Diastereoselective addition of α-metalated sulfoxides to imines revisited: Mechanism, computational studies, and the effect of external chiral ligands

Article abstract of DOI:10.1135/cccc20030885

Some new results on asymmetric synthesis via the addition of α-metalated methyl tolyl sulfoxides to imines are presented. Good diastereoselectivity (up to >98% d.e. for product 3g) can be obtained under conditions of kinetic control (short reaction time,

Full text of DOI:10.1135/cccc20030885

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
885
DIASTEREOSELECTIVE ADDITION OF α-METALATED SULFOXIDES
TO IMINES REVISITED: MECHANISM, COMPUTATIONAL STUDIES,
AND THE EFFECT OF EXTERNAL CHIRAL LIGANDS
1,
Brian PEDERSEN, Tobias REIN, Inger SØTOFTE, Per-Ola NORRBY * and
2,
David TANNER *
Department of Chemistry, Technical University of Denmark, Buildings 201 and 207, Kemitorvet,
DK-2800 Kgs. Lyngby, Denmark; e-mail: 1pon@kemi.dtu.dk, 2dt@kemi.dtu.dk
Received Decem ber 18, 2002
Accepted February 23, 2003
Dedicated to the memory of Professor Otakar Červinka.
Som e n ew results on asym m etric syn th esis via th e addition of α-m etalated m eth yl tolyl
sulfoxides to im in es are presen ted. Good diastereoselectivity (up to >98% d.e. for product
3g) can be obtain ed un der con dition s of kin etic con trol (sh ort reaction tim e, low tem pera-
ture). Th e tran sition state (a six-m em bered “flat ch air”) was probed by quan tum m ech an ical
calculation s, wh ich un derpin n ed th e idea of usin g extern al ch iral ligan ds to en h an ce th e
diastereoselectivity of oth erwise m oderately selective reaction s. In th is way, th e diastereo-
m eric ratio of th e product 3a could be raised from (84:16) to (>99:1) by use of a readily
available C2-sym m etric bis(sulfon am ide) ligan d.
Keyw ord s: Diastereoselectivity; Ch iral sulfoxides; Im in es; N ligan ds; Quan tum m ech an ical
calculation s; Asym m etric addition s; Carban ion s; Organ olith ium reagen ts.
Ch iral n ucleoph ilic species gen erated by α-m etalation of sulfoxides are at-
tractive reagen ts for asym m etric carbon –carbon bon d form ation , with m ost
exam ples of syn th etically useful reaction s in volvin g eith er 1,2-addition to
carbon yl groups or Mich ael addition 1. Diastereoselective 1,2-addition to
im in es h as recen tly been of in creasin g in terest2,3 (Sch em e 1).
Th is type of reaction dates back to 1973, wh en Tsuch ih ash i an d cowork-
ers4 reported th e com pletely diastereoselective addition of th e lith ium de-
rivative of en an tiom erically pure m eth yl p-tolyl sulfoxide to N-(ben zyl-
iden e)an ilin e. However, th is result was later ch allen ged by th e group of
Kagan 5 wh o dem on strated th at th e actual diastereom eric ratio un der th e
Tsuch ih ash i con dition s was on ly 75:25 an d th at th e diastereoselectivity was
m arkedly affected by variation s in th e tem peratures used for gen eration of
th e an ion an d for th e addition reaction , respectively. Un der optim ized con -
Collect. Czech. Chem. Commun. (Vol. 68) (2003)
doi:10.1135/cccc20030885

886
Pedersen et al.:
R'
H
N
NHR' O
S
+
S
p-Tol
*
R
R
p-Tol
O
M
3a–3g
1a–1g
1 or 3
R
R'
Ph
Ph
Ph
Ph
a
b
c
d
e
f
2-MeO-C6H4
4-CF3-C6H4
Ph
4-MeO-C6H4
4-MeO-C6H4
Ph
Ph
Ts
t-Bu
2-MeO-C6H4
g
SCHEME 1
Diastereoselective addition of α-m etalated sulfoxides to im in es
dition s, a n ear-quan titative yield of th e adduct was obtain ed after on ly a
few m in utes at –78 °C, th e diastereom eric ratio bein g 92:8. Pyn e6 th en
sh owed th at th e reaction is reversible, an d can be subject to eith er kin etic
or th erm odyn am ic con trol; it was also n oted th at, in gen eral, diastereo-
selectivity was substan tially lower un der con dition s of th erm odyn am ic
con trol. Two possible ch elated tran sition states for th e reaction (Fig. 1) were
proposed with th e ch air-like assem bly (TS-A) bein g favoured for steric rea-
son s.
R'
N
O
NHR' O
S
M
S
p-Tol
H
H
R
p-Tol
R
TS-A (chair)
R
NHR' O
S
O
N
M
p-Tol
R
p-Tol
S
R'
TS-B (boat)
R = Ph, 4-MeOC6H4, 4-CF3C6H4, t-Bu, R' = Ph, 2-MeOC6H4, 4-CF3C6H4, Ts
FIG. 1
Tran sition states proposed for addition to im in es 1 (see refs2a,6
)
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
887
More recen tly, Zan da an d coworkers2a h ave m ade an exten sive study of
th e addition of lith ium (R)-m eth yl p-tolyl sulfoxide to N-(arylm eth yl-
iden e)-p-an isidin es (N-PMP im in es) an d con firm ed th at good diastereo-
selectivity can be obtain ed un der kin etic con trol. Th ey also obtain ed som e
in terestin g results by varyin g th e electron ic n ature of th e ben zyliden e
group, an d suggested th at in certain cases th e boat-like tran sition state
(TS-B in Fig. 1) could be stabilized by attractive π-p in teraction s between an
electron -deficien t ben zyliden e m oiety an d th e sulfoxide oxygen . Th is
would allow TS-B to better com pete with TS-A, th us explain in g th e lower
diastereoselectivity observed in th e reaction s of im in es carryin g electron -
with drawin g substituen ts on th e ben zyliden e group.
As part of a research project in volvin g th e use of ch iral sulfoxides in
asym m etric syn th esis7 we h ave recen tly h ad occasion to study th e addition
of α-m etalated sulfoxides to im in es. In th e presen t paper we presen t (i) re-
sults wh ich com plem en t th ose reported earlier by oth ers2,5,6, (ii) th e first
com putation al studies of th e reaction m ech an ism , an d (iii) th e first use of
extern al ch iral ligan ds to en h an ce th e diastereoselectivity of th e reaction .
RESULTS AND DISCUSSION
We began by exam in in g th e reaction of lith ium (R)-m eth yl p-tolyl sulfoxide
with a n um ber of im in e substrates, in cludin g two studied previously2,5,6
,
un der con dition s of kin etic con trol. In our experim en ts, th e sulfoxide an -
ion was gen erated at –78 °C usin g LDA in THF, an d a precooled (–78 °C) so-
lution of th e im in e in THF was added, followed by stirrin g for 10 m in
before th e reaction was quen ch ed. Th e results are gath ered in Table I; th e
degree of con version an d th e d.e. values were m easured by HPLC of th e
crude reaction products. Before discussin g th e results, we would like to
poin t out th at we h ad con siderable difficulty in obtain in g h igh isolated
yields of th e products by con ven tion al flash ch rom atograph y; in our h an ds,
com m ercial silica gel (from two differen t sources) was n ot suitable, an d
on ly by usin g dem etalated silica gel8 could acceptable isolated yields
(>50%) be obtain ed. We surm ise th at th e β-am in o sulfoxides are good lig-
an ds for an y m etals presen t in th e silica gel, an d it is surprisin g th at th is
problem h as n ot been m en tion ed so far.
For th e “stan dard” substrate (Table I, en try 1), we observed 68% d.e.
wh ich is very sim ilar to th at obtain ed6a by Pyn e (72%) by m ixin g th e reac-
tan ts at –78 °C followed by reaction at 0 °C for 5 m in . For th is substrate,
Kagan 5 obtain ed 84% d.e. by gen eration of th e an ion at 0 °C, followed by
reaction with th e im in e at –78 °C for 10 m in . Th e o-MeO-substituted im in e
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

888
Pedersen et al.:
in en try 2 gave 62% d.e. an d th is can be com pared with Zan da’s results2a
with th e correspon din g N-PMP im in e wh ich gave a m arkedly h igh er d.e.
(84%) un der con dition s sim ilar to ours (gen eration of th e an ion an d reac-
tion at –70 °C). In en try 3, an electron -with drawin g substituen t in th e para
position of th e N-aryl m oiety (wh ich could be expected to accelerate th e re-
action by stabilization of th e presum ed N-an ion in term ediate) gave on ly
60% d.e. An im provem en t to 84% d.e. was observed for an electron -
don atin g para substituen t on th e ben zyliden e group (en try 4), wh ile an
electron -with drawin g group in th is position eroded th e diastereoselectivity
(54%, en try 5). Th e form er result can be com pared with th e 72% d.e. ob-
tain ed un der th e optim ized Kagan con dition s5, wh ile th e latter is in lin e
with Zan da’s observation s2a th at substrates with electron -deficien t
ben zyliden e groups gen erally give lower diastereoselectivity. Detailed
m ech an istic in terpretation is difficult sin ce th e variation s in d.e. values
sh own in en tries 1–5 are gen erally quite m odest. However, two extrem es
were observed for en tries 6 an d 7: th e N-tosyl group in th e form er totally
obliterated th e diastereoselectivity, wh ile th e latter com bin ation of a
tert-butyl an d an o-m eth oxyph en yl group provided a sin gle diastereom er of
th e product. Th is m aterial could be obtain ed as X-ray-quality crystals,
wh ich allowed un am biguous assign m en t of th e relative an d absolute
stereoch em istry (Fig. 2).
Th e con figuration at th e n ewly-form ed stereogen ic cen ter is th us in lin e
with th at expected from th e ch air-like tran sition state (TS-A in Fig. 1) pro-
TABLE I
Diastereoselectivity for th e reaction of (R)-m eth yl p-tolyl sulfoxide (2) with im in es 1
Con version
En try
Com poun d
R
R′
d.r.b
a
%
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
Ph
Ph
87
82
98
92
93
75
92
84:16
81:19
80:20
92:8
Ph
2-MeOC6H4
Ph
4-CF3C6H4
4-MeOC6H4
4-CF3C6H4
Ph
Ph
Ph
77:23
50:50
>99:1
Ts
3g
t-Bu
2-MeOC6H4
a
b
Measured by ch iral HPLC; d.r. m ean s diastereom eric ratio, m ajor product h as (2S,RS) con -
figuration .
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
889
posed by Pyn e6a an d th e (2S,RS) con figuration of th e m ajor diastereom ers of
th e oth er n ew com poun ds in Table I (en tries 2, 3, an d 5) is assign ed by
an alogy with com poun d 3g. Th e (2S,RS) con figuration h as earlier been as-
sign ed5,6a to th e m ajor products sh own in en tries 1 an d 4, an d our assign -
m en ts are also in agreem en t with th ose of Zan da2a. We suggest th at th e
tert-butyl substituen t in substrate 1g en h an ces th e diastereoselectivity by
purely steric effects, wh ile th e N-tosyl group in 1f m ay stabilize th e in ter-
m ediate N-an ion to th e exten t th at th e reaction becom es reversible, th us
erodin g th e selectivity.
If ch elated tran sition states such as TS-A are in deed im portan t, th en th e
diastereoselectivity of th e reaction would be expected to be depen den t on
th e n ature of th e m etal cation . We h ave in vestigated th is in th e sim ple set
of experim en ts sum m arized in Table II.
Th e (N-ben zyliden e)an ilin e substrate 1a was reacted with th e ch iral
sulfoxide 2 wh ich h ad been deproton ated by th e bases sh own in Table II. It
was n oted (en tries 1 an d 2) th at th e use of LiHMDS gave a slower reaction ,
but sligh tly im proved d.e., com pared with LDA. For th e h exam eth yl-
disilazan e bases (en tries 2–4), diastereoselectivity decreased as th e m etal
cation varied from Li to Na to K, as expected on th e basis of a ch elated tran -
sition state.
FIG. 2
X-ray structure of 3g
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

890
Pedersen et al.:
To furth er in vestigate possible tran sition state geom etries, we perform ed
DFT calculation s on th e sm all m odel system sh own in Sch em e 2, wh ere all
aryl substituen ts h ave been replaced by m eth yl groups. Th e m odel
sulfoxide, DMSO, is of course n ot ch iral, but th e correspon din g α-m etalated
species is, th us allowin g th e location of diastereom eric tran sition states.
Hen ce, it is possible to estim ate th e diastereoselectivity in th e reaction from
th e m odel system s used h ere.
All calculation s were perform ed at th e B3LYP/6-31+G* level of th eory us-
in g9 Jaguar version 4.0. For th e sim plest m odel system , th e calculated acti-
vation en ergy was in fact n egative. Th is is a well-kn own ph en om en on in
bim olecular reaction s, resultin g from th e form ation of a stron g pre-reaction
TABLE II
Reaction between im in e 1a an d sulfoxide 2 un der kin etic con trol. Depen den ce of con ver-
sion an d diastereoselectivity on base an d m etal coun terion
Base
Con version , %
d.r.a
LDA
90
50
60
77
84:16
87:13
81:19
69:31
LiHMDS
NaHMDS
KHMDS
a
d.r. m ean s diastereom eric ratio.
+
+
Li
NH
O
S
N
N
O
S
Li
O
+
+
Li
S
N
O
S
NH
O
S
N
N
+
+
Li
N
O
S
SCHEME 2
Model system s in vestigated by DFT calculation s
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
891
com plex in th e gas ph ase. A m ore correct represen tation can be obtain ed ei-
th er by calculatin g th e pre-com plex, or by estim atin g th e in fluen ce of th e
solven t on th e reaction . Here, we h ave ch osen th e latter altern ative, calcu-
latin g th e fin al en ergies usin g th e PB-SCRF m eth od9 in Jaguar at th e geom e-
tries determ in ed in gas ph ase, with param eters appropriate for THF (ε =
7.43, probe radius = 2.52372). From previous experien ce with an ion ic reac-
tion s10, we expect th at th is com bin ation procedure will provide relative en -
ergies of sufficien t accuracy for th e com parison s of in terest. Em ployin g gas
ph ase geom etries also allowed us to verify th e station ary poin ts by n orm al
m ode an alysis, an d to add th e th erm odyn am ic con tribution s to arrive at fi-
n al, com posite Gibbs free en ergies of activation (Eq. (1)).
∆G ‡ = ∆E(B3LYP/6-31+G*) + ∆∆GTHF + ∆ZPE + ∆∆Gth erm
(1)
In th e reactan t, th e Li cation coordin ates to both O an d C of th e sulfoxide
an ion . Th is is m ost probably an artefact in th e sim plified m odel system
(m on om eric gas-ph ase structure with solvation on ly in cluded as sin gle-
poin t calculation ). Th e real com plex is solvated, an d is expected to be pres-
en t as a dim er or h igh er oligom er, with a Gibbs free en ergy lower th an th at
of th e m on om eric com plex. Th us, activation barriers will m ost probably be
un derestim ated by an un kn own but con stan t factor. However, as we are
on ly in terested in relative activation barriers, n o attem pt was m ade to de-
term in e th e con stan t error. In th e TS, th e distan ce between Li an d C h as in -
creased to allow form ation of a n orm al six-m em bered cyclic tran sition
state. Th e diastereom eric tran sition states for th e sm allest m odel system (n o
ligan d) are sh own in Fig. 3. For th e m ost favored TS, th e six atom s in th e
cyclic array form a flatten ed ch air, with th e two substituen ts on th e im in e
n ecessarily occupyin g axial position s, an d th e sulfur substituen t occupyin g
an equatorial position . Th e diastereom eric TS is sim ilar, but th e con form a-
tion is n ow m ore boat-like in order to keep th e sulfur substituen t in an
equatorial position , away from th e axial im in e substituen t. Sin ce O an d Li
do n ot bear substituen ts, th e twisted boat con form ation does n ot result in
an y com pressed gauch e in teraction s, an d is th erefore on ly sligh tly h igh er
in en ergy th an th e flat ch air, ca 8 kJ/m ol.
Th e experim en tal result obtain ed for th e reaction of th e ch iral sulfoxide
an d N-ben zyliden ean ilin e sh own in Table I, en try 1 (diastereom eric ratio
84:16) correspon ds to an en ergy differen ce of ca 4 kJ/m ol between th e
diastereom eric path s. Th us, keepin g in m in d th e sim plicity of th e m odel
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

892
Pedersen et al.:
system used for th e calculation s, th ere is good agreem en t between th eory
an d experim en t, an d th is en couraged us to use our com putation al m eth ods
as a predictive tool in furth er refin em en t of th e stereoselectivity, as de-
scribed below.
A possible way of en h an cin g th e diasteroselectivity of th ese reaction s
would be to use an extern al ch iral ligan d11, th us providin g th e opportun ity
of a “m atch ” an d “m ism atch ” between th e ligan d an d th e ch iral sulfoxide.
We began by in vestigatin g th e effect of a sim ple ach iral extern al ligan d
(TMEDA) on th e calculated tran sition states, as sh own in th e lower part of
Sch em e 2.
Th e lowest activation en ergy in th e absen ce of ligan d is 95 kJ/m ol,
wh ereas th e presen ce of TMEDA raises th e barrier to 117 kJ/m ol, reflectin g
th e h igh er crowdin g aroun d Li in th e tran sition state com pared with th e
groun d state. Th us, for an y ligan d th at bin ds Li by less th an 20 kJ/m ol (cor-
respon din g to an equilibrium con stan t aroun d 1000), th e reaction is ex-
pected to go exclusively via free m etal ion in equilibrium with th e boun d
m etal. From th is, we con clude th at in order to in fluen ce th e reaction with a
ch iral ligan d, it is im portan t th at m etal “leakage” is proh ibited. In view of
th e th eoretical prediction th at coordin ation of th e m etal cation slows down
th e reaction , m etals th at are stron ger Lewis acids th an Li+ sh ould also be of
in terest. To test th ese ideas, we screen ed a variety of m etal–ligan d com bin a-
tion s as depicted in Sch em es 3 an d 4.
We ch ose th e C2-sym m etric biden tate ligan ds (4, 5, 6 an d 7, Sch em es 3
an d 4) in order to reduce th e n um ber of possible com petin g tran sition
states, an d com bin ation s of th ese ligan ds an d differen t cation s (Li+, Zn +2
,
Major: flat chair
Minor: twist boat
FIG. 3
Calculated diasterom eric tran sition states for a sm all m odel system
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
893
Ph
THF
N
NHPh O
S
S
+
Tol
–78 oC
Ph
H
Ph
Tol
O
Li
chiral ligand
1a
3a
Chiral ligands
NHMs
NHMs
NHTs
NHTs
O
O
NHMs
NHMs
NHTf
NHTf
N
N
t-Bu
t-Bu
4
ent-5
7
5
6
(5, ent-5, 6, and 7 used as N,N-dianions)
Ligand
none
4
5
6
7
Conversion% d.r.
87
43
98
80
90
84:16
85:15
91:9
99:1
88:12
SCHEME 3
Effect of extern al ch iral ligan ds on diastereoselectivity (Li cation )
Ph
H
NHTs
NHTs
N
+
+
S
+
Et2Zn
Tol
Ph
O
Li
7
1a
95% conversion
d.r. = 93:7
NHPh O
S
Ph
Tol
3a
91% conversion
d.r. = 95:5
Ph
H
NHTs
NHTs
N
+
+
S
+
AlMe3
H3C
Tol
Ph
O
1a
2
7
SCHEME 4
Effect of extern al ch iral ligan ds (Zn an d Al cation s)
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

894
Pedersen et al.:
Al+3) were used. For th e experim en ts with lith ium (Sch em e 3), a total of
th ree equivalen ts of BuLi were used to deproton ate both th e sulfoxide an d
ligan d 5 or 6; for th e case of zin c (Sch em e 4), th e lith iated sulfoxide
(m etalated with BuLi) was added to th e com plex gen erated by reaction of
ligan d 7 with on e equivalen t of dieth ylzin c; for alum in ium (Sch em e 4),
on e equivalen t of AlMe3 was used to deproton ate both th e sulfoxide an d
ligan d 7.
As sh own in Sch em e 3, th e n eutral species 4 h ad little or n o effect on th e
diastereoselectivity, an d th is ligan d was tested on ly with lith ium . Th e
dian ion s of ligan ds 5 an d 6, h owever, en h an ced th e diastereoselectivity,
with 6 givin g essen tially a sin gle diastereom er of th e product. To th e best of
our kn owledge, th is is th e h igh est diastereom eric ratio yet recorded for th is
reaction . Ligan d 7 proved to be th e best for both zin c an d alum in ium
(Sch em e 4) th e diastereom eric ratios bein g 93:7 an d 95:5, respectively. Both
th ese values are better th an th at for th e “stan dard” reaction (84:16, Table I,
en try 1). We are curren tly in vestigatin g th e tran sition states for th ese reac-
tion s com putation ally, an d results will be reported elsewh ere. Fin ally, th e
con cept of “m atch an d m ism atch ” was dem on strated as sh own in Sch em e 5,
usin g th e en an tiom ers of ligan d 5 togeth er with lith ium (R)-m eth yl p-tolyl
sulfoxide.
Ph
N
NHPh O
S
S
+
Tol
Ph
H
Ph
Tol
O
Li
1a
3a
No ligand:
d.r. = 84:16
d.r. = 91:9 (91% conversion)
In the presence of ligand ent-5: d.r. = 73:27 (72% conversion)
In the presence of ligand 5:
SCHEME 5
Match an d m ism atch between ch iral sulfoxide an d ch iral ligan d
In con clusion , we h ave dem on strated th at extern al ch iral ligan ds can be
used to en h an ce th e diastereoselectivity of th e addition of α-m etalated
sulfoxides to im in es, a con cept wh ich was th e direct result of detailed com -
putation al studies of th e reaction m ech an ism .
EXPERIMENTAL
Meltin g poin ts are un corrected. 1H (300 MHz) an d 13C (75 MHz) NMR spectra were recorded
for CDCl3 solution s on a Varian Mercury 300 spectrom eter, with residual solven t peaks as
referen ce. Ch em ical sh ifts are given in th e δ-scale (ppm ), couplin g con stan ts J in Hz. Specific
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
895
rotation s were m easured at 20 °C on a Perkin Elm er 241 polarim eter an d are given in 10–1
deg cm 2 g–1. Ch iral HPLC an alyses were perform ed usin g a Varian 9012 solven t delivery sys-
tem an d a Varian 9065 polych rom ph otodiode array detector, with OD-H or OJ ch iral col-
um n s from Diacel an d elutin g with m ixtures of h exan e an d 2-propan ol. High -resolution
m ass spectra (HRMS) were provided by th e Un iversity of Copen h agen . Th e im in es were pre-
pared by stan dard procedures from com m ercially available aldeh ydes an d prim ary am in es.
Im in es 1a–1f are kn own com poun ds12 an d spectral an d ph ysical data for data for 1g are
given below. Ligan ds 5–7 were prepared by stan dard m eth ods from th e com m ercially avail-
able (1R,2R)-cycloh exan e-1,2-diam in e. (R)-Meth yl p-tolyl sulfoxide an d its en an tiom er were
purch ased from Aldrich . Tetrah ydrofuran (THF) was distilled un der n itrogen from Na-
ben zoph en on e im m ediately before use. Diisopropylam in e was dried over calcium h ydride
an d distilled un der n itrogen . All reaction s were carried out un der n itrogen .
N-(2-Meth oxyph en yl)pivalim in e (1g)
Pivaldeh yde (1.4 m l, 14.9 m m ol), o-an isidin e (1.5 m l, 13.5 m m ol) an d a catalytic am oun t of
p-toluen esulfon ic acid were dissolved in ben zen e (50 m l) an d h eated to reflux overn igh t,
usin g a Dean –Stark apparatus. Th e m ixture was con cen trated by rotary evaporation an d th e
crude product distilled at reduced pressure to yield th e product as a colorless oil (b.p. 70–
75 °C at 3.5 m m Hg) wh ich was pure accordin g to TLC an d HPLC. Yield 2.1 g (81%); RF 0.77
(EtOAc/h exan e 1:1). HRMS, m/z for C12H17NO calculated: [M+] 191.2693; foun d: 191.2690.
1H NMR: 1.20 s, 9 H; 3.81 s, 3 H; 6.82 m , 1 H; 6.90 m , 2 H; 7.11 m , 1 H; 7.65 s, 1 H.
13C NMR: 26.9, 37.2, 56.1, 111.9, 120.7, 121.1, 125.8, 142.5, 152.0, 174.3.
Gen eral Procedure for th e Addition of α-Lith iated Sulfoxides to Im in es
Diisopropylam in e (41 µl, 0.36 m m ol) was dissolved in THF (0.5 m l) an d cooled with stirrin g
to –78 °C. A solution of butyllith ium (1.6 M in h exan e, 0.225 m l, 0.36 m m ol) was added an d
th e resultin g solution was stirred at –78 °C for 30 m in . A solution of (R)-m eth yl p-tolyl
sulfoxide (2; 46 m g, 0.3 m m ol) in THF (0.5 m l) was added an d th e m ixture was stirred
–78 °C for 30 m in . A precooled (–78 °C) solution of an im in e 1 (0.3 m m ol) in THF (0.5 m l)
was added via can n ula an d th e reaction m ixture was stirred at –78 °C for 10 m in before ad-
dition of aqueous Na2EDTA buffer solution (0.5 M, 1 m l). Th e reaction m ixture was allowed
to warm to room tem perature an d was extracted with dich lorom eth an e (3 × 2 m l). Th e com -
bin ed organ ic ph ases were dried over an h ydrous m agn esium sulfate an d con cen trated to
afford th e crude product 3 wh ich was an alysed by ch iral HPLC. Pure sam ples of sin gle
diastereom ers (on e spot on TLC) were obtain ed by flash ch rom atograph y on dem etalated
silica gel, elutin g with m ixtures of eth yl acetate an d h exan e. On ly th e data for th e m ajor
isom ers are given below. Th e diastereom ers of com poun d 3f (pale yellow oil, 1:1 m ixture of
isom ers) could n ot be separated by flash ch rom atograph y an d th e NMR spectra were com -
plex, due to overlappin g sign als. Th ese data are n ot in cluded h ere.
Data for Com poun ds Isolated as Sin gle Diastereom ers
2-(Anilino)-2-phenylethyl p-tolyl sulfoxide (3a). Accordin g to th e gen eral procedure, reaction
of im in e 1a (54.4 m g) an d sulfoxide 2 (46.3 m g) gave com poun d 3a (70.3 m g, 70%). Spec-
tral an d ph ysical data were in agreem en t with literature5 values.
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Pedersen et al.:
2-(2-Methoxyanilino)-2-phenylethyl p-tolyl sulfoxide (3b). Accordin g to th e gen eral proce-
dure, reaction of im in e 1b (63.4 m g) an d sulfoxide 2 (46.3 m g) gave com poun d 3b (63.5
m g, 58%); m .p. 112–114 °C; [α]D +157 (c 0.17, CHCl3); RF 0.50 (EtOAc/h exan e 1:1). HRMS,
m/z for C22H23NO2S calculated: [M+] 365.1450; foun d: 365.1447. 1H NMR: 2.40 s, 3 H;
3.00 dd, 1 H, J = 13.4, 9.8; 3.20 dd, 1 H, J = 13.4, 3.4; 3.80 s, 3 H; 4.9 m , 1 H; 5.70 br s, 1 H;
6.51 m , 2 H; 6.73 m , 2 H; 6.80 m , 2 H; 7.33 m , 5 H; 7.61 d, 2 H, J = 8. 13C NMR: 21.6, 53.8,
55.9, 65.8, 109.8, 112.5, 117.7, 121.3, 124.2, 126.5, 127.8, 129.1, 130.2, 135.8, 140.8, 141.3,
141.8, 145.5.
2-Phenyl-2-[4-(trifluoromethyl)anilino]ethyl p-tolyl sulfoxide (3c). Accordin g to th e gen eral
procedure, reaction of im in e 1c (63.4 m g) an d sulfoxide 2 (46.3 m g) gave com poun d 3c
(72.5 m g, 60%); m .p. 191–193 °C; [α]D +181 (c 0.45, CHCl3); RF 0.69 (EtOAc). HRMS, m/z for
C
22H20F3NOS calculated: [M+] 403.4007; foun d: 403.4009. 1H NMR: 2.40 s, 3 H; 3.20 m , 2 H;
4.80 m , 1 H; 5.91 br s, 1 H; 6.52 d, 2 H, J = 8; 7.32 m , 9 H; 7.50 d, 2 H, J = 8. 13C NMR:
21.6, 55.2, 63.1, 112.9, 113.5, 121.1, 123.9, 124.1, 124.2, 126.2, 128.2, 129.1, 130.1, 132.1,
140.5.
2-Anilino-2-[4-(methoxyphenyl)]ethyl p-tolyl sulfoxide (3d ). Accordin g to th e gen eral procedu-
re, reaction of im in e 1d (72.4 m g) an d sulfoxide 2 (46.3 m g) gave com poun d 3d (56.9 m g,
52%). Spectral an d ph ysical data were in agreem en t with literature5 values.
2-Anilino-2-[4-(trifluoromethyl)phenyl]ethyl p-tolyl sulfoxide (3e). Accordin g to th e gen eral
procedure, reaction of im in e 1e (63.4 m g) an d sulfoxide 2 (46.3 m g) gave com poun d 3e
(65.2 m g, 54%); m .p. 188-190 °C; [α]D +142 (c 0.30, CHCl3); RF 0.64 (EtOAc). HRMS, m/z for
C
22H20F3NOS calculated: [M+] 403.4007; foun d: 403.4005. 1H NMR: 2.40 s, 3 H; 3.10 m , 2 H;
4.80 m , 1 H; 5.41 br s, 1 H; 6.50 d, 2 H, J = 8; 6.70 m , 1 H; 7.00 m , 2 H; 7.32 d, 2 H, J = 8;
7.51 m , 4 H; 7.60 d, 2 H, J = 8. 13C NMR: 21.6, 54.5, 63.8, 114.1, 114.2, 118.5, 121.1, 123.7,
124.2, 125.91, 125.96, 126.7, 129.1, 129.4, 135.8, 144.5.
2-tert-Butyl-2-(2-methoxyanilino)ethyl p-tolyl sulfoxide (3g). Accordin g to th e gen eral proce-
dure, reaction of im in e 1g (63.4 m g) an d sulfoxide 2 (46.3 m g) gave com poun d 3g (62.1 m g,
60%); m .p. 131–132 °C; [α]D +130 (c 0.15, CHCl3); RF 0.54 (EtOAc/h exan e 1:1). HRMS, m/z
for C20H27NO2S calculated: [M+] 345.1763; foun d: 345.1758. 1H NMR: 0.90 s, 9 H; 2.40 s,
3 H; 2.55 dd, 1 H, J = 12, 11; 2.95 dd, 1 H, J = 12, 1; 3.42 m , 1 H; 3.80 s, 3 H; 5.42 br s, 1 H;
6.55 m , 1 H; 6.65 m 1 H; 6.75 m , 1 H; 6.95 m , 1 H; 7.22 d, 2 H, J = 8; 7.43 d, 2 H, J = 8.
13C NMR: 21.3, 26.8, 36.4, 55.5, 57.5, 64.0, 109.9, 112.0, 114.1, 116.7, 121.9, 124.2, 130.1,
138.97, 142.3, 146.9.
X-Ray Crystallograph y
Pale yellow crystals of th e com poun d 3g were cooled to 120 K usin g a Cryostream n itrogen
gas cooler system . Th e data were collected on a Siem en s SMART platform diffractom eter
with a CCD area-sen sitive detector. Crystal data: C20H27NO2S, M = 345.49, orth orh om bic,
space group P212121, a = 6.4435(6) Å, b = 7.3607(7) Å, c = 38.800(3) Å, V = 1840.2(3) Å3, Z =
4. Th e structures were solved by direct m eth ods an d refin ed by full-m atrix least-squares
again st F2 of all data. Th e n on -h ydrogen atom s were refin ed an isotropically. Th e h ydrogen
atom s were at calculated position s usin g a ridin g m odel with C–H = 0.95–0.99 Å an d fixed
th erm al param eters [U(H) = 1.2U for attach ed atom ]. Th e Flack x param eter13 is –0.13(15),
in dicatin g th at th is is th e correct absolute con figuration . Program s used for data collection ,
data reduction an d absorption were SMART, SAINT, an d SADABS 14,15. Th e SHELXTL version
16
17
5.03
program was used to solve th e structures an d for m olecular graph ics. PLATON
was
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

Diastereoselective Addition of α-Metalated Sulfoxides to Imines
897
used for m olecular geom etry calculation s. Th e fin al residuals were R1(obs) = 0.0697, wR2(all) =
0.1525 an d GOF = 1.048.
Addition of α-Metalated Sulfoxides in th e Presen ce of Ch iral Ligan ds: Li+ as Cation
A solution of (R)-m eth yl p-tolyl sulfoxide (2; 46 m g, 0.3 m m ol) in THF (0.5 m l) was cooled
with stirrin g to –78 °C, a solution of butyllith ium (1.6 M in h exan e, 225 µl, 0.36 m m ol) was
added an d th e resultin g solution was stirred at –78 °C for 30 m in . In an oth er flask, a solu-
tion of th e ligan d 5, en t-5 or 6 (0.3 m m ol) in THF (0.5 m l) was cooled to –78 °C before
addition of solution of butyllith ium (1.6 M in h exan e, 388 µl, 0.62 m m ol) an d th e resultin g
solution was stirred at –78 °C for 30 m in . Th e con ten ts of th e two flasks were m ixed via can -
n ula, before addition of a precooled (–78 °C) solution of th e im in e 1a (0.3 m m ol) in THF
(0.5 m l). Th e solution was stirred at –78 °C for 30 m in before bein g quen ch ed an d worked
up as described earlier. Th e crude m ixture was an alyzed by ch iral HPLC as previously de-
scribed. Isolation after ch rom atograph y afforded 52 m g (52%, d.r. 91:9), 49.2 m g (49%,
d.r. 73:27) an d 50.2 m g (50%, d.r. 99:1) of com poun d 3a, respectively, wh ich sh owed spec-
tral an d ph ysical data in agreem en t with an auth en tic sam ple, prepared as described earlier.
Addition of α-Metalated Sulfoxides in th e Presen ce of Ch iral Ligan ds: Zn 2+ as Cation
(R)-Meth yl p-tolyl sulfoxide (2; 46 m g, 0.3 m m ol) was lith iated with butyllith ium as de-
scribed above. In an oth er flask, a solution of ligan d 7 (0.3 m m ol) in THF (0.5 m l) was
cooled to –78 °C before addition of a solution of dieth ylzin c (1.0 M in h exan e, 310 µl,
0.31 m m ol) an d th e resultin g solution was stirred at –78 °C for 30 m in . Th e con ten ts of th e
two flasks were m ixed, before addition of a precooled (–78 °C) solution of th e im in e 1a
(0.3 m m ol) in THF (0.5 m l). Th e solution was stirred at –78 °C for 30 m in before bein g
quen ch ed, worked up, an d an alyzed as described earlier to afford 72.3 m g (72%, d.r. 93:7) of
com poun d 3a.
Addition of α-Metalated Sulfoxides in th e Presen ce of Ch iral Ligan ds: Al3+ as Cation
A solution of (R)-m eth yl p-tolyl sulfoxide (2; 46 m g, 0.3 m m ol) an d ligan d 7 (127 m g,
0.3 m m ol) in THF (0.5 m l) was cooled with stirrin g to –78 °C before addition of
trim eth ylalum in um (2 M in h exan e, 150 µl, 0.3 m m ol). Th e solution was stirred at –78 °C
for 30 m in before addition of a precooled (–78 °C) solution of th e im in e 1a (0.3 m m ol) in
THF (0.5 m l). Th e resultan t solution was th en stirred at –78 °C for 30 m in before bein g
quen ch ed, worked up, an d an alyzed as described earlier to afford 70.2 m g (70%, d.r. 95:5)
of com poun d 3a.
We thank the Danish Research Agency and the Carlsberg Foundation for financial support.
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