Asymmetric synthesis of 1-substituted-1-(pyridin-2-yl)methylamines by diastereoselective reduction of enantiopure N-p-toluenesulfinyl ketimines

Article abstract of DOI:10.1016/j.tetlet.2005.06.019

Reduction of enantiopure N-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones affords N-p-toluenesulfinyl amines with good yields and diastereoselectivities.

Full text of DOI:10.1016/j.tetlet.2005.06.019

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5555–5558
Asymmetric synthesis of 1-substituted-
1-(pyridin-2-yl)methylamines by diastereoselective reduction
of enantiopure N-p-toluenesulfinyl ketimines
Giorgio Chelucci,a,* Salvatore Baldino,a Rosanna Solinasa and Walter Barattab
a
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
`
Dipartimento di Scienze e Tecnologie Chimiche, Universita di Udine, Via Cotonificio 108, I-33100 Udine, Italy
b
Received 29 April 2005; revised 7June 2005; accepted 8 June 2005
Available online 5 July 2005
Abstract—Reduction of enantiopure N-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones affords N-p-toluenesulfinyl
amines with good yields and diastereoselectivities.
Ó 2005 Elsevier Ltd. All rights reserved.
In some recent reports, we have pointed out that ruthe-
nium(II) complexes having achiral 2-pyridyl amines as
R1
R
R1
N
co-ligands, namely RuCl[(2-CH2–6-MeC6H3)PPh2]-
(CO)(L),1a,b cis-RuCl2(PP)(L)1c (L = 1-(pyridin-2-yl)-
methylamine; PP = diphosphine) and RuCl(CNN)-
[Ph2P(CH2)4PPh2] (HCNN = 1-(6-phenylpyridin-2-yl)-
methylamine),2 exhibit high activity in transfer hydroge-
nation of ketones in 2-propanol. In order to prepare the
related chiral 2-pyridyl amine metal complexes, we
required a practical procedure for accessing chiral
nonracemic 1-substituted-1-(pyridin-2-yl)methylamines.
Among the approaches,3 we considered the diastereo-
selective reduction of enantiopure pyridyl imines derived
from 2-pyridyl ketones.4 For this purpose the proper
choice of the nitrogen chiral substituent is of crucial
importance, since it not only must enable the prepara-
tion of stable imine, but also must be inexpensive and
straightforward to remove without loss of optical purity
from the amine product. The N-p-toluenesulfinyl substi-
tuent pioneered by Davis and co-workers5 satisfies many
of these criteria.6 Moreover, high diastereofacial selec-
tivity has been obtained in the reduction of N-p-toluene-
sulfinyl ketimines derived from both dialkyl and aryl
alkyl ketones.7,8 Therefore, we sought to adapt this pro-
cedure to our specific needs (Fig. 1).
R
*
N
N
*
S
p-Tolyl
NH2
O
1
2
Figure 1.
Herein, we report the preliminary results obtained in the
reduction of a number of chiral N-p-toluenesulfinamides
2 derived from 2-pyridyl ketones 3 (Scheme 1).
N-p-Toluenesulfinyl ketimines (SS)-2a–f were obtained
by condensation of commercially available (S)-(+)-p-tolu-
enesulfinamide (SS)-4 (1 equiv) with a series of 2-pyridyl
ketones 3a–f (1.1 equiv) with varying steric and elec-
tronic demand about the carbonyl. The reactions were
performed9 employing Ti(OEt)4 (2 equiv) in CH2Cl2 at
40 °C for 2a (45%) and 2b (37%) or THF at 70 °C for
2c (40%), 2d (75%), 2e (34%) and 2f (67%). All imines
were obtained as a single isomer as determined by the
1H NMR spectra.
The reduction of (SS)-2a–f with three hydride transfer re-
agents under a variety of conditions was examined (Table
1). The extent of the asymmetric induction was deter-
mined directly by 1H NMR on the diastereoisomeric
mixture of sulfinamides 5a–f. All reductions were initially
carried out using NaBH4,10 which afforded good yields of
the sulfinamides 5a–f, but low diastereoselectivities.
Keywords: Pyridyl amines; N-p-Toluenesulfinyl ketimines; Nitrogen
heterocycles; Diastereoselective reduction.
*
Corresponding author. Tel.: +39 79 229539; fax: +39 79 229559;
e-mail: chelucci@uniss.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.019

5556
G. Chelucci et al. / Tetrahedron Letters 46 (2005) 5555–5558
R
O
S
p-Tolyl
NH2
a
b
S
R
p-Tolyl
N
+
N
R1
O
N
O
(SS)-4
(SS)-2a-g
3a-g
R1
O
S
R
H
O
S
R
p-Tolyl
N
p-Tolyl
N
c
H
H
H
+
N
N
R1
(SS,S)-5a-g
R1
+
(SS,S)-5a-g
R
R
R1
R1
N
N
NH2
NH2
(S)-1a-g
(R)-1a-g
a: R = Me, R1 = H; b: R = i-Pr, R1 = H; c: R = t-Bu, R1 = H; d: R = Ph, R1 = H
e: R = 2-furyl, R1 = H; f: R = 2-thienyl, R1 = H; g: R = Me, R1 = Br.
Scheme 1. Reagents and conditions: (a) Ti(OEt)4, CH2Cl2 (40 °C) or THF (70 °C), 24–36 h, 34–75%; (b): Table 1; (c) CF3COOH, MeOH, rt, 6 h.
Table 1. Reduction of (SS)-2a–g
Entry
Compound
Reducing agent/conditions
Reaction time (h)
Ratioa (SS,R):(SS,S)-5
Yieldb (%)
1
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2c
2c
2c
2d
2d
2d
2e
2e
2e
2f
NaBH4, MeOH, 25 °C
L-Selectride, THF, À78 °C
L-Selectride, THF, 0 °C
DIBAL, THF, À78 °C
NaBH4, MeOH, 25 °C
L-Selectride, THF, À78 °C
DIBAL, THF, À78 °C
NaBH4, MeOH, 25 °C
L-Selectride, THF, À78 °C
L-Selectride, THF, 0 °C
DIBAL, THF, À78 °C
DIBAL, THF, À20 °C
DIBAL, THF, 25 °C
NaBH4, MeOH, 25 °C
L-Selectride, THF, À78 °C
DIBAL, THF, À78 °C
NaBH4, MeOH, 25 °C
L-Selectride, THF, À78 °C
DIBAL, THF, À78 °C
NaBH4, MeOH, 25 °C
L-Selectride, THF, À78 °C
DIBAL, THF, À78 °C
DIBAL, THF, À20 °C
DIBAL, THF, À78 °C
1
3
55:45
74:26
68:32
16:84
47:53
97:3
95
77
75
90
—
77
87
2
3
3
4
6
5
1
6
3
7
6
71:29
53:4795
—
8
1
9
10
24
6
No reaction
40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1:1
96:4
92
91
6
92:8
92:8
6
45
88
1
54:46
67:33
60:40
1:1
3
93
91
6
1
87
32
3
71:29
1:1
1:1
24
1
40
89
2f
10
24
48
6
75:25
—
35
No reaction
2f
2f
2g
72:28
<2:>98
57
90
a Ratio of the crude reaction mixture determined by 1H NMR.
b Isolated yields.
Using L-Selectride11 or DIBAL,12 yields and diastereose-
lectivities were greatly dependent on the nature of the sub-
stituent on the imino moiety. Thus, with 2a (R = Me)
higher selectivity was obtained with DIBAL (68% de),
whereas L-Selectride was the better stereoselective reduc-
ing agent with 2b (R = iso-propyl) (94% de). Moreover,
with DIBAL as the reducing agent, the diastereoselectiv-
ity was reversed in going from 2a to 2b, yielding (SS,R)-5
as the major isomer in the reduction of 2b. L-Selectride
gave no reaction with 2c (R = tert-butyl) whereas DIBAL
gave high yield and diastereoselectivity (up to 92% de),
with minimal effect of reaction temperature on the stere-
oselective outcome. With 2d and 2f (R = phenyl and thi-
enyl, respectively) both L-Selectride and DIBAL gave
similar stereochemical results (up to 50% de). Finally,
with 2e (R = furyl) diastereoselective reduction occurred
only with L-Selectride (42% de).
In order to determine the configuration of the new ste-
reocentre in the reduction products, an enriched mixture

G. Chelucci et al. / Tetrahedron Letters 46 (2005) 5555–5558
5557
of the diastereoisomers of 5a,b and 5d was converted
(CF3COOH, MeOH, rt, 6 h, 85–90%)13 to the optically
active amines 1a,14 1b15 and 1d,14 respectively, for which
the correlation between configuration and sign of the
optical rotation has previously been established. In this
thesis of fine chemicals) and from the University of
Sassari is gratefully acknowledged.
1
References and notes
way, it has been possible to determine that in the H
NMR spectra the resonances of the protons at the 6-
position of the pyridine ring of the (SS,R)-diastereomers
of 5a,b and 5d are shifted downfield with respect to those
of the related (SS,S)-diastereomers. By analogy, the con-
figurations to the diastereomers of 5c and 5e–g have
been tentatively assigned.
1. (a) Baratta, W.; Da Ros, P.; Del Zott, A.; Sechi, A.;
Toniutti, M.; Zangrando, E.; Rigo, P. Angew. Chem., Int.
Ed. 2004, 43, 3584; (b) Baratta, W.; Del Zotto, A.;
Esposito, G.; Sechi, A.; Toniutti, M.; Zangrando, E.;
Rigo, P. Organometallics 2004, 23, 6264; (c) Baratta, W.;
Herdtweck, E.; Siega, K.; Toniutti, M.; Rigo, P. Organo-
metallics 2005, 24, 1660.
2. Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.; Toniutti,
M.; Zanette, M.; Zangrando, E.; Rigo, P., submitted for
publication.
3. For a review, see: Chelucci, G. Tetrahedron: Asymmetry,
in press.
It has been reported than 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 nonracemic 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 stereoselectivity (6% de) unless
the pyridine ring was also substituted at the 6-position.16
4. To our knowledge only a case of the application of this
approach to the synthesis of chiral 2-substituted pyridyl
amines has been reported. Miao et al. investigated the
diastereoselective reduction of chiral 2-(2-pyridyl)-1,3-
oxazolines and 2-pyridyl imines obtained as a mixture by
coupling of 2-cyclohexyl-1-(pyridin-2-yl)ethanone with the
(R)-phenylglicynol or (R)-valinol. Upon catalytic reduc-
tion (H2 on Pd/C) of the mixture followed by oxidative
removal (NaIO4) of the chiral auxiliary, the 2-cyclohexyl-
1-(pyridin-2-yl)ethylamine was obtained with good enan-
tiomeric excess (80–96%). However, the yield of the last
step was low (35–40%) Miao, C. K.; Sorcek, R.; Jones,
P.-J. Tetrahedron Lett. 1993, 34, 2259.
5. For a recent review, see: Zhou, P.; Chen, B.-C.; Davis, F.
A. Syntheses and Reactions of Sulfinimines. In Advances
in Sulfur Chemistry; Raynor, C. M., Ed.; JAl Press:
Stanford, CT, 2000; Vol. 2, pp 249–282.
6. Another very attractive N-substituent is the tert-butyl
sulfinyl group, however the enantiopure tert-butanesulfin-
amide is much more expensive than the (S)-(+)-p-toluene-
sulfinamide, therefore starting our investigation, we
decided to use the latter. For a review on N-tert-
butanesulfinyl imines, see: Ellman, J. A.; Owens, T. D.;
Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
7. (a) Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. J. Org.
Chem. 1991, 56, 4; (b) Annunziata, R.; Cinquini, M.;
Cozzi, F. J. Chem. Soc., Perkin Trans. 1 1982, 339; (c)
Cinquini, M.; Cozzi, F. J. Chem. Soc., Chem. Commun. 1,
1977, 502.
8. For a related paper, see: Hose, D. R. J.; Mahon, M. F.;
Molly, K. C.; Raynham, T.; Wills, M. J. Chem. Soc.,
Perkin Trans. 1 1996, 681.
9. Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.;
Fanelli, D.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
10. Representative procedure for the reduction with NaBH4:
A solution of (SS)-2a (52.0 mg, 0.20 mmol) in MeOH
(3 mL) was treated with NaBH4 (15.0 mg, 0.40 mmol) at
0 °C. After 1 h at 25 °C the reaction was quenched with
saturated aqueous ammonium chloride (4 mL). The crude
mixture was extracted with ethyl acetate, dried (Na2SO4)
and the solvent was evaporated under reduced pressure.
The residue was purified by flash chromatography (petro-
leum ether–ethyl acetate = 1:1) to afford a 55:45 mixture of
(SS,R)-5a: (SS,S)-5a (49.4 mg, 95%), mp 73–75 °C. 1H
NMR (300 MHz, CDCl3): d 8.55 (d, 1H, J = 4.8 Hz, major
isomer), 8.49 (d, 1H, J = 4.8 Hz, minor isomer), 7.70–7.42
(m, 1H, overlapping), 6.64 (d, 2H, J = 7.8 Hz, major
isomer), 7.53 (d, 2H, J = 7.8 Hz, minor isomer), 7.35–7.10
(m, 2H, overlapping), 7.31 (d, 2H, J = 7.8 Hz, minor
isomer), 7.00 (d, 1H, J = 7.8 Hz, minor isomer), 5.58 (d,
In order to probe the influence on the diastereoselectivity
of a substituent at the 6-position of the pyridine ring in
our system, the 4-methyl-N-[1-(6-bromopyridin-2-yl)eth-
ylidene]benzenesulfinamide (SS)-2g was prepared in the
usual way (Ti(OEt)4, THF, 60 °C, 4 h, 85%) from 1-(6-
bromopyridin-2-yl)ethanone (3g). Reduction of 2g with
DIBAL at À78 °C afforded a 1.5:98.5 mixture of diaste-
reomers. The increase in facial selectivity observed upon
reduction relative to the unsubstituted system 2a, ap-
pears 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 minimise disruption of the normal chelation-con-
trolled transition state,7a,8 thus disfavouring the compet-
ing nonstereoselective pathway for the reduction.
In conclusion, we have developed a method for the prep-
aration of 2-pyridyl amines with moderate to good dia-
stereoselectivities. This procedure, which complements
existing ones, has been particularly successful for the
preparation of a tert-butyl substituted pyridyl amine,
where all other methods failed. Moreover, the finding
that 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-
2-yl)methylamines (such as 5g) can be obtained with
very high diastereoselectivity and the consideration that
the N-toluenesulfinyl group can be considered as a N-
protecting group,17 should allow for further elaboration
of the 6-bromo substituent (e.g., via Ni(0)-catalysed
homocoupling, Suzuki-type heterocoupling, etc.). Fur-
ther studies on this subject are currently in progress.
Acknowledgements
Financial support from MIUR (PRIN 2003033857-Chi-
ral ligands with nitrogen donors in asymmetric catalysis
by transition metal complexes, novel tools for the syn-

5558
G. Chelucci et al. / Tetrahedron Letters 46 (2005) 5555–5558
1H, J = 7.2 Hz, major isomer), 5.31 (d, 1H, J = 6.9 Hz,
was added to a solution of (SS)-2a (52.0 mg, 0.20 mmol) in
THF (2 mL) at À78 °C. After 6 h MeOH (1 mL) was
added to the mixture, which was then 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 reaction was worked up as above to
give a 16:84 mixture of (SS,R)-5a:(SS,S)-5a (46.8 mg,
90%).
minor isomer), 4.65–4.10 (m, 2H), 2.42 (s, 3H, major
isomer), 2.37(3H, minor isomer), 1.60 (d, 3H, J = 6.9 Hz,
minor isomer), 1.30 (d, 3H, J = 6.9 Hz, major isomer).
Anal. Calcd for C14H16N2OS: C, 64.58; H, 6.19; N, 10.76.
Found: C, 63.86; H, 6.42; N, 10.65.
11. Representative procedure for the reduction with L-Select-
ride: A solution of (SS)-2a(52.0 mg, 0.20 mmol) in THF
(2 mL) was treated with L-Selectride (0.2 mL of a 1.0 M
solution in THF, 0.20 mmol) at À78 °C. After 3 h the
reaction was quenched with saturated aqueous ammonium
chloride (3 mL) and extracted with ethyl acetate. The
mixture was filtered through a Celite pad that was washed
with ethyl acetate. The organic phase was separated, dried
(Na2SO4), the solvent was evaporated and the residue was
purified by flash chromatography to give a 74:26 mixture
of (SS,R)-5a: (SS,S)-5a (40.0 mg, 77%).
13. Kikolajczyk, M.; Drabowicz, J.; Bujnicki, B. J. Chem.
Soc., Chem. Commun. 1976, 568.
14. Alvaro, G.; Martelli, G.; Savoia, D. J. Chem. Soc., Perkin
Trans. 1 1998, 775.
15. Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997, 3,
726.
16. 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.
12. Representative procedure for the reduction with DIBAL:
DIBAL (0.45 mL of a 1.0 M solution in THF, 0.45 mmol)
17. Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998,
27, 13.