Substituted Benzene Anions as Leaving Groups in the Reaction of Sulfinyl Derivatives with Grignard Reagents: A New and Convenient Route to Dialkyl Sulfoxides in High Enantiomeric Purity

Full text of DOI:10.1021/jo991912q

J . Org. Chem. 2000, 65, 2843-2846
2843
Sch em e 1
Su bstitu ted Ben zen e An ion s a s Lea vin g
Gr ou p s in th e Rea ction of Su lfin yl
Der iva tives w ith Gr ign a r d Rea gen ts: A
New a n d Con ven ien t Rou te to Dia lk yl
Su lfoxid es in High En a n tiom er ic P u r ity
Maria Annunziata M. Capozzi, Cosimo Cardellicchio,
Francesco Naso,* and Paolo Tortorella
synthetic interest,10-13 now can be considered easily
available by using our approach. In particular, methyl
alkyl sulfoxides can be obtained in high enantiomeric
purity (>98% ee).4 The method was also suitable for the
preparation of ethyl sulfoxides or phenyl sulfoxides in a
lower enantiomeric purity (ee values 91-94%). Metala-
tion of the substrate is a side reaction that causes the
incomplete conversion of the substrate and has to be
avoided by using a variation of the strategy.4
The displacement of an aryl carbanion from a sulfinyl
derivative by means of organometallic reagents has
various precedents in the literature.5-7 However, in no
case was the synthetic potential of this displacement
adequately considered for the synthesis of sulfoxides.
With this background, the evaluation of the possibility
of extending our two-step strategy (enantioselective
oxidation and carbon for carbon substitution)1-4 to aryl-
substituted systems appeared as an interesting procedure
to convert one readily available starting compound into
a series of chiral nonracemic sulfoxides.
Consiglio Nazionale delle Ricerche, Centro di Studio sulle
Metodologie Innovative di Sintesi Organiche, Dipartimento
di Chimica, Universita` di Bari, via Amendola 173,
70126 Bari, Italy
Received December 14, 1999
Carbanionic leaving groups (LG) can be displaced in
the reaction of organometallic reagents with suitable
sulfinyl compounds.1-9 The substitution occurs with full
inversion of configuration at the sulfur stereogenic center
(eq 1).1-6
Recently, special interest has grown about the stere-
ochemistry of this process1-4 and the fate of the leaving
group.8,9
In previous work,1 we have investigated mechanistic
and stereochemical aspects of the displacement of the
halovinyl group in the reaction represented in eq 1. Our
attention was then driven toward the use of the anions
of dialkyl methylphosphonates as leaving groups.2-4 The
results obtained were used as the basis of a new easy
and straightforward two-step route to chiral nonracemic
sulfoxides. In fact, we have devised a catalytic, simple,
and high-yield oxidation of commercially available (arylth-
io)- or (alkylthio)methylphosphonates to (arylsulfinyl)- or
(alkylsulfinyl)methylphosphonates in high enantiomeric
purity (91 to >98% ee).4 These easily obtained sulfinyl
compounds were converted into the corresponding sul-
foxides by Grignard reagents, with the release of the
anion of the diethyl methylphosphonate (Scheme).4
The second step of the procedure occurs with full
inversion of configuration. Several chiral dialkyl sulfox-
ides, a type of sulfoxide that has attracted considerable
Resu lts a n d Discu ssion
Our synthetic scheme required a preliminary choice
of the candidate for the displacement. Therefore, several
types of sulfoxides were investigated. Preliminary results,
obtained by using methyl phenyl sulfoxide, were totally
unsatisfactory. Indeed, the main reaction observed was
the reduction of the sulfinyl group and the formation of
a mixture of sulfides, a result that had been reported also
by other workers14 for the reaction of the same sulfoxide
with Grignard reagents in the presence of magnesium
amides. An analogous behavior was also shown by using
p-nitrophenyl methyl sulfoxide. Better results and a
different course were observed for the reaction between
aryl methyl sulfoxides 1-8 with alkylmagnesium bro-
mides. Alkyl methyl sulfoxides 9-14 were obtained
(eq 2).
The reaction of o-, m-, and p-anisyl methyl sulfoxides
1-3 with n-decylmagnesium bromide gave low isolated
yields (up to 48%) of n-decyl methyl sulfoxide (Table 1,
entries 1-3) due to the concurrent formation of reduction
products.
On the other hand, o-, m-, and p-halophenyl methyl
sulfoxides 4-8 yielded satisfactory isolated yields (64-
(1) Cardellicchio, C.; Fiandanese, V.; Naso, F. J . Org. Chem. 1992,
57, 1718-1722. Cardellicchio, C.; Fiandanese, V.; Naso, F.; Scilimati,
A. Tetrahedron Lett. 1992, 33, 5121-5124.
(2) Cardellicchio, C.; Iacuone, A.; Naso, F.; Tortorella, P. Tetrahedron
Lett. 1996, 37, 6017-6020.
(3) Cardellicchio, C.; Fracchiolla, G.; Naso, F.; Tortorella, P. Tetra-
hedron 1999, 55, 525-532.
(4) Capozzi, M. A. M.; Cardellicchio, C.; Fracchiolla, G.; Naso, F.;
Tortorella, P. J . Am. Chem. Soc. 1999, 121, 4708-4709.
(5) Durst, T.; LeBelle, M. J .; Van Der Elzen, R.; Tin, K.-C. Can. J .
Chem. 1974, 52, 761-766. Lockard, J . P.; Schroeck, C. W.; J ohnson,
C. R. Synthesis 1973, 485-486.
(10) Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J . J .; Clardy,
J .; Cherry, D. J . Am. Chem. Soc. 1992, 114, 5977-5985.
(11) Whitesell, J . K.; Wong, M.-S. J . Org. Chem. 1994, 59, 597-
601.
(12) Fernandez, I.; Khiar, N.; Llera, J . M.; Alcudia, F. J . Org. Chem.
1992, 57, 6789-6796.
(13) Rebiere, F.; Samuel, O.; Ricard, L.; Kagan, H. B. J . Org. Chem.
1991, 56, 5991-5999.
(6) Furukawa, N.; Ogawa, S.; Matsumura, K.; Fujihara, H. J . Org.
Chem. 1991, 56, 6341-6348. Ogawa, S.; Furukawa, N. J . Org. Chem.
1991, 56, 5723-5726.
(7) Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett.
1987, 28, 2727-2730.
(8) Satoh, T.; Kobayashi, S.; Nakanishi, S.; Horiguchi, K.; Irisa, S.
Tetrahedron 1999, 55, 2515-2528 and references therein.
(9) Hoffmann, R. W.; Nell, P. G. Angew. Chem., Int. Ed. Engl. 1999,
38, 338-340.
(14) Kobayashi, K.; Yokota, K.; Akamatsu, H.; Morikawa, O.;
Konishi, H. Bull. Chem. Soc. J pn. 1996, 69, 441-443. Kobayashi, K.;
Kawakita, M.; Yokota, K.; Mannami, T.; Yamamoto, K.; Morikawa,
O.; Konishi, H. Bull. Chem. Soc. J pn. 1995, 68, 1401-1407.
10.1021/jo991912q CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/12/2000

2844 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
Ta ble 2. En a n tioselective Cu m en e Hyd r op er oxid e
Ta ble 1. Rea ction of Su bstitu ted Ar yl Meth yl Su lfoxid es
w ith Gr ign a r d Rea gen ts
Oxid a tion of Su bstitu ted Ar yl Meth yl Su lfid es Med ia ted
by a (R,R)-Dieth yl Ta r tr a te Tita n iu m Com p lex
entry substrate
X
R
product yielda (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
2-OCH3 n-decyl
3-OCH3 n-decyl
4-OCH3 n-decyl
10
10
10
9
13
10
10
10
42
48
22
72
64
71
82
69
entry
X
yielda (%)
product
eeb (%)
88
93
92
2-Cl
4-Cl
2-Br
3-Br
4-Br
n-octyl
n-hexadecyl
n-decyl
n-decyl
n-decyl
1
2
3
4
5
6
7
8
2-OCH3
3-OCH3
4-OCH3
2-Cl
4-Cl
2-Br
86
70
72
94
76
77
67
88
(R)-1
2d
(R)-3
(R)-4
(R)-5
(R)-6
7d
80
91c
83c
a
Yields refer to pure isolated products.
3-Br
4-Br
97
(R)-8
95 (>98)e
a
b
Yields refer to pure isolated products. Determined by HPLC
(see text). c Determined by NMR (see text). The absolute config-
d
uration has not been reported, but it should be R (see footnote c
in Table 3). e After one recrystallization (see text).
(CHP) oxidation of the prochiral sulfides in the presence
of a complex Ti(O-i-Pr)4/(diethyl (R,R)-tartrate) gives
higher ee values.15,16 In our hands, the best results were
obtained by adopting a modification of the reported
reaction conditions,15,16 according to our previous work.3
The modification, which consists of the use of a lower
amount of oxidizing agent and water, gave both high
enantioselectivity (Table 2, 80-97% ee) and satisfactory
yields (67-94%) of the chiral sulfoxides 1-8. In particu-
lar (Table 2, entry 8), p-bromophenyl methyl sulfoxide 8
with a high ee value was easily obtained by enantiose-
lective oxidation (95% ee) followed by one recrystalliza-
tion (>98% ee).
The substituted enantiomerically enriched aryl methyl
sulfoxides 1-8 were reacted with alkyl Grignard reagents
(Table 3). The reaction occurred with inversion of con-
figuration, and the enantiomeric excess of the resulting
sulfoxides was found to be very close to the value
measured for the starting material ((2%).
82%) of the alkyl methyl sulfoxide (Table 1, entries 4-8)
and were used for further studies. For evaluation of the
reactivity order between the halophenyl methyl sulfox-
ides, two substrates (in a 1:1 ratio) were treated with a
deficiency of Grignard reagent. The reactivity ratios were
evaluated from the composition of the recovered un-
changed material, by assuming simple kinetic behavior.
p-Chloro- and p-bromophenyl methyl sulfoxides 5 and 8
showed no significant reactivity difference. The same
conclusion was reached in the case of the comparison
between m-bromophenyl methyl sulfoxide 7 and p-
bromophenyl methyl sulfoxide 8, whereas the reactivity
ratio between o-bromophenyl methyl sulfoxide 6 and
m- or p-bromophenyl compounds 7 or 8 was found to
be ca. 2.
To prepare chiral nonracemic dialkyl sulfoxides with
the carbon for carbon substitution strategy, optically
active starting alkyl aryl sulfoxides were required. These
substrates can be obtained by an enantioselective hydro-
peroxide oxidation of the prochiral sulfides in the pres-
ence of chiral titanium complexes.15-17 The procedure
represents indeed a simple and straightforward access
to these chiral substrates. Unfortunately, the ee values
are not generally high, and peak values are obtained only
for certain substrates.15-17
The oxidation of the prochiral sulfides with tert-butyl
hydroperoxide in the presence of a complex Ti(O-i-Pr)4/
(R)-BINOL, according to our previous reported proce-
dure,4 gave low enantioselectivity (1-18% ee). On the
other hand, it is known that the cumene hydroperoxide
Due to the higher ee value of the p-bromophenyl
methyl sulfoxide 8, further reactions were performed with
this compound (Table 3, entries 8-12). We focused in
particular on long-chain alkyl methyl sulfoxides (Table
3, entries 8-11), since we are currently investigating
these compounds as components of chiral metallome-
sogens. The dialkyl sulfoxides were obtained in the same
enantiomeric purity (>98%) and in satisfactory isolated
yields (72-90%). The reaction appeared to be not re-
stricted to primary alkyl Grignard reagents. Indeed, the
use of a secondary alkyl Grignard reagents, i.e., cyclo-
hexylmagnesium bromide (Table 3, entry 12), gave cy-
clohexyl methyl sulfoxide 14 in good isolated yields (72%)
and in high enantiomeric purity (>98%). However, a low
conversion was obtained in the reaction of tert-butylmag-
nesium bromide with substrate 8, and this reaction was
not investigated further.
(15) (a) Brunel, J . M.; Kagan, H. B. Synlett 1996, 404-406. (b) Zhao,
S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43, 5135-5144. (c)
Pitchen, P.; Dun˜ach, E.; Deshmukh, M. N.; Kagan, H. B. J . Am. Chem.
Soc. 1984, 106, 8188-8193.
(16) Bortolini, O.; Di Furia, F.; Licini, G.; Modena, G.; Rossi, M.
Tetrahedron Lett. 1986, 27, 6257-6260. Di Furia, F.; Modena, G.;
Seraglia, R. Synthesis 1984, 325-327.
(17) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S.J . Org.
Chem. 1993, 58, 7624-7626. Komatsu, N.; Hashizume, M.; Sugita, T.;
Uemura, S. J . Org. Chem. 1993, 58, 4529-4533.
Con clu sion s
Our work has shown that a variety of aryl methyl
sulfoxides could be subjected to a displacement at the
sulfur center. The most satisfactory substrate appears
to be the halo-derivatives, among which the p-bromo

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2845
Ta ble 3. Rea ction of Ch ir a l Su bstitu ted Ar yl Meth yl Su lfoxid es w ith Gr ign a r d Rea gen ts
ee substrate
(%)
yielda
(%)
ee productb
(%)
entry
substrate
X
R
product
1
2
3
4
5
6
7
8
9
(R)-1
(R)-2c
(R)-3
(R)-4
(R)-5
(R)-6
(R)-7c
(R)-8
(R)-8
(R)-8
(R)-8
(R)-8
2-OCH3
3-OCH3
4-OCH3
2-Cl
4-Cl
2-Br
3-Br
4-Br
4-Br
4-Br
88
93
92
80
91
n-decyl
n-decyl
n-decyl
n-octyl
n-decyl
n-octyl
n-decyl
n-octyl
n-tridecyl
n-tetradecyl
n-hexadecyl
cyclohexyl
(S)-10
(S)-10
(S)-10
(S)-9
(S)-10
(S)-9
(S)-10
(S)-9
11e
40
56
24
65
73
68
81
84
74
90
77
72
86
91
92
81
89
83
96
85d
96
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
10
11
12
12e
4-Br
4-Br
13e
(S)-14
a
b
Yield refer to pure isolated products. Determined by HPLC (see text). c The configuration has not been reported previously, but it
should be R because the reaction with n-decylmagnesium bromide yielded (S)-10 as in the case of other sulfoxides of known configuration,
d
and it seems reasonable to assume that also this reaction occurred with inversion of configuration. Determined by NMR (see text).
e The configuration has not been reported previously, but it should be S, provided that the reaction with Grignard reagents occurred with
full inversion of configuration also in this case.
was separated by column chromatography (eluent petroleum
sulfoxide has to be considered the starting compound of
choice due both to higher yields in the coupling and to
the very easy possibility to prepare it in an optically pure
form. The use of Grignard reagents appears to avoid the
partial or complete racemization reported in earlier
works5-7 for reactions with organolithium compounds.
Finally, a comparison between the present procedure and
the approach based upon the use of the anion of dialkyl
methylphosphonates as leaving group4 reveals that the
two methodologies are complementary for the synthesis
of alkyl methyl sulfoxides. In fact, whereas the use of the
latter can be considered of more general scope, but to a
certain extent affected by the metalation of the substrate,
this competing process does not afflict the reaction of the
aryl derivatives used in the present investigation.
ether/ethyl acetate 3:7). (R)-(+)-o-An isyl m eth yl su lfoxid e (1):
Kugelrohr oven temperature 90 °C, p ) 5 × 10-2 mbar; [R]D
)
+295 (c ) 1, acetone) for an 88% ee (lit.18 [R]D ) +340 (c ) 1,
acetone)). (+)-m -An isyl m eth yl su lfoxid e (2):19 Kugelrohr oven
temperature 110 °C, p ) 5 × 10-2 mbar; [R]D ) +127.8 (c ) 1.5,
chloroform) for a 93% ee. (R)-(+)-p-An isyl m eth yl su lfoxid e
(3): Kugelrohr oven temperature 100 °C, p ) 10-2 mbar; [R]D
)
+161.7 (c ) 2, chloroform) for a 92% ee (lit.20 [R]D ) +165.9 (c
) 0.38, chloroform)). (R)-(+)-o-Ch lor op h en yl m eth yl su lfox-
id e (4): Kugelrohr oven temperature 80 °C, p ) 10-2 mbar; [R]D
) +204 (c ) 1.5, THF) for an 80% ee (lit.21 [R]D ) +139 (c ) 1,
THF)). (R)-(+)-p-Ch lor op h en yl m eth yl su lfoxid e (5): Kugel-
rohr oven temperature 90 °C, p ) 10-2 mbar; [R]D ) +153 (c )
1, chloroform) for a 91% ee (lit.22 [R]D ) -158 (c ) 0.95,
chloroform)) for the S configuration. (R)-(+)-o-Br om op h en yl
m eth yl su lfoxid e (6): Kugelrohr oven temperature 110 °C; p
) 5 × 10-2 mbar; [R]D ) +207 (c ) 1.3, THF) for a 83% ee (lit.21
[R]D ) +251 (c ) 1, THF)). (+)-m -Br om op h en yl m eth yl
su lfoxid e (7):23 Kugelrohr oven temperature 110 °C, p ) 5 ×
10-2 mbar; [R]D ) +116.3 (1.2, acetone) for a 97% ee. (R)-(+)-
p-Br om op h en yl m eth yl su lfoxid e (8): mp 75-77 °C (hexane);
[R]D ) +98.3 (c ) 2.5, acetone) (lit.15c [R]D ) +77 (c ) 1.8,
acetone)) for a 80% ee.
Exp er im en ta l Section
1
The purified reaction products were characterized by their H
and 13C NMR spectra, recorded in CDCl3 at 500 and 125 MHz,
respectively, and their mass spectra determined by GC/MS
analysis (SE30, 30 m, capillary columns and mass selective
detector, 70 eV). Substituted aryl methyl sulfides were obtained
from the corresponding commercially available thiols and methyl
iodide. The ee values of the products were determined by 1H
NMR techniques (addition of (R)-(-)-3,5-dinitro-N-(1-phenyl-
ethyl)benzamide as a chiral solvating agent) or HPLC (Chiralcel
OB-H or OD-H). Only HPLC determinations were used for
substrates and products of high enantiomeric purity (>98%).
Su bstr a tes. Racemic aryl methyl sulfoxides 1-8 were ob-
tained by standard oxidation of the corresponding sulfides.
P r ep a r a tion of Ch ir a l Ar yl Meth yl Su lfoxid es (1-8) by
CHP En a n tioselective Oxid a tion of Su lfid es in th e P r es-
en ce of a Ch ir a l Tita n iu m Com p lex. A solution of Ti(O-i-
Pr)4 (1.48 mmol) in 3 mL of anhydrous CH2Cl2 was added to a
solution of diethyl tartrate (2.95 mmol) in 5 mL of anhydrous
CH2Cl2. After 2 min, 13 µL of water was added. The mixture
was stirred at room temperature for 20 min and then cooled to
-20 °C. After 20 min, 1.48 mmol of thioether in 3 mL of
anhydrous CH2Cl2 and 1.63 mmol of CHP were added. The
reaction mixture was stirred at -20 °C for 3 h and quenched
with a saturated solution of NH4Cl. The solids were removed
by filtration, and the organic layer was extracted with CH2Cl2.
The organic extracts were dried over anhydrous sodium sulfate
and then evaporated in vacuo. The obtained sulfinyl compound
Rea ction of Gr ign a r d Rea gen ts w ith Ra cem ic or En a n -
tiom er ic Su lfoxid es 1-8. A solution of 2.1 mmol of Grignard
reagents in THF was added to a solution of 1.4 mmol of sulfoxide
in 10 mL of THF at 0 °C and under N2. After 1.5 h, the reaction
mixture was quenched with a saturated solution of NH4Cl. After
the usual workup, the reaction mixture was separated by column
chromatography and recrystallized (hexane) or distilled.
(S)-(+)-Meth yl n -octyl su lfoxid e (9): mp 35-37 °C (hex-
ane); [R]D ) +77.3 (c ) 1, acetone) (lit.13 [R]D ) + 62.5 (acetone);
lit.4 [R]D ) -83.6 (c ) 1, acetone)) for the R configuration. (S)-
(+)-Meth yl n -d ecyl su lfoxid e (10): mp 48-51 °C (hexane); [R]D
) +54.0 (c)1, chloroform) (lit.4 [R]D ) -52.7 (c ) 1, chloroform))
for the R configuration. (+)-Meth yl n -tr id ecyl su lfoxid e (11):
24
mp 63-65 °C (hexane); [R]D ) +52.9 (c ) 1, chloroform).
(18) Bolm, C.; Mu¨ller, P.; Harms, K. Acta Chem. Scand. 1996, 50,
305-315.
(19) Racemic 3: Bordwell, F. G.; Boutan, P. J . J . Am. Chem. Soc.
1957, 79, 717-722.
(20) Brunel, J .-M.; Diter, P.; Duetsch, M.; Kagan, H. B. J . Org.
Chem. 1995, 60, 8086-8088.
(21) Imboden, C.; Renaud, P. Tetrahedron: Asymmetry 1999, 10,
1051-1060.
(22) Burgess, K.; Henderson, I. Tetrahedron 1991, 47, 6601-6616.

2846 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
(+)-Meth yl n -tetr a d ecyl su lfoxid e (12):25 mp 70-72 °C
(hexane); [R]D ) +49.4 (c ) 1, chloroform); (+)-n -Hexa d ecyl
m eth yl su lfoxid e (13):26 mp 78-79 °C (hexane); [R]D ) +43.7
(c ) 1.5, chloroform). (S)-(+)-Cycloh exyl m eth yl su lfoxid e
Ack n ow led gm en t. This work was financially sup-
ported in part by the Ministero dell’Universita` e della
Ricerca Scientifica e Tecnologica, Rome (National Project
“Stereoselezione in Sintesi Organica. Metodologie e
Applicazioni”) and by the University of Bari.
(14): Kugelrohr oven temperature 135 °C; p ) 10 mbar; [R]D
)
+67.7 (c ) 1, acetone) (lit.4 [R]D ) -69.5 (c ) 1, acetone)) for
the (R) configuration.
Su p p or tin g In for m a tion Ava ila ble: Relevant spectral
data for compounds 1-14; data concerning HPLC determina-
tion of the ee values. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) Racemic 7: Banerji, K. K. J . Chem. Soc., Perkin Trans. 2 1991,
759-763.
(24) Racemic 11: Entwistle, I. D.; J ohnstone, R. A. W. Chem.
Commun. 1965, 29-30.
(25) Racemic 12: Chada, V. K.; Leidal, K. G.; Plapp, B. V. J . Med.
Chem. 1983, 26, 916-922.
(26) Racemic 13: J erchel, D.; Dippelhofer, L.; Renner, D. Chem. Ber.
1954, 87, 947-955.
J O991912Q