The first approach to optically active 2,2′-bipyridine alkyl sulfoxides

Article abstract of DOI:10.1016/j.tetlet.2007.11.104

The synthesis of 6,6′-bis(alkylsulfanyl)-2,2′-bipyridines and their asymmetric oxidation to non-racemic 2,2′-bipyridine alkyl sulfoxides using either (+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine or a modified Sharpless reagent is reported.

Full text of DOI:10.1016/j.tetlet.2007.11.104

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 719–722
q
The first approach to optically active 2,20-bipyridine alkyl sulfoxides
a
b
b,
a,
*
Justyna Ławecka , Bogdan Bujnicki , Jozef Drabowicz *, Andrzej Rykowski
´
a
Department of Chemistry, University of Podlasie, 08-110 Siedlce, 3-Maja 54, Poland
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Ło´dz´, Sienkiewicza 112, Poland
b
Received 10 September 2007; revised 13 November 2007; accepted 20 November 2007
Available online 23 November 2007
Abstract
The synthesis of 6,60-bis(alkylsulfanyl)-2,20-bipyridines and their asymmetric oxidation to non-racemic 2,20-bipyridine alkyl sulfoxides
using either (+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine or a modified Sharpless reagent is reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Chiral 2,20-bipyridine alkyl sulfoxides; 5,50-Bi-1,2,4-triazine; Diels–Alder reaction
Recently, a number of chiral 2,20-bipyridines have been
prepared and tested in a variety of asymmetric reactions.1
In addition to their applications as ligands in transition
metal catalysis, chiral 2,20-bipyridine bis N-oxides have
been employed as selective organocatalysts in metal free
reactions.2 Most of the synthetic approaches to chiral
2,20-bipyridines are based on the transition metal catalyzed
heteroaryl homo-coupling and cross-coupling reactions of
chiral halopyridines,1–3 or Kro¨hnke-type synthesis from
pyridinium salts and chiral a,b-unsaturated ketones,4
which often require multistep procedures. In contrast, the
introduction of chirality to the 2,20-bipyridine framework
by secondary functionalization of substituents directly
attached to bipyridine rings has not received much atten-
tion. Examples in the literature refer mostly to the amidifi-
cation of mono and dicarboxy 2,20-bipyridines with amino
acids5,6 or non-racemic amines,7 esterification with (ꢀ)-
menthol,8 and lipase-catalyzed enantioselective acetylation
of 1-[(2,20-bipyridyl)] ethanol.9 The chirality could also be
introduced into the 2,20-bipyridine core via nucleophilic
halide substitution or the modification of a carbonyl group
as indicated by the preparation of ligands bearing camphor
sultam moieties10 or bis-oxazolidine substituents.11 The
limited use of these approaches for the preparation of
chiral 2,20-bipyridines may be due to the lack of suitable
substituents on the 2,20-bipyridine precursors or efficient
methods for their synthesis.
We have recently developed a simple route to 2,20-bipyr-
idine alkyl sulfides12 and now report their application to
the synthesis of previously unknown chiral 2,20-bipyridine
mono- and bis(sulfoxide)s via direct asymmetric oxidation.
Due to the presence of a good coordinating sulfinyl moi-
ety,136,60-mono- and bis-sulfinyl 2,20-bipyridines may con-
stitute a new group of chiral catalysts in asymmetric
reactions.
The synthesis of 2,20-bipyridine alkyl sulfides 3a–c is
based on Diels–Alder/retro Diels–Alder reaction of easily
accessible alkyl sulfides of 5,50-bi-1,2,4-triazines 2a–c with
norbornadiene as outlined in Scheme 1.14a–c As an exten-
sion of this investigation the functionalized sulfides 6 and
7 could be conveniently prepared in high yields under
non-basic conditions by heating methyl sulfide 3a with
ethyl haloacetates 4a–c and benzyl halides 5a–b, respec-
tively.15 Both S-transalkylation reactions proceed via reac-
tive sulfonium salts, 6a and 7a, which undergo methyl
group removal by the halides present in the reaction mix-
ture.16 Reactions of 3a with ethyl iodoacetate 4a or ethyl
bromoacetate 4b proceeded much faster than the analo-
q
Part 40 in ‘1,2,4-Triazines in organic synthesis’. For Part 39, see:
Karczmarzyk, Z.; Mojzych, M.; Rykowski, A. Anal. Sci. (X-Ray Struct.
On-Line) 2007, 23, x205.
*
Corresponding authors. Tel.: +48 25 6431093 (A.R.).
E-mail address: rykowski@ap.siedlce.pl (A. Rykowski).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.104

720
J. Ławecka et al. / Tetrahedron Letters 49 (2008) 719–722
N
N
N
KCN
N
N
N
-
,
, -2N2
N
N
N
N
N
R
S
1a-c
3a-c
R
S
S
R
R
S
S R
2a-c
1
R
X
CO2Et
X
Ph
5a-b
4a-c
CH3
C2H5
i-C3H7
a
b
c
-
-
2X
2X
R
N
N
R
R
N
N
R
S
S
7a
S
S
+
6a
+
+
+
Ph
Ph
EtO2C
CO2Et
-2CH3X
-2CH3X
N
N
N
N
S
S
6
S
S
7
EtO2C
CO2Et
Scheme 1. Synthesis of sulfides 3a–c, 6 and 7.
Ph
Ph
gous reaction of 3a with ethyl chloroacetate 4c. Likewise,
demethylation of 3a with benzyl bromide 5a gave com-
pound 7 almost quantitatively, within 2 h. However, the
formation of 7 by reaction of 3a with benzyl chloride 5b
was less favourable and needed forty five hours for comple-
tion. As expected, a similar order of reactivity was
observed on treatment of 3b (R = C2H5) or 3c (R = i-
C3H7) with ethyl bromoacetate 4b and benzyl bromide 5a
giving compounds 6 and 7 in reasonable yields (Scheme
1, Table 1).
With the 2,20-bipyridine alkyl sulfides in hand we next
evaluated their asymmetric sulfoxidation. Among the most
convenient and efficient methods for achieving high enanti-
oselectivity during oxidation of prochiral sulfides are the
catalytic reactions described by Kagan and co-workers17
who modified the Sharpless reagent, and with the chiral
oxaziridine developed by Davis et al.18 In addition, biolog-
ical oxidants such as enzymes, yeasts and microorganisms
can also be considered.19 We report here the results
obtained on the asymmetric oxidations of alkyl 2,20-bipyri-
dine sulfides 3a–c, 6 and 7 using (+)-(8,8-dichloro-
camphorylsulfonyl) oxaziridine20 (Method A) or Kagan
conditions21 (Method B), consisting of formation of a com-
plex between titanium(IV) isopropoxide, (R,R)-(+)-diethyl
tartrate (D-DET), H2O and tert-butylhydroperoxide
(TBHP). The reactions were performed in methylene
chloride giving the corresponding mono-sulfoxides 8a–e,
accompanied by small amounts of bis oxidation products
9a–e (Table 2).
Comparison of the two methods showed that better ees
were obtained using Kagan’s conditions. High enantio-
meric excesses were never obtained for sulfoxides 8d and
9d bearing an electron-withdrawing group on the sulfur,
whatever the method used. The highest enantioselectivity
was obtained for bis sulfoxide 9a (99% ee). The absolute
configuration at both sulfur atoms in 9a was confirmed
by X-ray analysis.22
To investigate the catalytic properties of chiral mono-
sulfoxide 8a and bis-sulfoxides 9c and 9d obtained here,
the asymmetric addition of diethylzinc to benzaldehyde
10 was carried out in benzene or toluene.23 The results
on the catalyst efficiencies and the enantiomeric excess of
the resulting 1-phenyl-1-propanol 11 are presented in Table
3. Although the catalytic efficiency of ligand 8a was poor,
those of ligands 9c and 9d possessing a bis-sulfinyl func-
tionality were promising. Ligand 9d which has only 17%
ee provided the chiral product 11 with 11% ee. This enanti-
oselectivity is probably due to the presence of two sulfinyl
groups in 9d which better coordinate the metal ion. These
results may thus provide impetus for further development
of more selective catalysts in this series. Work in this direc-
tion is underway in our laboratories.
Table 1
Synthesis of compounds 6 and 7
Compound
Halide
X
Time [h]
Sulfide
Yield [%]
3a
3a
3a
3a
3a
3b
3c
4a
4b
4c
5a
5b
4b
5a
I
1
8
6
6
6
7
7
6
7
91
98
75
95
60
60
76
Br
Cl
Br
Cl
Br
Br
20
2
45
13
8
In summary, the synthetic protocol described herein
provides an expedient access to a novel family of optically

J. Ławecka et al. / Tetrahedron Letters 49 (2008) 719–722
721
Table 2
Asymmetric oxidation of sulfides by the Davis and Kagan methods
[O]
+
Method
A or B
O
O
O
N
N
N
N
N
N
S
R
S
R
S
R
S
R
S
R
S
R
8a-e
9a-e
3a-c, 6, 7
Substrate
R
Product
Method
Yield [%]
ee [%]
Product
9a
Yield [%]
ee [%]
Aa
Bb
Aa
Bb
Aa
Bb
Aa
Bb
Aa
B
54
40
52
41
36
42
41
45
61
35
47c
70
8
13
42c
>99c
3a
3b
3c
6
–CH3
8a
8b
8c
8d
8e
76d
82d
51c
54d
5d
–C2H5
9be
11
9
12
26
23
17
22d
27d
17d
12d
40d
5d
–CH(CH3)2
9c
9d
–CH2CO2C2H5
–CH2Ph
14d
15d
62d
9e
7
a
Davis method.
Kagan method.
ee was determined by 1H NMR using the CSA method.24
ee was determined by HPLC analysis using a chiral stationary phase column (Chirobiotic T).
Bis sulfoxide 9b was not isolated.
b
c
d
e
4. (a) von Zelewsky, A.; Mamula, O. J. Chem. Soc., Dalton Trans. 2000,
219; (b) Malkov, A. V.; Baxendale, I. R.; Bella, M.; Langer, V.;
Fawcett, J.; Russel, D. R.; Mansfield, D. J.; Valko, M.; Kocovsky, P.
Organometallics 2001, 20, 673; and references cited therein.
5. (a) Imperiali, B.; Fisher, S. L. J. Am. Chem. Soc. 1991, 113, 8527; (b)
Imperiali, B.; Fisher, S. L. J. Org. Chem. 1992, 57, 757; (c) Imperiali,
B.; Fisher, S. L.; Prins, T. J. J. Org. Chem. 1993, 58, 1613; (d) Kise, K.
J.; Bowler, B. E. Tetrahedron: Asymmetry 1998, 9, 3319.
Table 3
Enantioselective diethylzinc addition to benzaldehyde 10
HO
C2H5
CHO
*
Et2Zn
L*
benzene/toluene
10
11
6. (a) Hopkins, R. B.; Hamilton, A. D. J. Chem. Soc., Chem. Commun.
1987, 171; (b) Hopkins, R. B.; Albert, J. S.; van Engen, D.; Hamilton,
A. D. Bioorg. Med. Chem. 1996, 4, 1121; (c) Ahn, D. R.; Hong, J. T.;
Kim, T. W. J. Org. Chem. 2001, 66, 5008.
7. (a) Ohkubo, K.; Hamada, T.; Ischida, H. J. Chem. Soc., Chem.
Commun. 1993, 1423; (b) Uppadine, L. H.; Keene, F. R.; Beer, P. D.
J. Chem. Soc., Dalton Trans. 2001, 2188.
L* ee [%] Amount of ligand Time
Solvent Yield
[%]
ee [%]
(mol %)
[days]
8a 54
9c 22
9d 17
2.5
2.5
3
6
5
5
Toluene 40
Benzene 41
Benzene 35
14 (26)a
14 (64)a
11 (68)a
L*: Ligands 8a, 9c,d.
8. Ohkubo, K.; Hamada, T.; Ischida, H.; Fukashima, M.; Watanabe,
M.; Kobayashi, H. J. Chem. Soc., Dalton Trans. 1994, 239.
9. Uenishi, J.; Hirada, T.; Hata, S.; Nishiwaki, O.; Yonemitsu, O.;
Nakamura, K.; Tsukube, H. J. Org. Chem. 1998, 63, 2481.
10. Kandzia, C.; Steckham, E.; Knoch, F. Tetrahedron: Asymmetry 1993,
4, 39.
11. Davies, S. R.; Cain, C. P.; Glossop, M. T.; Mengent, M.-l.; Kee, T. P.
Chem. Commun. 2004, 34, 1191.
12. (a) Rykowski, A.; Branowska, D.; Kielak, J. Tetrahedron Lett. 2000,
41, 3651; (b) Branowska, D.; Rykowski, A. Synlett 2002, 1892; (c)
Branowska, D. Molecules 2005, 10, 274; and references cited therein.
13. Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651.
14. (a) Typical three step procedure for the preparation of 2,20-bipyridine
alkyl sulfides 3a,b; (a) Synthesis of compound 1b. A solution of 5 g
(55 mmol) of thiosemicarbazide and 8.58 (55 mmol) of iodoethane in
40 ml of absolute ethanol was refluxed for 5 h. After that time ethanol
was evaporated in vacuo. A solution of 7.95 g (55 mmol) of 40%
glyoxal and 4.62 g (55 mmol) of sodium bicarbonate in 100 ml of
water was added to the brown residue. The mixture was stirred at 5 ꢁC
for 3 h and for an additional 12 h at room temperature. The resulting
precipitate was filtered and the filtrate was extracted with chloroform
(5 · 100 ml). After evaporation of the combined organic extracts the
remaining oily residue was purified by chromatography (SiO2,
methylene chloride) to give 3-(ethylsulfanyl)-1,2,4-triazine 1b
(7.04 g, 91% yield) as an orange oil. 1H NMR (200 MHz, CDCl3) d
(ppm): 1.37 (t, J = 7.2, 3H, CH3), 3.20 (q, J = 7.2, 1H, CH2), 8.33 (d,
a
Calculated ee based on pure catalyst.
active 2,20-bipyridine alkyl sulfoxides from readily accessi-
ble 2,20-bipyridine alkyl sulfides.
Acknowledgement
The authors are very grateful to Mrs. Agnieszka Toma-
szewska of the University of Podlasie for technical
assistance.
References and notes
1. For a review on the synthesis and utilization of chiral 2,20-bipyridines,
see: (a) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129; (b)
Fletcher, N. C. J. Chem. Soc., Perkin Trans. 1 2002, 1831.
2. For a review on chiral pyridine and 2,20-bipyridine N-oxides in
asymmetric catalysis, see: (a) Malkov, A.; Kocovsky, P. Eur. J. Org.
Chem. 2007, 29; (b) Chelucci, G.; Murineddu, G.; Pinna, G. A.
Tetrahedron: Asymmetry 2004, 15, 1373.
3. Newcome, G. R.; Patri, A. K.; Holder, E.; Schubert, U. S. Eur. J.
Org. Chem. 2004, 235.

722
J. Ławecka et al. / Tetrahedron Letters 49 (2008) 719–722
1H, J = 2.4 triazine hydrogen), 8.88 (d, 1H, J = 2.4 triazine hydro- 17. Pitchen, P.; Dunach, E.; Desmukh, M. N.; Kagan, H. B. J. Am.
gen). HRMS (EI): calcd for C5H7N3S (M+): 141.0364; found:
141.0360; (b) Synthesis of compound 2b. A solution of 3-(ethylsulf-
anyl)-1,2,4-triazine 1b (6.5 g, 46.1 mmol) in water (170 ml) was stirred
until complete dissolution. Excess potassium cyanide (4.8 g,
73.8 mmol) was added in five portions. The mixture was stirred at
room temperature for 2 h, after which the reaction mixture was
extracted with ethyl acetate (10 · 100 ml). The combined organic
extracts were dried over magnesium sulfate, then filtered and
concentrated in vacuo. The crude product was purified by chromato-
graphy (SiO2, CH2Cl2), to give pure 3,30-bis(ethylsulfanyl)-5,50-
Chem. Soc. 1984, 106, 8188.
18. Davis, F. A.; Reddy, T. R.; Weismiller, M. C. J. Am. Chem. Soc.
1989, 111, 5964.
19. Holland, H. L. Chem. Rev. 1988, 88, 473.
20. General procedure for asymmetric sulfoxidations of sulfides 3a–c, 6, 7
using (+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine. To a solution
of 1 mmol of the sulfide in anhydrous methylene chloride (30 ml),
0.75 mmol of oxaziridine was added and the reaction stirred at room
temperature for 24 h. Afterwards, the solvent was evaporated and the
residue was purified by flash chromatography (SiO2, methylene
chloride–acetone 10:1.5) to yield pure mono-sulfoxides 8a–e and
bis-sulfoxides 9a, c–e.
21. General procedure for asymmetric sulfoxidations of sulfides 3a–c, 6
and 7 using Kagan conditions: 3 mmol of titanium tetraisopropoxide
(0.9 ml) and 6 mmol (0.51 ml) of D-DET were introduced by a syringe
to a mixture of methylene chloride (10 ml) and water (1 ml). The
resulting mixture was stirred for 20 min at room temperature. Then
the sulfide (1 mmol) was added and the mixture was cooled to ꢀ20 ꢁC.
Finally, 0.8 mmol of TBHP (2 M solution in toluene) was added.
After 16 h at this temperature, water (10 ml) was added and stirring
was continued for an additional 1 h. After that time, Al2O3 (20 mg)
was added and the mixture was filtered and the residue was washed
with methylene chloride. The organic layer was stirred with 5%
sodium hydroxide and brine. After decantation, the organic phase
was dried with magnesium sulfate and the solvent was evaporated.
Flash chromatography of the crude product (SiO2, methylene
chloride) yielded pure mono-sulfoxides 8a–e and bis-sulfoxides
9a, c–e.
22. The results of the X-ray analysis will be published elsewhere.
23. General procedure for the asymmetric addition of diethylzinc to
benzaldehyde: To a solution of 8a, 9c (2.5 mol %) or 9d (3 mol %) in
anhydrous benzene was added diethylzinc (3 mmol, 1.0 M solution in
hexane) under argon and the reaction stirred for 10 min at room
temperature. The solution was cooled to 0 ꢁC, and benzaldehyde
(1 mmol) was added slowly. After being stirred for 2 h at 0 ꢁC, and
12 h at room temperature, the reaction was quenched with 1 M
aqueous HCl (20 ml). The mixture was extracted with Et2O, and the
combined organic layer dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by column
chromatography (SiO2, hexane–ethyl acetate 10:1) to afford 1-phenyl-
1-propanol as a colourless liquid.
1,2,4-triazine (2b) (5.28 g, 81% yield) as
a yellow solid. Mp
129–130 ꢁC. 1H NMR (400 MHz, CDCl3) d (ppm) 1.50 (t, 6H,
J = 7 Hz, CH3), 2.35 (q, 4H, J = 7 Hz, CH2), 9.85 (s, 2H, triazine
hydrogen). 13C NMR (100 MHz, CDCl3) d (ppm): 13.9 (CH3), 25.4
(CH2), 141.8, 149.9, 174.1 (triazine carbon atoms). Anal. Calcd for
C10H12N6S2: C, 42.86; H, 4.29; N, 30.00. Found: C, 42.90; H, 4.32; N,
29.89; (c) Synthesis of compound 3b. A solution of 2b (1.5 g,
5.35 mmol) in p-cymene (10 ml) and norbornadiene (3.6 ml,
25.7 mmol) was heated at 150 ꢁC for 30 h. p-Cymene was evaporated
in vacuo. The crude product was purified by chromatography (SiO2,
CH2Cl2–hexane 10:3) to give pure 6,60-bis(ethylsulfanyl)-2,20-bipyr-
idine (3b)(0.85 g, 58% yield) as an orange solid. Mp 68–70 ꢁC. 1H
NMR (400 MHz, CDCl3) d (ppm): 1.45 (t, 6H, J = 7.4 Hz, CH3), 3.28
(q, 4H, J = 7.2 Hz, CH2), 7.14 (d, 2H, J = 7 Hz, pyridine hydrogen),
7.58 (d, 2H, J = 7.8 Hz, pyridine hydrogen), 8.11 (d, 2H, J = 1.68 Hz,
pyridine hydrogen); 13C NMR (100 MHz, CDCl3) d (ppm): 14.6
(CH3), 24.4 (CH2), 116, 122, 136, 155 and 158 (pyridine carbon
atoms). Anal. Calcd for C14H16N2S2: C, 60.86; H, 5.79; N, 10.14.
Found C, 60,63; H, 5.76; N, 10.05. Compounds 2a, c and 3a, c were
obtained as indicated (in Ref. 12c).
15. Compounds 6 and 7 were prepared by refluxing 3a in the presence of
six molar excess of the corresponding alkylating agent 4a–c or 5a,b for
the time indicated in Table 1. After that time the reaction was cooled
and diethyl ether was added. The precipitates 6 and 7 were filtered off
and the crude products were purified by column chromatography
using CH2Cl2 as eluent. The mp and spectroscopic data of 6 and 7
were in good agreement with those reported earlier. For 6 see
reference (a), and for 7 see reference (b): (a) Branowska, D.;
Rykowski, A.; Wysocki, W. Tetrahedron Lett. 2005, 46, 6223; (b)
´
Branowska, D.; Buczek, I.; Kalinska, K.; Nowaczyk, J.; Rykowski,
A. Tetrahedron Lett. 2005, 46, 8539.
´
16. Labuschagne, A. J.; Malherbe, J. S.; Meyer, C. J.; Schnaider, D. F. J.
Chem. Soc., Perkin Trans. 1 1978, 955.
24. Drabowicz, J.; Dudzinski, B.; Mikołajczyk, M. Tetrahedron: Asym-
metry 1992, 3, 1231.