Diastereoselective reduction of enantiopure N-p-toluenesulfinyl ketimines derived from pyridyl ketones

Article abstract of DOI:10.1016/j.tet.2005.10.011

DIBAL reduction of enantiopure N-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones bearing an additional substituent on the 6-position of the pyridine ring afforded the related N-p-toluenesulfinyl amines with high yields and diastereoselectivitie

Full text of DOI:10.1016/j.tet.2005.10.011

Tetrahedron 62 (2006) 619–626
Diastereoselective reduction of enantiopure N-p-toluenesulfinyl
ketimines derived from pyridyl ketones
*
Giorgio Chelucci, Salvatore Baldino and Simona Chessa
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 5 August 2005; revised 23 September 2005; accepted 6 October 2005
Available online 8 November 2005
Abstract—DIBAL reduction of enantiopure N-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones bearing an additional substituent
on the 6-position of the pyridine ring afforded the related N-p-toluenesulfinyl amines with high yields and diastereoselectivities. The results
of a number experiments exploring the conversion of a optically active 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-2-yl)methylamine
in a number of more complex pyridine derivatives with maintenance of the toluenesulfinyl group N-protecting group is also reported.
q 2005 Published by Elsevier Ltd.
1. Introduction
chiral N-p-toluenesulfinyl ketimines 5 derived from
2-pyridyl ketones 3 bearing an additional substituent on
the 6-position of the pyridine ring (Scheme 2). The results of
some experiments exploring the conversion of one optically
active 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-
2-yl)methylamine in a number of pyridylmethylamine
derivatives with maintenance of the toluenesulfinyl group
N-protecting group are also reported (Scheme 3).
Optically active 1-substituted-1-(pyridyl)methylamines
have attracted much academic and commercial interest,1
primarily due to their existence in naturally occurring
compounds such as tobacco alkaloids (nicotine, nornicotine,
anabatine, etc.)2 or as key fragments within potential drug
candidates.3 Moreover, they have proven utility as ligands
in metal complexes for asymmetric catalysis.4
Notwithstanding the many routes an asymmetric syntheses
of these compounds that have been developed,1 new
opportunities are yet to be explored. Accordingly, we
have recently investigated the diastereoselective reduction
of enantiopure N-p-toluenesulfinyl pyridyl ketimines with a
variety of hydride transfer reagents obtaining 1-substituted-
1-(pyridin-2-yl)methylamines with diastereomeric excesses
up to 94% (Scheme 1).5
2. Results and discussion
It has been reported that the diastereoselectivity of addition
reactions involving functionalised pyridines depends on the
position of the functional group with respect to the pyridine
nitrogen. For instance, the Michael addition of chiral
non-racemic lithium amides to tert-butyl 3-(pyridin-3-yl)-
and 3-(pyridin-4-yl)prop-2-enoates afforded the addition
product in good yields and diastereoselectivities (84%),
whereas the application of this methodology to the
analogous b-2-pyridyl system afforded very low levels of
In this paper, as part of our ongoing work in this area, we
report the results obtained in the reduction of a number of
Scheme 1.
Keywords: Pyridyl amines; N-p-Toluenesulfinyl ketimines; Nitrogen heterocycles; Diastereoselective reduction.
*
Corresponding author. Tel.: C39 (0)79 229539; fax: C39 (0)79 229559; e-mail: chelucci@uniss.it
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.10.011

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G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
stereoselectivity (6% de) unless the pyridine ring was also
substituted at the 6-position.6
The extent of the asymmetric induction was determined
1
directly by H NMR spectroscopy of the crude reaction
mixture of the diastereoisomeric sulfinyl amines. In order to
confirm unambiguously these results, all reductions were also
carried out using NaBH4 that afforded sulfinyl amines in high
yields and low selectivities, except in the case of sulfinyl
amines (SS)-6d and (SS)-6e (RZtert-Bu) that were obtained
with moderate diastereoselectivities (83:17 dr).
In order to probe the influence on the diastereoselectivity of
an additional substituent on the 6-position of the pyridine
ring in our system, the 4-methyl-N-[1-(6-methylpyridin-
2-yl)ethylidene]benzenesulfinamide (SS)-5a was prepared
from 1-(6-methylpyridin-2-yl)ethanone (3a) (Scheme 2).
Reduction of 5a at K78 8C with DIBAL, which was on
average the best performing hydride transfer reagent among
those evaluated in the reduction of 2a–f, afforded a 2:98
mixture of diastereomers (SS,R)-6a:(SS,S)-6a with an
improved facial selectivity with respect to the unsubstituted
system 2a ((SS,R):(SS,S)Z16:84). Encouraged by this result,
we investigated the diastereoselective reduction of a set of
related pyridyl systems (SS)-5a–h with varying steric and
electronic demand about the pyridine and imine moieties
(Scheme 2).
Table 1. Reduction of (SS)-5a–h with DIBAL (Scheme 2)
Compound
Substituents
Ratioa (SS,R)-6: Yieldb (%)
(SS,S)-6
R
R1
5a
5b
5c
5d
5e
5f
Me
Me
Me
t-Bu
t-Bu
Ph
Me
Br
Ph
Br
Ph
Me
Br
2:98
!2:O98
28:72
98:2
O99:1
92:8
82
92
87
95
95
85
76
86
5g
5h
Ph
Ph
88:12
93:7
Ph
N-p-Toluenesulfinyl ketimines 5a–h were obtained by
condensation7 of commercially available (S)-(C)-N-
p-toluenesulfinamide 4 (1 equivalent) with a series of
2-pyridyl ketones 3a–h (1.1 equiv) with different steric
and/or electronic demands on the carbonyl and the pyridine
ring. The reactions were performed employing Ti(OEt)4
(2 equivalents) in CH2Cl2 at 40 8C for 2a (47%), 2b (75%)
and 2c (78%) or THF at 70 8C for 2d (41%), 2e (49%),
2f (75%), 2g (86%) and 2h (85%). All imines were obtained
a Ratio of the crude reaction mixture determined by 1H NMR spectroscopy.
b Isolated yields.
The substitution of the 2-pyridyl system resulted in a
significant increase of diastereoselectivity upon reduction
compared with the related 6-unsubstituted pyridine
(Scheme 1). The only exception was the sulfinyl imine
(SS)-5c (RZMe, R1ZPh) that afforded a lower diastereo-
selectivityincomparisonwithitsunsubstitutedcounterpart2a.
1
as a single stereoisomer as determined by the H NMR
spectra (for the related configurations vide infra).
The configuration of the new stereocentre in the reduction
products was tentatively assigned by comparison of 1H NMR
chemical shifts of the benzylic protons of 6 with those of
the related known unsubstituted pyridines 2.5 Moreover, this
Sulfinyl imines (SS)-5a–h were reduced with DIBAL at
K78 8Ctogivethecorrespondingsulfinylamines(SS,R)-6a–h
and (SS,S)-6a–h. The obtained results are reported in Table 1.
Scheme 2.

G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
621
assignment was corroborated by converting the bromo-
pyridine 6d both into the sulfinyl amines 6e and 2c5 (vide
infra).
large group on the imine are in pseudo-equatorial positions
(Fig. 1). It has been assumed that the imine exists in the
configuration in which the sulfoxide moiety is trans to the
larger group on the imine moiety. According to this model,
the reduction of imines 5d and 5e (RZt-Bu) affords the
predominant diastereomers (SS,R)-6d and (SS,R)-6e through
the transition states 8 (RZt-Bu) whereas the reduction of
imines 6a–c (RZMe) gives (SS,S)-6a–c through the
transition states 9 (RZMe). In the case of the reduction of
imines 6f–h (RZPh) the situation appears less clear and to
explain the stereochemical result using this model it must be
supposed that in these imines the phenyl group assumes a
configuration trans to the sulfoxide moiety rather than the
pyridyl group. Accordingly, also in the reduction of the
analogous unsubstituted pyridyl imine 1d the prevailing
diastereomer 2d has the same (SS,R)-configuration, although
the diastereoselectivty was much lower.
It should be noted that independently from the 6-substituent
on the pyridine the reduction of the sulfenyl imines 6a–c
(RZMe) gave the opposite prevailing diastereomer with
respect to the other imines 6d–h (RZt-Bu or Ph). Moreover,
the very high diastereoselectivity of the imine reduction
process achieved with DIBAL compared to the much lower
selectivity with NaBH4 suggests that the coordination with
the imines 6 is essential. According to models proposed for
related systems,8 the reduction would take place through the
chelated species illustrated in Figure 1.
The increase in facial selectivity observed upon reduction
relative to the unsubstituted system 2a, appears to indicate
that the group at the 6-position of the pyridine ring serves to
sterically impede the competing coordination of the pyridyl
nitrogen to the aluminium. This reduced coordination to
the pyridyl nitrogen would then minimize the disruption of
the normal chelation-controlled transition state,8 thus
disfavouring the competing nonstereoselective pathway
for the reduction.
The finding that 1-substituted N-toluenesulfinyl 1-(6-
bromopyridin-2-yl)methylamines such as 5b and 5d can be
obtained with high diastereoselectivity and the consideration
that the N-toluenesulfinyl group can be considered as a
N-protecting group,9 should allow for further elaboration of
the 6-bromo substituent in order to build up more complex
pyridine derivatives. With the aim of demonstrating this
opportunity a number of reactions have been carried out
using (SS,R)-6d as a model substrate (Scheme 3).
Figure 1.
The coordination of the aluminium with the sulfoxide
oxygen would be expected to form a chelation controlled
chair-like transition state [for instance 8 (RZt-Bu) and
9 (RZMe)] in which the groups on the sulfur atom and the
Scheme 3.

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G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
Since the Suzuki cross-coupling reaction between a pyridyl
halide or triflate with boronic acids or esters offers the
opportunity to introduce a variety of substituents on a
pyridine ring,10 the coupling reaction of the bromopyridine
(SS,R)-6d (96% d.e.) with the phenylboronic acid was
initially examined. Under standard Suzuki-type conditions
(Pd(PPh3)4, PhB(OH)2 in MeOH, aqueous Na2CO3, toluene,
80–85 8C, 14 h) the phenylpyridine (SS,R)-6e was obtained
in 85% yield and as a 98:2 mixture of diastereomers,
demonstrating the compatibility of the starting point with
the conditions of the Suzuki cross-coupling reaction
(Scheme 3).
when the pressure was increased to 3 atm (Parr apparatus)
only the amine (R)-1-(6-bromopyridin-2-yl)-2,2-dimethyl-
propan-1-amine derived from hydrogenolysis of the N–S
bond was obtained in very low yield. To overcome this
drawback the metal-catalysed reductive debromination was
examined. Taking into account the successfully palladium-
catalysed reductive hydrodebromination of highly
brominated benzenes, we sough to adapt this procedure to
our specific needs.14 Gratifyingly, stirring at room tempera-
ture (SS,R)-6d with NaBH4 in the presence of a Pd-catalyst
(Pd(OAc)2, PPh3, TMEDA, THF, 3 h) the pyridine 2c was
obtained in excellent yield (O90%). The diastereomeric
excess of the obtained 2a was estimated to be 96%
indicating no racemization occurred during the reaction.
The metal-catalysed amination reaction has proved to be a
valuable strategy for the selective introduction of an amino
group on a pyridine ring. As a prototype of amination
reaction, the Pd-catalysed reaction of (SS,R)-6d with
morpholine (Pd2(dba)3, dppp, NaOBut, toluene, 70 8C,
9 h) was checked.11 The reaction proceeded smoothly
affording the reaction product (SS,R)-11 in high yield
(93%) and with the same diastereomeric purity of the
starting material (Scheme 3).
Interestingly, the high diastereoselectivity obtained in the
reduction of 1-substituted N-toluenesulfinyl 1-(6-bromo-
pyridin-2-yl)methylamines and the possibility to remove the
bromine with high yield and maintenance of the integrity of
the stereocentres can make up a strategy to obtain
monosubstituted pyridyl amines with high diastereomeric
excess. This opportunity is exemplified in the Scheme 4
where the methyl derivative (SS,S)-2a can be obtained in
68% de through reduction of imine (SS,S)-1a, prepared from
2-bromopyridine, or in 96% de by hydrodebromination of
the amine (SS,S)-6a obtained in the usual way from the 2,6-
dibromopyridine.
The preparation of the C2-symmetric 2,20-bipyridine 12 was
pursued by nickel-catalysed homo-coupling reaction of
bromopyridine (SS,R)-6d (Scheme 4). The bipyridine 12
was obtained in 33% yield according to Tiecco’s
procedure12 that entails the in situ formation of a
Ni(0)-catalyst (NiCl2–6H2O, Zn, PPh3, DMF, 60 8C, 1 h)
followed by addition of 6d (70 8C, 8 h). Interestingly, we
noted no difference in the yield when the reaction was
performed mixing all components at once and then heating
the mixture for 8 h at 70 8C.
In conclusion, we have demonstrated that the DIBAL
reduction of enantiopure N-p-toluenesulfinyl ketimines
derived from 2-pyridyl ketones bearing a substituted
on the 6-position of the pyridine ring affords the related
N-p-toluenesulfinyl amines with a significant increase of the
diastereoselectivity compared to the unsubstituted counter-
parts. This approach can also be pursued to obtain
monosubstituted pyridyl amines with high diastereomeric
excess. Finally, we presented a variety of examples in which
a 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-
2-yl)methylamine is converted in more complex pyridine
derivatives with maintenance of the toluenesulfinyl group
N-protecting group. Further studies on this subject are
currently in progress.
Hoping to increase the yield, a preformed Ni(0)-catalyst was
also employed (Ni(CO)2(PPh3)2, DMF, 70 8C, 10 h),13 but
all attempts failed.
Finally, substitution of the bromine with hydrogen was
obtained. Initial attempts of carrying out the hydro-
dehalogenation by hydrogenolysis catalysed by palladium
metal on carbon or palladium hydroxide (H2, MeOH,
NaOAc, rt, 48 h) at atmospheric pressure failed, whereas
Scheme 4.

G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
623
3. Experimental
3.1. General methods
petroleum ether/ethyl acetate Z7/3; 0.126 g (75%); yellow
solid; mp 54–55 8C; [a]2D5 C35.2 (c 0.55, CHCl3); 1H NMR:
d 8.13 (d, 1H, JZ7.5 Hz), 7.72 (d, 2H, JZ8.1 Hz),
6.63–7.53 (m, 2H), 7.33 (d, 2H, JZ8.1 Hz), 2.82 (s, 3H),
2.41 (s, 3H). 13C-NMR: d 173.1, 155.5, 142.7, 142.2, 141.0,
138.7, 130.3, 129.9, 125.0, 121.0, 21.4, 19.0. Anal. Calcd
for C14H13BrN2OS: C, 49.86; H, 3.89; N, 8.31. Found: C,
49.66; H, 3.67; N, 8.12.
Melting points were determined on a Bu¨chi 510 capillary
apparatus and are uncorrected. The NMR spectra were
obtained with a Varian VXR-300 spectrometer at 300 for
1H and 75.4 MHz for 13C. Chemical shifts are reported in
ppm downfield from internal Me4Si in CDCl3. Optical
rotations were measured with a Perkin-Elmer 241 polari-
meter in a 1 dm tube. Elemental analyses were performed
on a Perkin-Elmer 240 B analyser. Ethyl acetate and
petroleum ether were distilled before use. THF was distilled
from sodium-benzophenone ketyl and CH2Cl2 from P2O5.
Both solvents were degassed thoroughly with dry nitrogen
directly before use.
3.2.3. (SS)-N-(1-(6-Phenylpyridin-2-yl)ethylidene)-
4-methylbenzenesulfinamide (5c). Reaction solvent:
CH2Cl2; reaction time: 48 h; chromatographic eluent:
petroleum ether/ethyl acetateZ1/1; 0.130 g (78%); yellow
1
oil: [a]2D5 K32.8 (c 0.66, CHCl3); H NMR: d 8.13 (d, 1H,
JZ6.0 Hz), 8.04 (d, 2H, JZ8.1 Hz), 7.84–7.67 (m, 4H),
7.47–7.40 (m, 3H), 7.32 (d, 2H, JZ8.1 Hz), 2.96 (s, 3H),
2.40 (s, 3H). 13C-NMR: d 175.1, 156.0, 154.3, 143.0, 142.0,
138.4, 137.3, 129.8, 129.3, 128.7, 126.7, 125.1, 122.1,
120.5, 21.4, 19.1. Anal. Calcd for C20H18N2OS: C, 71.83; H,
5.42; N, 8.38. Found: C, 71.98; H, 5.44; N, 8.39.
(S)-(C)-N-p-Toluenesulfinamide was purchased from
Aldrich. 1-(6-Bromopyridin-2-yl)ethanone (3b),15 1-(6-
phenylpyridin-2-yl)ethanone (3c),16 1-(6-bromopyridin-
2-yl)-2,2-dimethylpropan-1-one (3d),15 1-(6-phenylpyridin-
2-yl)-2,2-dimethylpropan-1-one (3e),15 (6-phenylpyridin-
2-yl)phenylmethanone (3h)17 were prepared according to
reported procedures. 1-(6-Methylpyridin-2-yl)ethanone (3a)
and (6-methylpyridin-2-yl)phenylmethanone (3f) were
obtained by addition of the Grignard reagent prepared
from bromobenzene and methyliodide, respectively to
2-cyano-6-methylpyridine following the procedure reported
by Case et al.16 (6-Bromopyridin-2-yl)phenylmethanone
(3g) was prepared by addition of the 2-lithio-6-bromo-
pyridine to benzonitrile according to Bolm et al.15
3.2.4. (SS)-N-(1-(6-Bromopyridin-2-yl)-2,2-dimethyl-
propylidene)-4-methylbenzenesulfinamide (5d). Reaction
solvent: THF; reaction time: 36 h; chromatographic
eluent: petroleum ether/ethyl acetateZ8/2 then 1/1;
0.077 g (41%); yellow solid; mp 111–112 8C, [a]D25
K73.0 (c 0.19, CHCl3). 1H NMR: 7.67–7.59 (m, 3H),
7.52 (d, 1H, JZ9.0 Hz), 7.31 (d, 2H, JZ8.1 Hz), 7.18 (d,
1H, JZ7.5 Hz), 2.41 (s, 3H), 1.22 (s, 9H). 13C-NMR: d
183.7, 156.1, 142.6, 141.9, 141.5, 138.1, 129.7, 128.1,
125.3, 120.9, 41.7, 27.9, 21.5. Anal. Calcd for C17H19-
BrN2OS: C, 53.83; H, 5.05; N, 7.39. Found: C, 53.85; H,
5.03; N, 7.41.
3.2. General procedure for the preparation
of N-p-toluenesulfinyl ketimines 5a–h
3.2.5. (SS)-N-(1-(6-phenylpyridin-2-yl)-2,2-dimethyl-
propylidene)-4-methylbenzenesulfinamide (5e). Reaction
solvent: THF; reaction time 48 h; chromatographic eluent:
petroleum ether/ethyl acetateZ1/1; 92.1 mg (49%);
yellow solid; mp 110–111 8C; [a]2D5 K78.5 (c 0.11,
CHCl3). 1H NMR: d 7.99 (dd, 2H, JZ6.9, 1.5 Hz),
7.88–7.76 (m, 2H), 7.57 (d, 2H, JZ8.4 Hz), 7.52–7.42 (m,
3H), 7.21 (d, 2H, JZ8.4 Hz), 7.13 (dd, 1H, JZ6.9,
1.5 Hz), 2.37 (s, 3H), 1.27 (s, 9H). 13C-NMR: d 148.4,
125.2, 124.5, 115.2, 114.2, 111.5, 110.4, 104.9, 104.3,
102.8, 102.5, 101.7, 97.7, 97.4, 37.9, 27.5, 22.5. Anal.
Calcd for C23H24N2OS: C, 73.37; H, 6.42; N, 7.44.
Found: C, 73.54; H, 6.45; N, 7.43.
A solution of 2-pyridyl ketone 3 (0.55 mmol), (S)-(C)-N-
p-toluenesulfinamide (78.0 mg, 0.5 mmol) and Ti(OEt)4
(0.228 g, 1.0 mmol) in anhydrous CH2Cl2 or THF (2 mL)
was heated at 40 or 70 8C, respectively, for the proper time.
After cooling the solvent was removed under vacuum and
the residue was taken up in ethyl acetate (10 mL). This
solution was vigorously stirred while a saturated solution of
brine (2 mL) was slowly added. After 15 min the mixture
was filtered through a plug of Celite that was washed with
ethyl acetate. The organic phase was separated and dried
(Na2SO4). The solvent was evaporated and the residue was
purified by flash chromatography.
3.2.1. (SS)-N-(1-(6-Methylpyridin-2-yl)ethylidene)-
4-methylbenzenesulfinamide (5a). Reaction solvent:
CH2Cl2; reaction time: 60 h; chromatographic eluent:
petroleum ether/ethyl acetateZ1/1; 0.062 g (47%); yellow
oil; [a]2D5 C84.5 (c 0.21, CHCl3). 1H NMR: d 7.98 (d, 1H, JZ
7.8 Hz), 7.73 (d, 2H, JZ8.4 Hz), 7.59 (t, 1H, JZ7.8 Hz),
7.31 (d, 2H, JZ8.4 Hz), 7.19 (d, 1H, JZ7.8 Hz), 2.84
(s, 3H), 2.54 (s, 3H), 2.38 (s, 3H). 13C NMR: d 175.2, 157.4,
153.9, 142.9, 141.8, 136.4, 129.6, 125.2, 124.9, 119.1, 24.2,
21.2, 19.0. Anal. Calcd for C15H16N2OS: C, 66.15; H, 5.92;
N, 10.29. Found: C, 66.36; H, 5.90; N, 10.31.
3.2.6. (SS)-N-((6-Methylpyridin-2-yl)phenylmethylene)-
4-methylbenzenesulfinamide (5f). Reaction solvent:
THF; reaction time: 48 h; chromatographic eluent:
petroleum ether/ethyl acetateZ1/1; 0.125 g (75%); oil;
1
[a]2D5 C25.6 (c 0.66, CHCl3); H NMR: d 7.92 (d, 2H,
JZ6.6 Hz), 7.76–7.62 (m, 3H), 7.44 (t, 1H, JZ8.1 Hz),
7.38–7.21 (m, 5H), 7.12 (d, 1H, JZ6.6 Hz), 2.60 (s, 3H),
2.34 (s, 3H). 13C-NMR: d 172.6, 158.0, 152.3, 142.1,
141.2, 136.2, 136.0, 131.8, 129.6, 129.1, 127.9, 125.3,
124.2, 121.2, 23.9, 21.0. Anal. Calcd for C20H18N2OS: C,
71.83; H, 5.42; N, 8.38. Found: C, 71.62; H, 5.45;
N, 8.36.
3.2.2. (SS)-N-(1-(6-Bromopyridin-2-yl)ethylidene)-
4-methylbenzenesulfinamide (5b). Reaction solvent:
CH2Cl2; reaction time 12 h; chromatographic eluent:
3.2.7. (SS)-N-((6-Bromopyridin-2-yl)phenylmethylene)-
4-methylbenzenesulfinamide (5g). Reaction solvent:

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G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
THF; reaction time: 48 h; chromatographic eluent: petroleum
ether: ethyl acetateZ7/3; 0.172 g (86%); yellow solid
mp 44–45 8C; [a]D25 C37.0 (c 0.71, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.94 (s broad, 2H), 7.70–7.52 (m, 4H),
7.46 (t, 1H, JZ7.5 Hz), 7.45–7.26 (m, 5H), 7.35 (s, 3H). 13C
NMR: d 169.83, 153.77, 142.74, 141.75, 141.31, 138.52,
135.51, 132.15, 129.39, 129.31, 128.13, 125.46, 123.09,
60.01, 21.21. Anal. Calcd for C19H15BrN2OS: C, 57.15; H,
3.79; N, 7.02. Found: C, 57.35; H, 3.81; N, 7.04.
4.97 (d, 1H, JZ7.2 Hz, major isomer), 4.54 (q, 1H, JZ
7.2 Hz, major isomer), 4.49 (q, 1H, JZ7.2 Hz, minor
isomer), 2.37 (s, 3H, major isomer), 2.43 (s, 3H, minor
isomer), 1.57 (d, 3H, JZ7.2 Hz, major isomer), 1.31 (d,
3H, JZ7.2 Hz, minor isomer). 13C-NMR: d 163.7, 141.6,
141.2, 141.2, 138.8, 129.3, 126.4, 125.8, 119.8, 52.6, 24.1,
21.3. Anal. Calcd for C14H15BrN2OS: C, 49.57; H, 4.46;
N, 8.26. Found: C, 49.68; H, 4.44; N, 8.24.
3.3.3. (SS,R)- and (SS,S)-N-(1-(6-Phenylpyridin-2-yl)-
ethyl)-4-methylbenzenesulfinamide (6c). This compound
was obtained as a mixture of diastereomers ((SS,R)-
6c:(SS,S)-6cZ28:72); 58.5 mg (87%); oil; 1H NMR:
d 7.96 (d, 2H, JZ8.1 Hz, major isomer), 7.92 (d, 2H, JZ
8.1 Hz, minor isomer), 7.66–7.50 (m, 4H, major isomer),
7.50–7.35 (m, 3H, major isomer), 7.22 (d, 2H, JZ8.1 Hz,
major isomer), 7.02 (d, 2H, JZ8.1 Hz, minor isomer), 6.97
(d, 1H, JZ7.5 Hz, major isomer), 6.92 (d, 1H, JZ7.5 Hz,
minor isomer), 6.36 (d, 1H, JZ7.8 Hz, minor isomer), 5.38
(d, 1H, JZ6.6 Hz, major isomer), 4.61 (q, 1H, JZ6.6 Hz,
major isomer), 4.54 (q, 1H, JZ6.6 Hz, minor isomer), 2.36
(s, 3H, major isomer), 2.24 (s, 3H, minor isomer), 1.49
(d, 3H, JZ6.6 Hz, minor isomer), 1.66 (d, 3H, JZ6.6 Hz,
major isomer). Anal. Calcd for C20H20N2OS: C, 71.40;
H, 5.99; N, 8.33. Found: C, 71.61; H, 5.98; N, 8.31.
3.2.8. (SS)-N-((6-Phenylpyridin-2-yl)phenylmethylene)-
4-methylbenzenesulfinamide (5h). Reaction solvent:
THF; reaction time: 48 h; chromatographic eluent:
petroleum ether/ethyl acetateZ1/1; 0.168 g (85%); yellow
solid; mp 102–104 8C; [a]2D5 C43.1 (c 0.60, CHCl3);
1H NMR: d 7.98–7.52 (m, 8H), 7.51 (t, 1H, JZ7.5 Hz),
7.48–7.36 (m, 5H), 7.29–7.21 (m, 3H), 2.38 (s, 3H).
13C-NMR: d 173.0, 157.2, 153.6, 143.2, 141.6, 138.0,
137.1, 136.3, 132.2, 129.9, 129.5, 129.4, 128.6, 128.2,
127.1, 125.7, 122.4, 121.4, 21.3. Anal. Calcd for
C25H20N2OS: C, 75.73; H, 5.08; N, 7.07. Found: C,
75.55; H, 5.10; N, 7.06.
3.3. General procedure for the reduction of imines 5a–h
Diisobutylaluminium hydride (0.45 mL of a 1.0 M solution
in THF, 0.45 mmol) was added to a solution of 5
(0.20 mmol) in THF (2 mL) at K78 8C. After 6 h MeOH
(1 mL) was added at K78 8C to the mixture, which was
then warmed at room temperature and evaporated under
reduced pressure. Aqueous 2 M NaOH (2 mL) was added
to the residue and the crude mixture was extracted with
ethyl acetate. The organic phase was separated, dried
(Na2SO4), the solvent was evaporated and the residue was
purified by flash chromatography (petroleum ether/ethyl
acetateZ7/3 to ethyl acetate)
3.3.4. (SS,R)-N-(1-(6-Bromopyridin-2-yl)-2,2-dimethyl-
propyl)-4-methylbenzenesulfinamide (6d). This com-
pound was obtained as a mixture of diastereomers
((SS,R)-6d:(SS,S)-6dZ98:2); 72.4 mg (95%); mp 91–92 8C;
[a]2D5 C258.0 (c 0.14, CHCl3); 1H NMR: d 7.56 (d, 2H, JZ
8.1 Hz), 7.46 (t, 1H, JZ7.5 Hz), 7.32 (t, 3H, JZ9.9 Hz),
7.08 (d, 1H, JZ7.5 Hz), 5.64 (d, 1H, JZ9.6 Hz), 3.84
(d, 1H, JZ9.6 Hz), 2.42 (s, 3H), 0.70 (s, 3H). 13C-NMR:
d 162.3, 141.2, 141.2, 141.0, 138.1, 129.3, 126.3, 126.0,
122.1, 62.9, 34.9, 26.6, 21.4. Anal. Calcd for C17H21BrN2-
OS: C, 53.54; H, 5.55; N, 7.35. Found: C, 53.64; H, 5.54;
N, 7.37.
3.3.1. (SS,R)- and (SS,S)-N-(1-(6-Methylpyridin-2-yl)-
ethyl)-4-methylbenzenesulfinamide (6a). This com-
pound was obtained as a mixture of diastereomers
((SS,R)-6a:(SS,S)-6aZ2:98); 43.6 mg (82%); oil; 1H
NMR: d 7.55 (d, 2H, JZ8.1 Hz), 7.44 (t, 1H, JZ7.5 Hz),
7.23 (d, 2H, JZ8.1 Hz), 6.96 (d, 1H, JZ7.5 Hz), 6.83 (d,
1H, JZ7.5 Hz), 5.79 (d, 1H, JZ6.3 Hz, minor isomer),
5.41 (d, 1H, JZ6.6 Hz), 4.55 (q, 1H, JZ6.6 Hz), 2.48 (s,
3H), 2.38 (s, 3H), 1.58 (d, 3H, JZ6.6 Hz). 13C-NMR: d
161.0, 157.8, 141.6, 140.9, 136.7, 129.3, 125.9, 121.6,
117.5, 60.3, 53.3, 24.3, 24.2. Anal. Calcd for C15H18N2OS:
C, 65.66; H, 6.61; N, 10.21. Found: C, 65.52; H, 6.63; N,
10.25.
3.3.5. (SS,R)-N-(2,2-Dimethyl-1-(6-phenylpyridin-2-yl)-
propyl)-4-methylbenzenesulfinamide (6e). This com-
pound was obtained as a sole diastereomer; 71.8 mg
1
(95%); oil; [a]2D5 C223.7 (c 0.77, CHCl3). H NMR: d
7.99 (d, 2H, JZ8.1 Hz), 7.70–7.52 (m, 3H), 7.50–7.38 (m,
4H), 7.25 (d, 2H, JZ8.1 Hz), 7.07 (d, 1H, JZ7.5 H Hz),
6.01 (d, 1H, JZ9.3 Hz), 4.00 (d, 1H, JZ9.3 Hz), 2.38 (s,
3H), 0.75 (s, 9H). 13C-NMR: d 159.8, 155.2, 141.6, 140.7,
138.9, 136.2, 128.9, 128.5, 128.3, 126.5, 125.6, 121.5,
118.1, 63.3, 34.6, 26.5, 21.0. Anal. Calcd for C23H26N2OS:
C, 72.98; H, 6.92; N, 7.40. Found: C, 72.76; H, 6.94;
N, 7.38.
3.3.2. (SS,R)- and (SS,S)-N-(1-(6-Bromopyridin-2-yl)-
ethyl)-4-methylbenzenesulfinamide (6b). This com-
pound was obtained as a mixture of diastereomers
((SS,R)-6b:(SS,S)-6bZ98:2; 62.4 mg (92%); oil; 1H
NMR: d 7.63 (d, 2H, JZ8.1 Hz, minor isomer), 7.51 (d,
2H, JZ8.1 Hz, major isomer), 7.50 (t, 1H, JZ7.8 Hz,
minor isomer), 7.38 (t, 1H, JZ7.5 Hz, major isomer),
7.34 (t, 2H, JZ8.7 Hz, minor isomer), 7.29 (d, 1H, JZ
7.5 Hz, major isomer), 7.21 (d, 2H, JZ8.1 Hz, minor
isomer), 7.21 (d, 2H, JZ8.1 Hz, major isomer), 7.22 (d,
1H, JZ7.8 Hz, minor isomer), 6.94 (d, 1H, JZ7.5 Hz,
major isomer), 5.29 (d, 1H, JZ7.2 Hz, minor isomer),
3.3.6. (SS,R)- and (SS,S)-N-((6-Methylpyridin-2-yl)-
(phenyl)methyl)-4-methylbenzenesulfinamide (6f). This
compound was obtained as a mixture of diastereomers
1
((SS,R)-6f:(SS,S)-6fZ92:8); 57.1 mg (85%); oil; H NMR
(300 MHz, CDCl3): d 7.60 (d, 1H, JZ8.1 Hz, minor
isomer), 7.46–7.36 (m, 3H, major isomer), 7.50–7.00
(m, 6H, major isomer), 6.60 (d, 1H, JZ7.5 Hz, major
isomer), 6.93–6.86 (m, 2H, major isomer), 6.82 (d, 1H, JZ
7.5 Hz, major isomer), 6.17 (d, 1H, JZ3.6 Hz, minor
isomer), 5.67 (d, 1H, JZ3.6 Hz, minor isomer), 5.51 (d, 1H,
JZ4.8 Hz, major isomer), 2.57 (s, 3H, major isomer),

G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
625
2.46 (s, 3H, minor isomer), 2.39 (s, 3H, minor isomer), 2.30
(s, 3H, major isomer). 13C-NMR: d 158.8, 157.1, 142.8,
140.6, 140.5, 136.9, 128.9, 127.9, 127.6, 126.6, 126.2,
121.5, 119.3, 55.6, 24.4, 21.1. Anal. Calcd for C20H20N2OS:
C, 71.40; H, 5.99; N, 8.33. Found: C, 71.61; H, 5.98;
N, 8.32.
3.3.10. (SS,R)-N-(2,2-Dimethyl-1-(6-phenylpyridin-2-
yl)propyl)-4-methylbenzenesulfinamide (6e). A solution
of the bromopyridine (SS,R)-6d (0.183 g, 0.48 mmol, 96%
de) and tetrakis(triphenylphosphane)palladium(0) (16.0 mg,
0.014 mmol) in toluene (0.96 ml) was treated with a
solution of Na2CO3 (0.10 g, 0.95 mmol) in H2O (0.48 ml)
followed by a solution of phenylboronic acid (0.07 g,
0.57 mmol) in methanol (0.24 ml). The mixture was heated
at 80–85 8C under argon for 14 h. After cooling at room
temperature, a solution of concentrated aqueous NH3
(0.24 ml) in saturated aqueous Na2CO3 (2.4 ml) was
added and the mixture was extracted with CH2Cl2 (3!
10 ml). The combined organic layers were washed with
brine (5 ml) and dried over anhydrous Na2SO4. Removal of
the solvent under reduced pressure gave a residue with was
purified by flash chromatography (petroleum ether: ethyl
acetateZ6:4) to give compound 6e as a mixture of
diastereomers ((SS,R)-6e:(SS,S)-6eZ98:2): 96.4 mg (85%).
Spectroscopic data of this compound were identical to all
respect with the above.
3.3.7. (SS,R)- and (SS,S)-N-((6-Bromopyridin-2-yl)-
(phenyl)methyl)-4-methylbenzenesulfinamide (6g). This
compound was obtained as a mixture of diastereomers
((SS,R)-6g:(SS,S)-6gZ88:12); 60.9 mg (76%); oil; 1H NMR:
d 7.54 (d, 2H, JZ8.1 Hz, minor isomer), 7.45 (d, 2H,
JZ8.1 Hz, major isomer), 7.42–7.18 (m, 4H), 7.12–7.05
(m, 4H), 6. 99 (d, 1H, JZ7.5 Hz, minor isomer), 6.96–6.91
(m, 2H), 6.42 (d, 1H, JZ5.4 Hz, major isomer), 5.67 (d, 1H,
JZ4.8 Hz, minor isomer) 5.63 (d, 1H, JZ4.8 Hz, minor
isomer), 5.50 (d, 1H, JZ5.4 Hz, major isomer), 2.38 (s, 3H,
minor isomer), 2.33 (s, 3H, major isomer). Anal. Calcd for
C19H17BrN2OS: C, 56.86; H, 4.27; N, 6.98. Found:
C, 56.68; H, 4.13; N, 6.77.
3.3.11. (SS,R)-N-[2,2-Dimethyl-1-(6-morpholinopyridin-
2-yl)propyl]-4-methylbenzenesulfinamide (11). Bromo-
pyridine (SS,R)-6d (114.3 mg, 0.30 mmol, 96% de),
morpholine (31.3 mg, 3.6 mmol), Pd2(dba)3 (6.0 mg,
0.012 mmol), 1,3-bis(diphenylphosphino)propane (4.8 mg,
0.012 mmol), NaO-t-Bu (40.2 mg, 0.42 mmol) and toluene
(2.7 mL) were introduced in a oven-dried Schenk flask that
was purged with argon. The mixture was heated at 70 8C
under argon for 9 h. After cooling, the mixture was taken up
in diethyl ether and washed three times with saturated brine.
The organic phase was separated and dried (Na2SO4). The
solvent was evaporated and the residue was purified by flash
chromatography (diethyl ether/petroleum etherZ1/1) to
give the starting material (SS,R)-6d (63.0 mg) and
compound 11 as a mixture of diastereomers ((SS,R)-11:
(SS,S)-11Z98:2): 48.4 mg (93% based on the converted
starting material); foam solid; [a]2D5 C173.1 (c 0.19,
3.3.8. (SS,R)- and (SS,S)-N-(Phenyl(6-phenylpyridin-2-yl)-
methyl)-4-methylbenzenesulfinamide (6h). This com-
pound was obtained as a mixture of diastereomers ((SS,R)-
1
6h:(SS,S)-6hZ93:7); 68.5 mg (86%); oil; H NMR: d 7.97
(d, 2H, JZ8.1 Hz, major isomer), 7.90 (d, 2H, JZ8.1 Hz,
minor isomer), 7.62–7.40 (m, 7H), 7.26–6.84 (m, 8H), 6.18
(d, 1H, JZ4.2 Hz, minor isomer), 5.75 (d, 1H, JZ4.2 Hz,
minor isomer), 5.62 (d, 1H, JZ4.2 Hz, major isomer),
2.35 (s, 3H, minor isomer), 2.31 (s, 3H, major isomer).
13C-NMR: d 159.3, 155.8, 142.6, 140.7, 140.4, 138.8, 137.5,
129.1, 128.9, 128.6, 128.0, 127.6, 126.9, 126.7, 126.2,
120.9, 118.8, 56.0, 21.1. Anal. Calcd for C25H22N2OS: C,
75.35; H, 5.56; N, 7.03. Found: C, 75.55; H, 5.59; N, 7.04.
3.3.9. (SS,R)-N-(2,2-Dimethyl-1-(pyridin-2-yl)propyl)-
methylbenzenesulfinamide (2c). Bromopyridine (SS,R)-6d
(126.0 mg, 0.33 mmol, 96% de), Pd(OAc)2 (7.4 mg,
0.033 mmol), PPh3 (35.4 mg, 0.135 mmol), NaBH4
(40.2 mg, 3.96 mmol), TMEDA (0.576 g, 4.96 mmol) and
anhydrous THF (30 mL) were introduced in a oven-dried
Schenk flask that was purged with argon. The mixture was
stirred at room temperature under argon for 3 h and then the
solvent was evaporated under vacuum. The residue was
taken up in H2O and extracted with ethyl acetate. The
organic phase was separated, dried (Na2SO4), the solvent
was evaporated and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate Z1/1)
to give compound 2c as a mixture of diastereomers
((SS,R)-2c:(SS,S)-2cZ97:3): 87.0 mg (95%); oil; [a]D25
1
CHCl3); H NMR: d 7.52 (d, 2H, JZ8.1 Hz), 7.43 (dd,
1H, JZ8.7, 7.5 Hz), 7.26 (d, 2H, JZ8.1 Hz), 7,51 (dd, 2H,
JZ8.7, 7.5 Hz), 5.65 (d, 1H, JZ9.0 Hz), 3.86 (d, 1H, JZ
9.0 Hz), 3.84–3.56 (m, 4H), 3.48–3.40 (m, 4H), 2.41 (s, 3H),
0.73 (s, 9H). 13C-NMR: d 158.3, 158.3, 142.1, 141.0, 137.3,
129.2, 125.8, 113.4, 105.1, 66.7, 64.1, 45.2, 34.9, 29.7, 26.8.
Anal. Calcd for C21H29N3O2S: C, 65.08; H, 7.54; N, 10.84.
Found: C, 65.16; H, 7.51; N, 10.87.
3.3.12. 6,60-Bis{[(SS,R)-2,2-dimethyl-1-(methylbenzene-
sulfinyl)propyl)]}-2,20-bipyridine (12). Zinc powered
(44.0 mg, 0.7 mmol) was added at 60 8C to a stirred mixture
of nickel(II) chloride hexahydrate (0.159 g, 0.7 mmol) and
triphenylphosphine (0.64 g, 2.4 mmol) in carefully
degassed (by three freeze-pump-thaw cycles) DMF (5 ml).
After 1 h, a solution the bromopyridine (SS,R)-6d (0.229 g,
0.6 mmol, 96% de) in DMF (3 ml) was added. The mixture
was stirred at 70 8C for 7 h and then taken up with ethyl
acetate. The organic phase was washed with dilute ammonia
solution (12 ml), with H2O (10 ml) and then dried
(Na2SO4). The solvent was evaporated and the residue
was purified by flash chromatography (CH2Cl2/methanolZ
9/1) to give 12: 63.2 mg (35%); mp 62–64 8C; [a]2D5 K34.2
1
C226.1 (c 0.57, CHCl3); H NMR: d 8.55 (d, 1H, JZ
4,5 Hz, major isomer), 8.46 (d, 1H, JZ4,8 Hz, major
isomer), 7.63–7.48 (m, 1H), 7.56 (d, 2H, JZ10, 5 Hz), 7.29
(d, 1H, JZ8,1 Hz), 7.23–7.01 (m, 3H), 5.85 (d, 1H, JZ
9,3 Hz major isomer), 5.68 (d, 1H, JZ8,4 Hz, minor
isomer), 4.17 (d, 1H, JZ8,4 Hz, major isomer), 3.92 (d,
1H, JZ9,3 Hz, minor isomer), 2.41 (s, 3H, major isomer),
2.38 (s, 3H, minor isomer), 0.96 (s, 9H minor isomer), 0.71
(s, 9H, major isomer). 13C-NMR: 160.4, 148.3, 141.5,
141.0, 135.5, 129.2, 125.9, 123.3, 121.9, 63.6, 34.9, 26.7,
21.3. Anal. Calcd for C18H25N2OS: C, 68.10; H, 7.94; N,
8.82. Found: C, 68.36; H, 7.91; N, 8.81.
1
(c 0.43, CHCl3); H NMR: 7.47 (d, 2H, JZ8.1 Hz), 7.34
(t, 1H, JZ7.8 Hz), 7.21 (d, 2H, JZ8.1 Hz), 6.84 (d, 1H,

626
G. Chelucci et al. / Tetrahedron 62 (2006) 619–626
4. (a) Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.;
Toniutti, M.; Zanette, M.; Zangrando, E.; Rigo, P. Angew.
Chem. 2005, 44, 6214. (b) Haas, J.; Piguel; Wirth, T. Org. Lett.
2002, 4, 297. (c) Brunner, H.; Markus, N. Monatsh. Chem.
2002, 133, 115. (d) Chelucci, G.; Pinna, G. A.; Saba, A.
Tetrahedron: Asymmetry 1997, 8, 2571. (e) Canary, J. W.;
Allen, C. S.; Castagnetto, J. M.; Wang, Y. J. Am. Chem. Soc.
1995, 117, 8484. (f) Chelucci, G.; Conti, S.; Falorni, M.;
Giacomelli, G. Tetrahedron 1991, 38, 8251. (g) Brunner, H.;
Heinrich, F. J. Organomet. Chem. 1987, 335, 1.
JZ7.8 Hz), 6.73 (d, 1H, JZ7.8 Hz), 3.57 (s, 1H), 2.39
(s, 3H), 0.86 (s, 9H). 13C-NMR: d 162.3, 160.1, 139.1,
135.8, 135.4, 130.0, 127.2, 119.2, 118.7, 65.3, 35.1, 26.5,
21.2. Anal. Calcd for C34H42N4O2S2: C, 67.74; H, 7.02; N,
9.29. Found: C, 68.01; H, 7.04; N, 9.25.
Acknowledgements
Financial support from MIUR (PRIN 2003033857-Chiral
ligands with nitrogen donors in asymmetric catalysis by
transition metal complexes, novel tools for the synthesis of
fine chemicals) and from the University of Sassari is
gratefully acknowledged by G. C.
5. Chelucci, G.; Baldino, S.; Solinas, R.; Baratta, W. Tetrahedron
Lett. 2005, 46, 5555.
6. Bull, S. D.; Davies, S. G.; Fox, D. J.; Gianotti, M.;
Kelly, P. M.; Pierres, C.; Savory, E. D.; Smith, A. D.
J. Chem. Soc., Perkin Trans. 1 2002, 1858.
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Wills, M. J. Chem Soc., Perkin Trans. 1 1996, 681. (b)
Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org. Chem.
1991, 56, 4.
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