A General and Expeditious One-Pot Synthesis of Sulfoxides in High Optical Purity from Norephedrine-Derived Sulfamidites

Full text of DOI:10.1021/ol027232i

ORGANIC
LETTERS
2003
Vol. 5, No. 1
75-78
A General and Expeditious One-Pot
Synthesis of Sulfoxides in High Optical
Purity from Norephedrine-Derived
Sulfamidites
Jose´ L. Garc´ıa Ruano,* Carlos Alemparte, M. Teresa Aranda, and
Mar´ıa M. Zarzuelo
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
joseluis.garcia.ruano@uam.es
Received November 5, 2002
ABSTRACT
A general and simple procedure for preparing any kind of enantiomerically enriched sulfoxide starting from norephedrine-derived
N-benzyloxycarbonylsulfamidite 3a is reported. After one-pot reaction of 3a with RMgX, HBF , and R′MgX, a variety of sulfoxides 6 are obtained
4
in ee usually higher than 93% and isolated yields ranging between 50 and 78%. The obtained configuration is tunable by simply electing the
order of the addition of the reagents.
The great importance of enantiomerically enriched sulfoxides
in asymmetric synthesis can be inferred from the large
number of papers concerning their use as chiral auxiliaries1
and, more recently, as chiral ligands in asymmetric catalysis.2
As a consequence, the search of general and efficient
methods to prepare any kind of chiral nonracemic sulfoxides
has been a matter of great interest.3 Excluding resolution,
asymmetric oxidation of sulfides and nucleophilic substi-
tution on chiral sulfur derivatives are the two main meth-
odologies for the preparation of chiral sulfoxides.3 De-
spite many efforts made in this field, the procedure reported
by Andersen forty years ago,4 and substantially improved
by Solladie´,5 is still the most frequently used method for
the synthesis of these compounds. The procedure consists
of the reaction of diastereomerically pure menthyl sulfinates
with Grignard reagents. However, only arenesulfinates are
achievable in optically pure form. Other chirality sources
have been employed to circumvent these drawbacks such as
diacetone D-glucose, DAG methodology described by Khiar,
Alcudia et al.,6 and trans-2-phenylcyclohexanol introduced
by Whitesell’s group.7 Sulfinylating agents different than
(1) (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717 and references therein.
(b) Hua, D. H. AdV. Heterocycl. Nat. Prod. Synth. 1996, 3, 151. (c) Abu-
Jusef, I. A.; Harpp, D. N. Sulfur Rep. 1997, 20, 1. (d) Kita, I. Phosphorous,
Sulfur, Silicon Relat. Elem. 1997, 120, 145. (e) Allin, S. M. Organosulfur
Chem. 1998, 2, 157. (f) Baird, C. P.; Rayner, C. M. J. Chem. Soc., Perkin
Trans. 1 1998, 1973. (g) Garc´ıa Ruano, J. L.; Cid, B. In Topics in Current
Chemistry; Page, P. C. B., Ed.; Springer: Berlin, 1999; Vol. 204, p 1.
(2) For recent references see: (a) Priego, J.; Garc´ıa Manchen˜o, O.;
Cabrera, S.; Carretero, J. C. J. Org. Chem. 2002, 67, 1346. (b) Pezet, F.;
Ait-Haddou, H.; Daran, J.-C.; Sasaki, I.; Balavoine, G. G. A. Chem.
Commun. 2002, 510. (c) Watanabe, K.; Hirasawa, T.; Hiroi, K. Chem.
Pharm. Bull. 2002, 50, 372.
(4) (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93. (b) Andersen, K.
K.; Gafield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, J. I. J. Am.
Chem. Soc. 1964, 86, 5637. (c) Andersen, K. K. Int. J. Sulfur. Chem. 1971,
6, 79.
(5) (a) Mioskowski, C.; Solladie, G.; Tetrahedron 1980, 36, 227. (b)
Solladie´, G. Synthesis 1981, 185. (c) Solladie´, G.; Hutt, J.; Girardin, A.
Synthesis 1987, 173.
(3) Khiar, N.; Fernandez, I.; Alcudia, A.; Alcudia, F. AdVances in Sulfur
Chemistry; Rayner, C. M., Ed.; JAI Press, Inc.: Stanford, 2000, Vol. 2, p
57 and references therein.
(6) Fernandez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789. See also ref 3.
10.1021/ol027232i CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/14/2002

sulfinates have also been utilized, especially N-p-tolylsulfi-
nylsultam introduced by Oppolzer,8 N-acylsulfinamides
developed by us,9 Ellman’s tert-butyl t-butanethiosulfinate,10
N-sulfinyloxazolidinones reported by Evans,11 of a wider
scope, and Naso’s recent approach based on the use of
carbanionic leaving groups.12 All these methodologies have
a limited scope.
1 failed. However, treatment of 1 with ClCO2Bn and reaction
of the resulting carbamate 2 with SOCl2 in the presence of
a base smoothly afforded N-benzyloxycarbonyl derivatives
3a and 3b.
The observed diastereomeric ratio greatly depends on the
reaction conditions, with the base and solvent being critical
(Table 1). Thus, isomer 3a is favored in CH2Cl2, whereas
Chiral sulfur compounds containing two leaving groups
attached to the SO unit are especially attractive. In this sense,
several approaches have been reported. Kagan13 described
the use of optically pure cyclic sulfites as starting compounds,
but a lack of regioselectivity in the first attack restricts their
usefulness for the synthesis of tert-butylsulfoxides and
determines the need of purification of the intermediate
hydroxysulfinate. This problem was solved with the use of
cyclic sulfamidites, initially reported by Wudl and Lee14 and
further improved by Benson and Snyder.15 After reaction with
RMgX (R cannot be Ar), sulfinamides are obtained and, due
to the low reactivity of these compounds, activation with
Me3Al prior to addition of the second Grignard reagent is
required. The obtainment of epimeric mixtures of sulfina-
mides in some cases and the use of different solvents in each
step preclude the possibility of a one-pot procedure.
On the basis that N-acylated sulfinamides are at least 2
orders of magnitude more reactive than sulfinates,9a,11 we
reasoned that N-EWG-substituted sulfamidites would exhibit
a quite better reactivity pattern in sulfinylation reactions.16
The more favored cleavage of the S-N bond versus the S-O
bond should afford a sulfinate, sufficiently reactive to evolve
into a sulfoxide upon reaction with a second organometallic
reagent without needing any additive. These two steps can
now be performed in a single flask (Scheme 1). In this paper
Table 1. Synthesis of N-Benzyloxycarbonylsulfamidites 3a and
3b
entry
base
NEt3
NEt3
NEt3
DMAP
DMAP
DMAP
DMAP
solventa
3a /3bb
1
2
3
4
5
A, B, C
D, E
F
A
B
76/24
57/43
49/51
92/8c
76/24
70/30
46/54
6
7
D, E
F
8
DMAP
C
9
DBU
A
A
A
A
A
D
F
A
76/24
45/55
21/79
70/30
7/93d
complex mixture
complex mixture
8/92
10
11
12
13
14
15
16
pyridine
imidazole
i-Pr2NEt
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,4,6-colidine
a A, CH2Cl2; B, acetone; C, CH3CN; D, THF; E, Et2O; F, toluene.
b Determined by 1H NMR from the reaction crude. c Isolated yield of 3a )
62%. d Isolated yield of 3b ) 44%.
Scheme 1
the amount of 3b increases in less polar solvents (entries
1-3). The use of DMAP provided the highest de (84%, entry
4), 3a being the major isomer. The opposite diastereoselec-
tivity was observed by using methylpyridines (86 and 84%
de, entries 13 and 16), though lower yields were obtained.
we report the use of N-benzyloxycarbonylsulfamidites de-
rived from (1R,2S)-(-)-norephedrine 1 as starting compounds
in the one-pot synthesis of any kind of enantiomerically
enriched sulfoxides by consecutive reaction with two dif-
ferent Grignard reagents.17
(11) Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.;
Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977.
(12) (a) Annunziata, M.; Capozzi, M.; Cardellicchio, C.; Naso, F.; Rosito,
V. J. Org. Chem. 2002, 67, 7289. (b) Annunziata, M.; Capozzi, M.;
Cardellicchio, C.; Naso, F.; Spina, G.; Tortorella, P. J. Org. Chem. 2001,
66, 5933. (c) Annunziata, M.; Capozzi, M.; Cardellicchio, C.; Naso, F.;
Tortorella, P. J. Org. Chem. 2000, 65, 2843. (d) Annunziata, M.; Capozzi,
M.; Cardellicchio, C.; Fracciolla, G.; Naso, F.; Tortorella, P. J. Am. Chem.
Soc. 1999, 121, 4708.
(13) (a) Reviere, F.; Samuel, O.; Ricard, L.; Kagan, H. B. J. Org. Chem.
1991, 56, 5991. (b) Reviere, F.; Kagan, H. B. Tetrahedron Lett. 1989, 30,
3659.
(14) Wudl, F., Lee, T. B. K. J. Am. Chem. Soc. 1973, 95, 6349.
(15) Benson, S. C.; Snyder, J. K. Tetrahedron Lett. 1991, 32, 5885.
(16) A similar strategy for preparing enantiomerically pure sulfinamides
from the N-tosylsulfamidite obtained by reaction of (1R,2S)-N-tosylami-
noindanol with SOCl2 has been reported very recently (Han, Z.; Krishna-
murthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc.
2002, 124, 7880).
Despite the diversity of conditions studied, all our attempts
to obtain the N-acetylsulfamidite derived from norephedrine
(7) Whitesell, J. K.; Chen, H. H.; Lawrence R. M. J. Org. Chem. 1985,
50, 4663.
(8) Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernardelly, G.
Tetrahedron Lett. 1997, 38, 2825.
(9) (a) Alonso, R.; Garc´ıa Ruano, J. L.; Noheda, P.; Zarzuelo, M. M.
Tetrahedron: Asymmetry 1995, 6, 1133. (b) Bueno, A. B.; Carren˜o, M.
C.; Garc´ıa Ruano, J. L.; Gomez-Arraya´s, R.; Zarzuelo, M. M. J. Org. Chem.
1997, 62, 2139.
(10) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913. (b) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011.
(17) Preliminary results have been presented: Alemparte, C.; Zarzuelo,
M. M.; Garc´ıa Ruano, J. L. Book of Abstracts, Belgian Organic Synthesis
Symposium, 9th ed., Namur, Belgium, July, 2002; TH 016.
76
Org. Lett., Vol. 5, No. 1, 2003

The best results were achieved at -40 °C. Worse diastereo-
meric ratios and significant amounts of byproducts were
detected at higher and lower temperatures, respectively. The
preparation of 3a can be performed in a one-pot procedure
starting from norephedrine 1 (both enantiomers are com-
mercially available) by reaction with ClCO2Bn in CH2Cl2
and subsequent addition of SOCl2 in the presence of DMAP.
Sulfamidite 3a is isolated in 57% overall yield after
chromatographic purification.
The configurational assignment of both diastereoisomers
was initially based on the deshielding of the heterocyclic
protons when they are in a cis arrangement with regard to
the sulfinylic oxygen14 and further confirmed from the
absolute configuration of the obtained sulfoxides.
The results obtained in the reactions of 3a18 with different
organometallic reagents (1 equiv) are depicted in Table 2.
Zn and MeCeCl2. The use of CH2Cl2 as a solvent at -78 °C
proved to be critical (entry 8). These optimal reaction
conditions were applied to other Grignard reagents (except
to the less reactive t-BuMgCl, which required -40 °C and
1.5 equiv of nucleophile, entry 9). As shown in Table 2,
only ethyl (entry 11) and vinyl (entry 14) Grignard reagents
led to significant amounts of 3a and 5, whereas Me, i-Pr,
t-Bu, and different aryl derivatives (entries 8-10, 12, and
13) provided sulfinate 4 in high proportion. These results
must be taken into account when deciding the addition order
of the reagents for the one-pot synthesis.
The first one-pot reaction attempt carried out was the
formation of (R)-methylphenylsulfoxide 6a by consecutive
reaction of compound 3a with PhMgBr and MeMgBr.
Sulfoxide 6a was cleanly obtained in 70% yield after
chromatographic purification, though with only 73% ee.20
It is well-known that reactions of RMgX with both N-
acylsulfinamides and sulfinates evolve with complete inver-
sion of the configuration at sulfur. We reasoned that
racemization could be produced as a consequence of an
intramolecular N-sulfinylation of the deprotonated ben-
zenesulfinate intermediate 4a (Scheme 2) yielding ben-
Table 2. Reactions of 3a with Organometallic Reagents
Scheme 2
entry
RM
solvent
T (°C)
3a /4/5a
4b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Me2CuLi
MeLi
THF/CH2Cl2
THF
THF
toluene
hexane
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
-20
-78
-78
-78
0
37/0/43c
55/15/30
45/43/12
18/60/22
81/3/16
45/28/27
34/26/40
12/71/17 65
10/90/0
5/91/4
26/54/20 46
6/90/4
3/89/8
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
t-BuMgCld
i-PrMgCl
EtMgBr
-50
0
-78
-40
-78
-78
-78
-78
-78
82
81
zenesulfinamide 4a′ with the opposite configuration at sulfur.
Both species are able to act as sulfinylating agents in the
attack of the second Grignard reagent to yield opposite
enantiomers of 6a, thus decreasing its ee. This equilibrium
must be mostly shifted toward 4a (only sulfinates are isolated
when the reaction is quenched after the first addition of
Grignard reagent), but the higher reactivity of 4a′ could be
responsible for the observed racemization.
PhMgBr
p-anisylMgBr
vinylMgBr
74
75
30/50/20
a Determined by 1H NMR of the reaction crude. b Isolated yield.
c Corresponding sulfonate (20%) was also detected. d Used 1.5 equiv.
If this assumption was true, the use of 1 equiv of any
electrophilic additive able to trap the nitrogen anion would
avoid this equilibrium and therefore the racemization.
Consequently, we explored the influence of different elec-
trophilic additives on the ee of 6a.
The reaction mixtures are usually composed by the envi-
sioned sulfinates 4, symmetric sulfoxides 5 (obtained by
reaction of 4 with a second molecule of RM), and conse-
quently, the equivalent amount of unreacted 3a. Since
N-acylsulfinamides have been shown to be quite more
reactive than sulfinates,9a,11 the formation of compound 5 in
significant amounts was not expected and suggests that
sulfinates 4 could be better sulfinylating agents than the usual
sulfinates, thus making easier the second attack of RM.19
Optimization of the organometallic nucleophile was in-
vestigated by comparing different methylating reagents.
MeMgBr (entry 3) provided better results than MeLi (entry
2) or Me2CuLi (entry 1). No reaction was observed with Me2-
The best results (93% ee) were achieved by addition of
1.2 equiv of HBF4 after the first Grignard reagent and prior
(19) This higher reactivity would be interesting in the target one-pot two-
step procedure. It was confirmed from the results obtained in the following
competence experiment:
where DMSO is formed by the attack of MeMgBr on sulfinate 4, whereas
menthyl sulfinate remains unaltered (no menthol was detected).
(20) Enantiomeric excess was 99% when a two-step synthesis of 6a
(purifying intermediate sulfinate 4a before its reaction with MeMgBr) was
performed.
(18) The reactivity of both diastereoisomers was found to be similar,
but 3a was the substrate of choice because it could be prepared in higher
yield.
Org. Lett., Vol. 5, No. 1, 2003
77

to the addition of the second one.21 This simple procedure22
was applied to the synthesis of a wide number of structurally
diverse sulfoxides (Table 3), evidencing the great scope of
to take place to a greater degree. More intriguing are the
results obtained when t-BuMgCl was used in the first step.
Under the usual conditions, the formation of the correspond-
ing sulfoxide did not occur (entries 17 and 18). However, in
the absence of HBF4, the product was formed in 70% yield
(entry 19), although in a predictable low ee.23
Table 3. Synthesis of Sulfoxides from 3a by the One-Pot
The best ees (95-98%) and yields (64-78%) are obtained
when MesMgBr is used in the first step (entries 10-13),
but no large differences with the results obtained in other
cases are observed. As expected, the order of the addition
of the reagents determines the observed absolute configu-
ration of the sulfoxides (compare entries 2 and 5 or 11 and
14).
Procedure
entry
R
R′a
Me
i-Pr
vinyl
Et
yield
configuration (ee)b
In conclusion, the one-pot reaction of compound 3a with
RMgX, HBF4, and R′MgX must be considered a very general
and powerful approach for the synthesis of sulfoxides in good
yields and very high enantiomeric excess. Dialkyl, alkylaryl,
arylvinyl, and diarylsulfoxides can be efficiently prepared
in a single laboratory operation starting from a common
precursor. The obtained configuration is tunable by simply
electing the order of the addition of the reagents. Studies
directed toward clarifying and solving the problems associ-
ated with the synthesis of tert-butylsulfoxides are in progress.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19e
Ph
Ph
Ph
i-Pr
i-Pr
54
58
53
52
75
56
57
61
52
71
73
78
64
53
60
50
R (93)
R (93)
R (95)
R (-)c
S (95)
R (93)
R (95)
R (93)
R (76)
R (97)
R (97)
Sd (98)
R (95)
S (86)
R (90)
R (93)
Ph
Et
p-anisyl
p-anisyl
p-anisyl
p-anisyl
mesityl
mesityl
mesityl
mesityl
Me
p-Tol
vinyl
t-Bu
p-Tol
Me
Me
vinyl
mesityl
i-Pr
decyl
Me
Acknowledgment. We thank CAICYT (Grant PB2000-
196) for financial support. C.A. thanks Ministerio de
Educacio´n, Cultura y Deportes for a grant.
cyclohexyl
cyclohexyl
t-Bu
Supporting Information Available: Experimental pro-
t-Bu
t-Bu
p-anisyl
p-anisyl
1
cedures, [R]D, and H and 13C NMR data for compounds
70
S (77)
3a, 3b, sulfinates 4, and sulfoxides 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Temperature and number of equivalents employed in the second step
were variable (see Supporting Information). b By HPLC. c Could not be
determined. d Starting from 3b. e Without adding HBF4.
OL027232I
(21) Rates of the acid-base reaction of R′MgX with the NH proton and
the substitution on sulfur are in the same range (the reaction between an
isolated sulfinate 4 and 1 equiv of R′MgX gave rise to 30% conversion to
the sulfoxide). Thus, only a proportion of molecules of 4 are deprotonated
(with the consequent possibility of O f N sulfinyl migration) when reacting
with R′MgX.
(22) Experimental one-pot procedure: RMgX (1 equiv) was added to a
solution of 3a in dry CH2Cl2 at -78 °C. Then, HBF4 (1.2 equiv) was added
after 10-25 min and R′MgX (2.5-5 equiv) 5 min later followed by
quenching with aqueous NH4Cl. The usual workup and chromatography
afforded the sulfoxides in good overall yields.
this methodology. Alkylaryl (entries 1, 2, 5, 6, 9 11, 12, and
14), diaryl (entries 7 and 10), dialkyl (entries 4, 15, and 16),
and arylvinyl (entries 3, 8, and 13) sulfoxides were readily
prepared in 50-78% yield and high ees. The configuration
of the resulting sulfoxides was unequivocally established by
comparison of their specific rotations with those reported in
the literature.
The observed decrease in the ee in entries 9 and 14 could
be due to the lower reactivities of MesMgBr and especially
t-BuMgCl, allowing the equilibration shown in Scheme 2
(23) S)-t-BuSO-p-anisyl and (R)-t-BuSOMe can be successfully prepared
by addition of the corresponding Grignard reagents to isolated t-butane-
sulfinate 4.
78
Org. Lett., Vol. 5, No. 1, 2003