universita¨t Marburg,
Hans Meerwein Str. D-35032 Marburg, Germany
rwho@chemie.uni-marburg.de
Received J anuary 31, 2003
SCHEME 2
Abstr a ct: The addition of R-haloalkyl Grignard reagents
to benzaldehyde occurs with simple diastereoselectivity
substantially higher than that of the corresponding lithium
reagents. Reaction in the presence of dimethyl-aluminum
chloride suppresses subsequent Oppenauer oxidation of the
resulting Mg-alkoxides by excess benzaldehyde.
The addition of a chiral organolithium compound (1)
to an aldehyde is a stereogenic carbon-carbon bond
forming reaction. Two diastereomeric products, syn-2 and
anti-2, are generated, which could be used to prepare
stereodefined epoxides 3 and 4 (Scheme 1).This approach
to epoxides is hardly used, because simple diastereose-
lectivity1 i.e., the ratio between syn-2 and anti-22 is low.3,4
Seebach, when studying the reaction of 5 with benzal-
dehyde, showed5-7 that a change from an organolithium
compound 5a to the corresponding organomagnesium
compound 5b led to high syn/anti selectivity in the
formation of 6 (Scheme 2).We therefore surmised that a
transmetalation of 1 to the corresponding magnesium
reagents8 could lead to higher and, hence, useful levels
of diastereoselectivities on addition to aldehydes. We
report here on the simple diastereoselectivity on addition
of chiral R-haloalkyl-magnesium reagents 7-9 to ben-
zaldehyde. These reactions had actually been studied
with a different objective.9-12 Here we focus on the
attendant simple diastereoselectivity. The reagents 7-9
were generated from the 1-halo-1-iodo-2-phenyl-ethane
in an iodine/lithium or iodine/magnesium exchange reac-
tion using n-butyllithium or isopropyl-magnesium chlo-
ride,9,10 or by a sulfoxide/magnesium exchange reaction
from R-haloalkyl sulfoxides and ethyl-magnesium chlo-
ride.11 Depending on the workup procedure, halohydrins
derived from 2 or epoxides 3 and 4 were obtained and
analyzed for diastereomer composition by NMR spectros-
copy. The simple diastereoselectivities recorded for the
addition of the R-haloalkyl-metal reagents 7-9 to ben-
zaldehyde are compiled in Table 1.
The data in the table show that a marked increase in
simple diastereoselectivity results on going from the
organolithium to the organomagnesium reagents 7 and
8. Moreover, high simple diastereoselectivity has been
recorded for the addition of the Grignard reagents 9 and
10 to benzaldehyde. The presence of Me2AlCl or of a
bisoxazoline ligand has only small (beneficial) effects on
simple diastereoselectivity.
(1) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; Vol. 3; pp 111-212.
(2) A major part of this chemistry had been explored before the
advent of high-field NMR spectroscopy. Hence, reactions that led to
diastereomer mixtures had been avoided or diastereomer ratios have
not been determined.
It has been suggested by Gawley7 that organolithium
and organomagnesium reagents react with benzaldehyde
by different reaction mechanisms: Grignard reagents are
postulated to add in a concerted polar process with a late
transition state, which favors significant stereodifferen-
tiation14 in the formation of the products. In the reaction
of the more basic organolithium compounds SET may
precede carbon-carbon bond formation, which then
occurs with an early transition state by combination of
a radical pair. Stereodifferentiation is accordingly low.
(3) For
a review, see: Hoppe, D. In Houben-Weyl, Methods of
Organic Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J .,
Schaumann, E., Eds.; G. Thieme: Stuttgart, 1995; Vol. E21b; pp 1341-
1347.
(4) For further examples of diastereogenic addition of R-hetero-
substituted organolithium compounds to aldehydes: R-nitrogen-
substituted cases, see ref 20; R-oxygen-substituted cases, see refs 21
and 22; R-sulphur-substituted cases, see ref 23; R-selenium-substituted
cases, see ref 24; for unexpected high diastereoselectivities in these
reactions see refs 22 and 25.
(5) (a) Seebach, D.; Syfrig, M. A. Angew. Chem. 1984, 96, 235-236;
Angew. Chem., Int. Ed. Engl. 1984, 23, 248. (b) Seebach, D.; Hansen,
J .; Seiler, P.; Gromek, J . M. J . Organomet. Chem. 1985, 285, 1-13. (c)
Seebach D.; Huber, I. M. P.; Syfrig, M. A. Helv. Chim. Acta 1987, 70,
1357-1379. These findings on the system 5 have since been substanti-
ated by others.
(6) (a) Rein, K. S.; Gawley, R. E. J . Org. Chem. 1991, 56, 1564-
1569. (b) Zhang, P.; Gawley, R. E. Tetrahedron Lett. 1992, 33, 2945-
2948. (c) Gawley, R. E.; Zhang, P. J . Org. Chem. 1996, 61, 8103-8112.
(7) Rein, K. S.; Chen, Z.-H.; Perumal, P. T.; Echegoyen, L.; Gawley,
R. E. Tetrahedron Lett. 1991, 32, 1941-1944.
(8) The beneficial effect of transmetalation from lithium to magne-
sium on simple diastereoselectivity in the addition to aldehydes has
been noted on several occasions.26-30
(9) Mu¨ller, M.; Stiasny, H.-C.; Bro¨nstrup, M.; Burton, A.; Hoffmann,
R. W. J . Chem. Soc., Perkin Trans. 2 1999, 731-736.
(10) Schulze, V.; Hoffmann, R. W. Chem. Eur. J . 1999, 5, 337-344.
(11) Hoffmann, R. W.; Nell, P.; Leo, R.; Harms, K. Chem. Eur. J .
2000, 6, 3359-3365.
(12) Nell, P. G. New. J . Chem. 1999, 23, 973-975.
(13) Ko¨brich, G.; Trapp, H. Chem. Ber. 1966, 99, 670-679.
(14) Bassindale, A. R.; Ellis, R. J .; Lau, J . C. Y.; Taylor, P. G. J .
Chem. Soc., Chem. Commun. 1986, 98-100.
10.1021/jo034138m CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
4546
J . Org. Chem. 2003, 68, 4546-4548

TABLE 1. Sim p le Dia ster eoselectivity on Rea ction of
r-Ha loa lk yl-m eta l Com p ou n d s 1 (R ) Bn ) w ith
Ben za ld eh yd e
SCHEME 3
ide 14 coordinates further benzaldehyde, it will do so as
a bidentate Lewis acid19 in the µ-position. This could
prevent subsequent reduction of the benzaldehyde, which
possibly originates from a monodentate coordination of
benzaldehyde by the magnesium cation via a monocyclic
six-membered transition state.
Addition of dimethyl-aluminum chloride to the Grig-
nard reagents 7-9 presumably generates initially a
chloro-bridged reagent 13. As there is no substantial
difference in the syn/anti ratio of the alkoxides 11 formed
in the absence or presence of dimethyl-aluminum chlo-
ride, the chloro-bridged reagent 13 reacts apparently with
a similar simple diastereoselectivity as the Grignard
reagent 7(MgCl) (cf. 8 and 9). There are no obvious
indications for a transmetalation of 7(MgCl) with di-
methyl-aluminum chloride to an trialkyl-aluminum com-
pound 15 under the conditions applied, as 15 should be
less reactive toward benzaldehyde. Transmetalation of
7(Li), though, with dimethyl-aluminum chloride to give
15 appears to proceed at -110 °C, as subsequently no
addition occurred to benzaldehyde at the low tempera-
ture.10
a
Trapp ) Trapp solvent mixture.13
b
L* )
c Low conversion, because an excess of 1-bromo-1-iodo-2-phenyle-
thane was used.
The absence of a SET process in the addition of simple
Grignard reagents to benzaldehyde has been demon-
strated.15
(18) Yamazaki, S.; Yamabe, S. J . Org. Chem. 2002, 67, 9346-9353.
(19) Ooi, T.; Miura, T.; Itagaki, Y.; Ichikawa, K. M.; Maruoka, K.
Synthesis 2002, 279-291.
(20) (a) Pearson, W. H.; Lundbeck, A. C. J . Org. Chem. 1989, 54,
5651-5655. (b) Barrett, A. G. M.; Flygare, J . A. F. J . Org. Chem. 1991,
56, 638-642. (c) Barrett, A. G. M.; Hill, J . M.; Wallace, E. M.; Flygare,
J . A. F. Synlett 1991, 764-770. (d) Moody, C. J .; Rees, C. W.; Young,
R. G. J . Chem. Soc., Perkin Trans. 1 1991, 323-327. (e) Tsunoda, T.;
Fujiwara, K.; Yamamoto, Y.; Ito, S. Tetrahedron Lett. 1991, 31, 1975-
1978.
The Grignard addition of 7(MgX) to excess benzalde-
hyde (especially with MgiPr in nonpolar solvents and
letting the reaction mixture warm to room temperature
before quenching) was accompanied by considerable
Oppenauer oxidation of 11 by benzaldehyde to the iodo-
ketone 12, resulting in lower yields of the halohydrins,10
cf. Scheme 3. This oxidation could affect the syn/anti ratio
of the halohydrins obtained, if this oxidation is in any
way diastereomer-selective. We have indeed indications
that syn-11 is more readily oxidized than anti-11.16
This annoying oxidation of the primary adducts 11
could be suppressed by carrying out the reaction in the
presence of dimethyl-aluminum chloride.10 This proce-
dure probably leads to the chloro-bridged17 alkoxide 14
as the primary adduct.18 When the chloro-bridged alkox-
(21) Cohen, T.; Matz, J . R. J . Am. Chem. Soc. 1980, 102, 6900-
6902.
(22) Barner, B. A.; Mani, R. Tetrahedron Lett. 1989, 30, 5413-5416.
(23) J ohnson, C. R.; Nakanishi, A.; Nakanishi, N.; Tanaka, T.
Tetrahedron Lett 1975, 2865-2868.
(24) Sarkar, T. K.; Satapathi, T. K. Tetrahedron Lett. 1989, 30,
3333-3334.
(25) Katritzky, A. R.; Zhao, X.; Shcherbakova, V. J . Chem. Soc.,
Perkin Trans. 1 1991, 3295-3299.
(26) Seyferth, D.; Lefferts, J . L.; Lambert, R. L., J r. J . Organomet.
Chem. 1977, 142, 39.
(27) Perrier, H.; Huyer, G.; Young, R. N. Tetrahedron Lett. 1992,
33, 725-728.
(15) (a) Gajewski, J . J .; Bocian, W. B.; Harris, N. J .; Olson, L. P.;
Gajewski, J . P. J . Am. Chem. Soc. 1999, 121, 326-334. (b) Hoffmann,
R. W.; Ho¨lzer, B. Chem. Commun. 2001, 491-492.
(16) Schulze, V. Ph.D. Dissertation, University Marburg, 1997.
(17) Markies, P. R.; Akkerman. O. S.; Bickelhaupt, F.; Smeets, W.
J . J .; Spek, A. L. Adv. Organomet. Chem. 1991, 32, 147-226.
(28) Hoffmann, R. W.; J ulius, M.; Chemla, F.; Ruhland, T.; Frenzen,
G. Tetrahedron 1994, 50, 6049-6060.
(29) Klute, W.; Kru¨ger, M.; Hoffmann, R. W. Chem. Ber. 1996, 129,
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9, 3125-3128.
J . Org. Chem, Vol. 68, No. 11, 2003 4547

THF (5 mL). After 10 min of stirring, benzaldehyde (31 µL) was
added. The mixture was allowed to reach room temperature over
15 h. Saturated aqueous NH4Cl solution (5 mL) was added, and
the aqueous layer was extracted with diethyl ether (3 × 5 mL).
The combined organic layers were washed with brine (10 mL),
dried (Na2SO4), and concentrated. Flash chromatography with
petroleum ether/diethyl ether 10:1 furnished the epoxides 3, 4
(1.1:1, R ) Bn)10 (50 mg, 85%).
Rea ction of n -Bu tyllith iu m w ith 1,1-Dibr om o-2-p h en yl-
eth a n e. A solution of n-butyllithium (1.55 M, 0.21 mL, 0.32
mmol) was added at -100 °C under a nitrogen atmosphere to a
solution of 1,1-dibromo-2-phenyl-ethane10 (200 mg, 0.76 mmol)
in THF (5 mL). After 10 min of stirring, benzaldehyde (31 µL)
was added. The mixture was allowed to reach room temperature
over 15 h. Saturated aqueous NH4Cl solution (5 mL) was added,
and the aqueous layer was extracted with diethyl ether (3 × 5
mL). The combined organic layers were washed with brine (10
mL), dried (Na2SO4), and concentrated. Flash chromatography
with petroleum ether/diethyl ether 10:1 furnished the epoxides
3, 4 (1.5:1 R ) Bn)10 (66 mg, 32%).
Exp er im en ta l Section
Gen er a l P r oced u r es. The preparation of the starting ma-
terials, the reactions and the products have been described
before.9-12
Rea ction of Diisop r op yl-m a gn esiu m w ith 1,1-Diiod o-2-
p h en yl-eth a n e. A solution of diisopropyl-magnesium (0.59 M
in diethyl ether, 1.01 mL, 0.60 mmol) was cooled under a
nitrogen atmosphere to -78 °C. A solution of the diiodoalkane10
(0.5 M in THF, 2.00 mL, 1.00 mmol) was added slowly along
the wall of the flask. After 2 h of stirring at -78 °C the deep
yellow color had disappeared. THF (4.5 mL) and benzaldehyde
(0.25 mL, 2.5 mmol) were added dropwise, and the mixture was
allowed to reach room temperature over 15 h. Saturated aqueous
NH4Cl solution (20 mL), aqueous Na2S2O3 solution (20%, 3 mL),
and tert-butyl methyl ether (20 mL) were added. The layers were
separated, and the aqueous layer was extracted with tert-butyl
methyl ether (3 × 20 mL). The combined organic layers were
washed with brine (10 mL), dried (Na2SO4), and concentrated.
p-Xylene (20.5 µL) was added as internal standard, and the
yields of the different products were determined by 1H NMR
spectroscopy (300 MHz). Flash chromatography with petroleum
ether/ethyl acetate 30:1 furnished the epoxides 3, 4 (R ) Bn)10
(57 mg, 27%) and 2-iodo-1,3-diphenyl-1-propanone 12 (160 mg,
47%).10
Ack n ow led gm en t. We are grateful to the Deutsche
Forschungsgemeinschaft (SFB 260 and Graduierten-
Kolleg “Metallorganische Chemie”) as well as the Fonds
der Chemischen Industrie for generous support of this
study.
Rea ction of n -Bu tyllith iu m w ith 1,1-Diiod o-2-p h en yl-
eth a n e. A solution of n-butyllithium (1.55 M, 0.21 mL, 0.32
mmol) was added at -100 °C under a nitrogen atmosphere to a
solution of 1,1-diiodo-2-phenyl-ethane10 (100 mg, 0.32 mmol) in
J O034138M
4548 J . Org. Chem., Vol. 68, No. 11, 2003