Synthesis of functionalized pyridine derivatives by an amidoalkylation/ Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1016/j.tetlet.2012.09.022

A new efficient methodology for the preparation of 3,4-difunctionalized pyridine derivatives by an amidoalkylation/ Staudinger/aza-Wittig sequence has been developed. The synthesis includes condensation of 3-azidopropanal with urea and p-toluenesulfinic acid followed by reaction of the N-[(3-azido-1-tosyl) propyl]urea obtained with Na-enolates of tosylacetophenone or acetyl acetone to give N-[(5-azido- 1-oxo-1-phenyl-2-tosyl)pent-3-yl]urea and 5-acetyl-6-(2- azidoethyl)-4-hydroxy-4-methylhexahydropyrimidin- 2-one, respectively. These compounds are transformed into 6-phenyl-5-tosyl-4-ureido- and 5-acetyl-6-methyl-4-ureido-1,2,3,4-tetrahydropyridines by treatment with PPh3. The former is aromatized under the action ofMnO2 or reduced by NaBH4/CF3COOH system to provide 2-phenyl-3-tosylpyridine and 2-phenyl-3-tosyl-4- ureidopiperidine.

Full text of DOI:10.1016/j.tetlet.2012.09.022

Tetrahedron Letters 53 (2012) 6261–6264
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of functionalized pyridine derivatives by an
amidoalkylation/Staudinger/aza-Wittig sequence
⇑
Anastasia A. Fesenko, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow State University of Fine Chemical Technologies, 86 Vernadsky Ave., 119571 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2012
Revised 29 August 2012
Accepted 6 September 2012
Available online 15 September 2012
A new efficient methodology for the preparation of 3,4-difunctionalized pyridine derivatives by an amido-
alkylation/Staudinger/aza-Wittig sequence has been developed. The synthesis includes condensation of
3-azidopropanal with urea and p-toluenesulfinic acid followed by reaction of the N-[(3-azido-1-tosyl)
propyl]urea obtained with Na-enolates of tosylacetophenone or acetyl acetone to give N-[(5-azido-
1-oxo-1-phenyl-2-tosyl)pent-3-yl]urea and 5-acetyl-6-(2-azidoethyl)-4-hydroxy-4-methylhexahydro-
pyrimidin-2-one, respectively. These compounds are transformed into 6-phenyl-5-tosyl-4-ureido- and
5-acetyl-6-methyl-4-ureido-1,2,3,4-tetrahydropyridines by treatment with PPh3. The former is aroma-
tized under the action of MnO2 or reduced by NaBH4/CF3COOH system to provide 2-phenyl-3-tosylpyridine
and 2-phenyl-3-tosyl-4-ureidopiperidine.
Keywords:
Amidoalkylation
d-Azido ketones
Pyrimidines
Staudinger/aza-Wittig reaction
Pyridines
Ó 2012 Elsevier Ltd. All rights reserved.
The ring system of pyridine and its hydrogenated derivatives
occurs in many pharmacologically active natural compounds,
including alkaloids, vitamins, cofactors, and antibiotics.1 Pyridines,
piperidines, dihydro-, and tetrahydropyridines have found various
applications in medicinal chemistry.1 Remarkable progress has
been achieved in the development of effective approaches to pyri-
dines, including hydrogenated ones.1e,g,h,2,3 The Staudinger/intra-
molecular aza-Wittig reaction sequence4 provides a convenient
method for the preparation of tetrahydropyridines that can be eas-
ily transformed into piperidines.5 This protocol uses d-azido ke-
tones as starting materials. However, the synthesis described for
these compounds have some disadvantages, such as the low avail-
ability of starting compounds, multi-step synthesis, small-scale
preparations, harsh reaction conditions, long reaction times, poor
yields, laborious procedures, etc. In addition, it is difficult to obtain
d-azido ketones bearing a functional group at the b-position (e.g.,
Cl, Br, OH, OR, NHR, etc.). This limits the application of the above
approach to the synthesis of 4-functionalized tetrahydropyridines
and piperidines as well as aromatic pyridines. Thus, in the context
of pyridine synthesis, the development of new general approaches
to d-azido ketones, particularly with additional functional groups
or/and D using the Staudinger/intramolecular aza-Wittig reaction
sequence (Scheme 1). Subsequent aromatization or reduction of
compounds C and D would give 3-functionalized pyridines E or
piperidines F.
Previously, we demonstrated that the products of the amidoal-
kylation reaction between enolates of various ketones and readily
available N-(a-tosyl)alkylureas can serve as versatile precursors
for the preparation of functionalized hexahydro-, 1,2,3,4-tetrahy-
dro-, and 1,2-dihydropyrimidin-2-ones, tetrahydro-1H-1,3-diaze-
pin-2-ones, 4,5-dihydrofurans, and 1-carbamoyl-1H-pyrroles.6 In
continuation of our interest in the development of new methodol-
ogies using amidoalkylation we describe herein the synthesis of
at the
We hypothesized that amidoalkylation of enolates of
tionalized ketones with N-( -azidoalkyl)amides A bearing a leav-
ing group at the position to nitrogen could give d-azido
a- and b-positions, is highly desirable.
a-func-
c
a
ketones B which could be transformed into tetrahydropyridines C
⇑
Corresponding author. Tel.: +7 495 936 8908; fax: +7 495 936 8909.
E-mail address: shutalev@orc.ru, anatshu@gmail.com (A.D. Shutalev).
Scheme 1. Retrosynthesis of functionalized pyridines and their hydrogenated
derivatives via amidoalkylation/Staudinger/aza-Wittig reactions.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.022

6262
A. A. Fesenko, A. D. Shutalev / Tetrahedron Letters 53 (2012) 6261–6264
d-azido-b-ureido ketones by the reaction of N-[(2-azido-1-
tosyl)propyl]urea with enolates of tosylacetophenone and acetyl
acetone and their transformation into functionalized 4-ureido-tet-
rahydropyridines using the Staudinger/aza-Wittig sequence. We
also report oxidative aromatization and reduction of one of the tet-
rahydropyridines to give a pyridine and piperidine derivative,
respectively.
The N-[(c-azido-a-tosyl)alkyl]ureas (A R = NH2, Scheme 1) re-
quired as starting amidoalkylation reagents for the pyridine
synthesis can be prepared by the reaction of readily available
b-azido aldehydes with p-toluenesulfinic acid and urea. In this
work, we used 3-azidopropanal (1) as an example of a b-azido
aldehyde. Aldehyde 1 was obtained according to the literature
method7 by reaction of acrolein (2) with NaN3 in aqueous acetic
acid (Scheme 2). The product was isolated from reaction mixture
as a yellowish oil in 62% yield after extraction with diethyl ether
followed by neutralization of the ether extracts with aqueous
Na2CO3, drying and evaporation of the solvent in vacuum. The
crude 1 was >95% pure according to 1H NMR data and was used
in the next stage without additional purification. Reaction of 1 with
p-toluenesulfinic acid (3) and urea (1:1:3 molar ratio, respectively)
proceeded in water at room temperature for 24 h to give sulfone 4
in an 86% yield.8 A threefold excess of urea was used to prevent the
formation of the N,N0-disubstituted side product.
Scheme 3. Synthesis of 3-functionalized 4-ureido-1,2,3,4-tetrahydropyridines 9a,b
using the amidoalkylation/Staudinger/aza-Wittig sequence.
The reaction of sulfone 4 with the sodium enolate of tosylace-
tophenone (5a) in dry MeCN proceeded at room temperature for
8 h to give oxoalkylurea 6a as a mixture of two diastereomers in
a ratio of 54:46 in a 93% yield (Scheme 3).9 No cyclic isomer, the
4-hydroxyhexahydropyrimidin-2-one 7a, was detected by 1H
NMR spectroscopy.
Scheme 4. Reduction and elimination/oxidation of tetrahydropyridine 9a.
Under similar conditions, the reaction of urea 4 with the Na-
enolate of acetyl acetone (5b) afforded the 4-hydroxyhexahydro-
pyrimidin-2-one 7b as a single (4R⁄,5R⁄,6R⁄)-isomer in 75% yield.10
Based on the values of spin couplings, the orientations of substitu-
ents in 7b were determined as equatorial for the acetyl and azido-
3
ethyl groups (3J5-H,6-H = 11.7, JN(1)H,6-H ꢀ0 Hz) and axial for the
hydroxyl group (4J5-H,OH = 0.7 Hz).
The d-azido ketone 6a was reacted with PPh3 (1 equiv) in THF
(reflux, 3 h) to give 1,2,3,4-tetrahydropyridine 9a in 90% yield.11
Under these conditions, the intermediate 2,3,4,5-tetrahydropyri-
dine 8a was transformed into 9a via an imine–enamine tautomeric
shift. Treatment of pyrimidine 7b with 1 equiv of PPh3 (THF, reflux,
2 h) produced 1,2,3,4-tetrahydropyridine 9b in 70% yield through
the intermediate formation of the d-azido ketone 6b.12 According
to 1H NMR spectroscopic data (DMSO-d6 solutions), compounds
9a,b exist in the conformation with a pseudo axial orientation of
the ureido group.
Tetrahydropyridines 9a,b are versatile precursors for prepara-
tion of various aromatic and hydrogenated pyridines. Treatment
of 9a with active MnO2 in refluxing toluene resulted in the elimi-
nation of urea followed by oxidative aromatization affording
2-phenyl-3-tosylpyridine (10) in a 64% yield (Scheme 4).13
The structure of 10 was confirmed by IR and NMR spectroscopic
data, and an X-ray single crystal analysis (Fig. 1).14
Figure 1. The X-ray crystal structure of 10.
reduction of 1,2,3,4-tetrahydro- and 4-hydroxy- or 4-alkoxyhexa-
hydropyrimidine-2-thiones/ones.15 The reaction proceeded with
high stereoselectivity to give 4-ureidopiperidine 11 as a mixture
of three diastereomers with a ratio of 70:25:5 in a 66% combined
yield.16 The major isomer was isolated from the diastereomeric
mixture by single crystallization. Its configuration and conforma-
tion was determined using 1H NMR data and 1H,1H-NOESY. The ax-
ial orientation of the ureido group and the equatorial orientation of
the phenyl group were confirmed by the cross peaks between the
NH proton of the ureido fragment and the axial protons 2-H and 6-
H in the 1H,1H-NOESY. The low values of vicinal coupling between
2-H, 3-H, and 4-H (3J2-H,3-H = 3.3, 3J3-H,4-H = 2.7 Hz) proved the axial
orientation of the tosyl group. Thus, the major diastereomer of 11
has the (2R⁄, 3R⁄, 4S⁄)-configuration.
Reduction of 9a was carried out with the NaBH4/CF3COOH
system in THF which previously we successfully used for the
In summary, we have shown that amidoalkylation of Na-eno-
lates of
a-functionalized ketones with readily available N-[(3-azi-
do-1-tosyl)propyl]urea gives general access to d-azido-b-ureido
ketones or their cyclic isomers, 6-(2-azidoethyl)-4-hydroxyhexa-
hydropyrimidin-2-ones. These compounds can be transformed into
4-ureido-substituted 1,2,3,4-tetrahydropyridines via Staudinger/
Scheme 2. Synthesis of the starting amidoalkylation reagent, N-[(3-azido-1-
tosyl)propyl]urea (4).

A. A. Fesenko, A. D. Shutalev / Tetrahedron Letters 53 (2012) 6261–6264
6263
4. For reviews on Staudinger/aza-Wittig reaction, see: (a) Hajós, G.; Nagy, I. Curr.
Org. Chem. 2008, 12, 39–58; (b) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales,
G.; DelosSantos, J. M. Tetrahedron 2007, 63, 523–573; (c) Eguchi, S. ARKIVOC
2005, 98–119; (d) Fresneda, P. M.; Molina, P. Synlett 2004, 1–17; (e) Wamhoff,
H.; Richardt, G.; Stölben, S. In Adv. Heterocycl. Chem; Katritzky, A. R., Ed.;
Academic Press: New York, 1995; Vol. 64, pp 159–249; (f) Molina, P.; Vilaplana,
M. J. Synthesis 1994, 1197–1218; (g) Gololobov, Yu. G.; Kasukhin, L. F.
Tetrahedron 1992, 48, 1353–1406; (h) Barluenga, J.; Palacios, F. Org. Prep.
Proced. Int. 1991, 23, 1–65; (i) Gololobov, Yu. G.; Zhmurova, I. N.; Kasukhin, L. F.
Tetrahedron 1981, 37, 437–472.
aza-Wittig reactions promoted by PPh3. 1,2,3,4-Tetrahydropyri-
dines were reduced by the NaBH4/CF3COOH system or aromatized
under the action of MnO2 with the loss of urea to give 3-function-
alized 4-ureidopiperidines and pyridines, respectively. We envis-
age that the synthesis of functionalized pyridine derivatives
described herein is an attractive alternative to classical procedures.
This synthesis is flexible and can be adapted to the preparation of a
library of 3-functionalized 4-ureido-1,2,3,4-tetrahydopyridines
and 4-ureido-piperidines which are of great interest as potential
pharmacologically active compounds (see Ref. 1).
5. For recent examples of tetrahydropyridine and piperidine syntheses via
intramolecular aza-Wittig reaction, see: (a) Duroure, L.; Jousseaume, T.;
Aráoz, R.; Barré, E.; Retailleau, P.; Chabaud, L.; Molgó, J.; Guillou, C. Org.
Biomol. Chem. 2011, 9, 8112–8118; (b) Huh, C. W.; Schroeder, C.; Singh, G.;
ˇ
Aubé, J. J. Org. Chem. 2011, 76, 3160–3165; (c) Kavala, M.; Mathia, F.; Kozíšek, J.;
Acknowledgments
Szolcsányi, P. J. Nat. Prod. 2011, 74, 803–808; (d) Liau, B. B.; Shair, M. D. J. Am.
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M.; Hsung, R. P. Tetrahedron 2008, 64, 883–893; (h) Hotchkiss, D. J.; Kato, A.;
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Loiseleur, O.; Ritson, D.; Nina, M.; Crowley, P.; Wagner, T.; Hanessian, S. J. Org.
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This research was supported by the Presidential grant for young
scientists no. MK-4400.2011.3. We thank Dmitry A. Cheshkov for
2-D NMR experiments.
Supplementary data
Supplementary data (IR, 1H and 13C NMR spectra of 4, 6a, 7b,
9a,b, 10, (2R⁄,3R⁄,4S⁄)-11, 2-D NMR spectra of (2R⁄,3R⁄,4S⁄)-11
(1H,1H-COSY, 1H,13C-HSQC, 1H,1H-NOESY) in DMSO-d6 and X-ray
structural data for 10) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
022.
6. (a) Fesenko, A. A.; Trafimova, A. A.; Shutalev, A. D. Org. Biomol. Chem. 2012, 10,
447–462; (b) Kurochkin, N. N.; Fesenko, A. A.; Cheshkov, D. A.; Davudi, M. M.;
Shutalev, A. D. Tetrahedron Lett. 2011, 52, 88–91; (c) Fesenko, A. A.; Tullberg, M.
L.; Shutalev, A. D. Tetrahedron 2009, 65, 2344–2350; (d) Shutalev, A. D.; Kishko,
E. A.; Sivova, N. V.; Kuznetsov, A. Yu. Molecules 1998, 3, 100–106.
7. (a) Davies, A. J.; Donald, A. S. R.; Marks, R. E. J. Chem. Soc. 1967, 2109–2112; (b)
Boyer, J. H. J. Am. Chem. Soc. 1951, 73, 5248–5252.
8. Synthesis of N-[(3-azido-1-tosyl)propyl]urea (4): To a stirred emulsion of 3-
azidopropanal (1) (8.81 g, 88.91 mmol) in H2O (50 mL) was added p-
toluenesulfinic acid (3) (13.88 g, 88.86 mmol) under vigorous stirring for
1 min followed by the addition of H2O (80 mL). After 23 min to the obtained
suspension were added urea (16.01 g, 266.59 mmol) and H2O (90 mL). The
reaction mixture was stirred at rt for 24 h, cooled to 0 °C, the precipitate was
filtered, washed with ice-cold water, petroleum ether, and dried to give 22.75 g
(86%) of 4, which was used further without additional purification. Mp 108.5–
References and notes
1. (a) McAteer, C. H.; Balasubramanian, M.; Murugan, R. In Comprehensive
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pp 246–300; (c) Sainsbury, M. In Supplements to the 2nd Edition of Rodd’s
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Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 2, pp
511–524; (e) Bailey, T. D.; Goe, G. L.; Scriven, E. F. V. In The Chemistry of
Heterocyclic Compounds; Newkome, G. R., Ed.; John Wiley: New York, 1984; Vol.
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183–307. Part 1; (h) Brody, F.; Ruby, P. R. In The Chemistry of Heterocyclic
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589. Part 1.
2. (a) González-Bello, C.; Castedo, L. In Modern Heterocyclic Chemistry; Alvarez-
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Part 1.
110 °C (decomp., MeCN). IR (Nujol):
3065 (w) ( CHarom), 2161 (m), 2122 (s), 2105 (vs) (
1592 (m) ( CCarom), 1522 (s) (amide-II), 1283 (s) (mas SO2), 1142 (s) (ms SO2),
813 (m) (d CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO-d6): d = 7.67–7.72 (2H,
m
= 3461 (s), 3348 (s), 3330 (br m) (
m NH),
m
m
N3), 1666 (vs) (amide-I),
m
.
m, C(2)H and C(6)H in 4-MeC6H4), 7.39–7.45 (2H, m, C(3)H and C(5)H in 4-
3
MeC6H4), 6.97 (1H, d, JNH,CH = 10.2 Hz, NH), 5.72 (2H, s, NH2), 5.01 (1H, ddd,
3
3
3JCH,CH(D) = 11.1, JCH,NH = 10.2, JCH,CH(C) = 3.2 Hz, CHSO2), 3.54 (1H, ddd,
2JCH(A),CH(B) = 12.4, JCH(A),CH(C) = 6.5, JCH(A),CH(D) = 4.7 Hz, CH(A) in CH(A)H(B)N3),
3
3
2
3
3
3.31 (1H, ddd, JCH(B),CH(A) = 12.4, JCH(B),CH(C) = 9.2, JCH(B),CH(D) = 5.8 Hz, CH(B) in
CH(A)H(B)N3), 2.19 (1H, dddd,
2JCH(C),CH(D) = 14.0, 3JCH(C),CH(B) = 9.2,
3JCH(C),CH(A) = 6.5, JCH(C),CH = 3.2 Hz, CH(C) in CH(C)H(D)CH2N3), 2.40 (3H, s, CH3
3
2
3
3
in Ts), 1.76 (1H, dddd, JCH(D),CH(C) = 14.0, JCH(D),CH = 11.1, JCH(D),CH(B) = 5.8,
3JCH(D),CH(A) = 4.7 Hz, CH(D) in CH(C)H(D)CH2N3). 13C NMR (75.48 MHz, DMSO-d6):
d = 156.6 (C@O), 144.5 (C-4 in 4-MeC6H4), 133.9 (C-1 in 4-MeC6H4), 129.7 (C-3
and C-5 in 4-MeC6H4), 129.0 (C-2 and C-6 in 4-MeC6H4), 67.9 (CHSO2), 46.9
(CH2CH2N3), 26.6 (CH2CH2N3), 21.2 (CH3). Anal. Calcd for C11H15N5O3S: C,
44.44; H, 5.09; N, 23.55. Found: C, 44.60; H, 5.41; N, 23.38.
9. Synthesis of N-[(5-azido-1-oxo-1-phenyl-2-tosyl)pent-3-yl]urea (6a): To
a
mixture of tosylacetophenone (5a)17 (3.922 g, 14.30 mmol) and NaH (0.343 g,
14.29 mmol) was added dry MeCN (14 mL), the obtained mixture was stirred
for 15 min and to the resulting dense enolate suspension were added sulfone 4
(4.245 g, 14.28 mmol) and dry MeCN (6 mL). The formed suspension was
stirred at rt for 8 h, and the solvent was removed in vacuum. To the white solid
residue was added a saturated aqueous solution of NaHCO3 (22 mL). The
obtained mixture was left for 2 h in a water bath (40 °C), overnight at rt, and
cooled (0 °C). The precipitate was filtered, washed with ice-cold water,
petroleum ether, cold (–10 °C) Et2O, and dried to give 6a (5.492 g, 93%) as a
mixture of two diastereomers in a ratio of 54:46. After crystallization from
EtOH the diastereomeric ratio changed to 51:49. Mp 166 °C (decomp., EtOH). IR
3. For recent examples, see: (a) Gati, W.; Rammah, M. M.; Rammah, M. B.; Couty,
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Okamoto, K.; Murakoso, M.; Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 3182–
3185; (c) Wen, J.; Zhang, R.-Y.; Chen, S.-Y.; Zhang, J.; Yu, X.-Q. J. Org. Chem.
(Nujol):
3054 (w), 3039 (w) (
1627 (m) ( C@O, amide-I), 1595 (m), 1579 (w), 1489 (w) (
(amide-II), 1294 (mas SO2), 1141 (ms SO2), 813 (m) (d CHarom in Ts), 744 (s), 691
(m) (d CHarom in Ph) cmꢁ1 1H NMR of the 51:49 diastereomeric mixture
m
= 3450 (s), 3374 (s), 3332 (s), 3224 (s) (
m
NH), 3087 (w), 3066 (w),
N3), 1673 (s), 1661 (s),
CCarom), 1550 (s)
m
CHarom), 2167 (m), 2104 (vs) (
m
m
m
ˇ
2012, 77, 766–771; (d) Bezenšek, J.; Prek, B.; Grošelj, U.; Kasunic, M.; Svete, J.;
.
Stanovnik, B. Tetrahedron 2012, 68, 4719–4731; (e) Chen, M. Z.; Micalizio, G. C.
J. Am. Chem. Soc. 2012, 134, 1352–1356; (f) Donohoe, T. J.; Bower, J. F.; Baker, D.
B.; Basutto, J. A.; Chan, L. K. M.; Gallagher, P. Chem. Commun. 2011, 10611–
10613; (g) Andersson, H.; Olsson, R.; Almqvist, F. Org. Biomol. Chem. 2011, 9,
337–346; (h) Zhang, F.; Duan, X.-F. Org. Lett. 2011, 13, 6102–6105; (i) Kim, S.-
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Tetrahedron Lett. 2010, 51, 2657–2659; (k) Coleridge, B. M.; Bello, C. S.;
Ellenberger, D. H.; Leitner, A. Tetrahedron Lett. 2010, 51, 357–359; (l) Luzung, M.
R.; Patel, J. S.; Yin, J. J. Org. Chem. 2010, 75, 8330–8332; (m) Campeau, L.-C.;
Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058–1068; (n) Zeni, G.; Larock, R. C. Chem.
Rev. 2006, 106, 4644–4680; (o) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285–2309.
(300.13 MHz, DMSO-d6): d = 7.29–7.90 (9H, m, Ph and C6H4 in both isomers),
3
6.160 (0.51H, d, JCH,CH = 8.9 Hz, CHSO2 in major isomer), 6.159 (0.49H, d,
3
3JCH,CH = 8.0 Hz, CHSO2 in minor isomer), 5.98 (0.49H, d, JNH,CH = 7.1 Hz, NH in
3
minor isomer), 5.93 (0.51H, d, JNH,CH = 7.0 Hz, NH in major isomer), 5.56
(1.02H, s, NH2 in major isomer), 5.51 (0.98H, s, NH2 in minor isomer), 4.39
3
3
3
3
(0.51H, dddd, JCH(A) = 10.5, JCH,CH = 8.9, JCH,NH = 7.0, JCH,CH(B) = 3.3 Hz, CHN in
3
3
3
major isomer), 4.25 (0.49H, dddd, JCH(A) = 8.5, JCH,CH = 8.0, JCH,NH = 7.1,
3JCH,CH(B) = 5.3 Hz, CHN in minor isomer), 3.33–3.43 (0.98H, m, CH2N3 in
minor isomer), 3.16–3.30 (1.02H, m, CH2N3 in major isomer), 2.36 (1.47H, s,
CH3 in minor isomer), 2.33 (1.53H, s, CH3 in major isomer), 2.00–2.11 (0.51H,
m, CH(B) in CH2CH2N3 of major isomer), 1.75–1.89 (1.49H, m, CH(A) in

6264
A. A. Fesenko, A. D. Shutalev / Tetrahedron Letters 53 (2012) 6261–6264
3
2
CH2CH2N3 of major isomer, CH(A) and CH(B) in CH2CH2N3 of minor isomer). 13
C
4J2-He,4-H = 1.4 Hz, 2-He), 2.95 (1H, ddd, J2-Ha,3-Ha = 13.3, J2-Ha,2-He = 12.8,
NMR of the 51:49 diastereomeric mixture (75.48 MHz, DMSO-d6): d = 192.9,
192.3 (C@O in Bz), 157.8 (CONH2), 144.9, 144.8 (C-4 in 4-MeC6H4), 137.1, 136.9
(C-1 in Ph), 135.8, 135.2 (C-1 in 4-MeC6H4), 134.2, 134.0 (C-4 in Ph), 129.6,
129.5; 128.99, 128.95; 128.8; 128.6, 128.5 (C-2, C-3, C-5, C-6 in Ph and 4-
MeC6H4), 70.5, 69.7 (CHSO2), 47.6, 47.5 (CH2CH2N3), 47.2 (CHNH), 30.7, 32.4
(CH2CH2N3), 21.10, 21.06 (CH3). Anal. Calcd for C19H21N5O4S: C, 54.93; H, 5.09;
N, 16.86. Found: C, 54.88; H, 5.22; N, 16.88.
3J2-Ha,3-He = 3.4 Hz, 2-Ha), 2.15 (3H, s, CH3 in Ac), 1.99 (3H, s, 6-CH3), 1.79
2
3
3
3
(1H, dddd, J3-He,3-Ha = 13.1, J3-He,2-Ha = 3.4, J3-He,4-H = 2.8, J3-He,2-He = 2.1 Hz,
3
2
3
3-He), 1.38 (1H, dddd, J3-Ha,2-Ha = 13.3, J3-Ha,3-He = 13.1, J3-Ha,2-He = 4.8,
3J3-Ha,4-H = 3.4 Hz, 3-Ha). 13C NMR (75.48 MHz, DMSO-d6): d = 193.4 (C@O in
Ac), 157.6 (NH2C@O), 155.5 (C-6), 101.6 (C-5), 43.1 (C-4), 35.7 (C-2), 27.6 (CH3
in Ac), 27.6 (C-3), 21.9 (6-CH3). Anal. Calcd for C9H15N3O2: C, 54.81; H, 7.67; N,
21.30. Found: C, 54.67; H, 7.83; N, 21.16.
10. Synthesis of 5-acetyl-6-(2-azidoethyl)-4-hydroxy-4-methylhexahydropyrimidin-2-
one (7b): To a stirred, cooled in an ice bath suspension of NaH (0.289 g,
12.04 mmol) in dry MeCN (8 mL) was added dropwise the solution of acetyl
acetone (5b) (1.218 g, 12.17 mmol) in dry MeCN (10 mL) and the resulting
suspension was stirred for 25 min. To the formed suspension were added
sulfone 4 (3.252 g, 10.94 mmol) and dry MeCN (3 mL). The reaction mixture
was stirred at rt for 7 h 45 min, and the solvent was removed in vacuum. The
residue was triturated with petroleum ether (4 ꢂ 10 mL), after decantation of
the last portion of petroleum ether saturated aqueous solution of NaHCO3
(9 mL) and petroleum ether (10 mL) were added, the obtained suspension was
left overnight at rt, and cooled (0 °C). The precipitate was filtered, washed with
ice-cold water, petroleum ether, cold (–10 °C) Et2O (2 ꢂ 10 mL), and dried to
give compound 7b (1.974 g, 75%) as a single (4R⁄,5R⁄,6R⁄)-diastereomer. Mp
13. Synthesis
of
2-phenyl-3-tosylpyridine
(10):
The
suspension
of
tetrahydropyridine 9a (0.718 g, 1.93 mmol) and active MnO2 (2.528 g) in
toluene (25 mL) was refluxed under stirring for 1.5 h, cooled to room
temperature, filtered through a silica gel pad (0.5 cm), the filter cake was
washed with acetone (5 ꢂ 15 mL), the combined filtrates were evaporated in
vacuum. The residue was dried in vacuum and triturated with petroleum ether
(3 mL) until crystallization was complete. The precipitate was filtered, washed
with petroleum ether (3 ꢂ 3 mL), and dried to give 10 (0.384 g, 64%). Mp
140.5–141 °C (EtOH). IR (Nujol):
m
= 3079 (w), 3065 (w) (
m
m
CHarom), 1593 (m),
as SO2), 1160 (s) (ms
1567 (m), 1550 (s), 1510 (w) ( CNarom
m
,
m
CCarom), 1322 (s) (
SO2), 817 (s) (d CHarom in Ts), 764 (s), 702 (s) (d CHarom in Ph) cmꢁ1 1H NMR
.
3
4
(600.13 MHz, DMSO-d6): 8.86 (1H, dd, J6-H,5-H = 4.8, J6-H,4-H = 1.6 Hz, 6-H),
3
4
3
8.62 (1H, dd, J4-H,5-H = 8.2, J4-H,6-H = 1.6 Hz, 4-H), 7.73 (1H, dd, J5-H,4-H = 8.2,
160.5 °C (decomp., EtOH). IR (Nujol):
NH), 2148 (m), 2108 (s), 2088 (s) (
(amide-I), 1501 (s) (amide-II), 1135 (s) (
m
= 3298 (s), 3266 (s), 3100 (br s) (
N3), 1714 (s) ( C@O in Ac), 1653 (vs)
C-O) cmꢁ1 1H NMR (300.13 MHz,
m
OH,
3J5-H,6-H = 4.8 Hz, 5-H), 7.39–7.43 (1H, m, C(4)H in Ph), 7.27–7.31 (2H, m, C(3)
H
m
m
.
and C(5)H in Ph), 7.15–7.19 (4H, m, C6H4), 7.06–7.09 (2H, m, C(2)H and C(6)H in
Ph), 2.31 (3H, s, CH3). 13C NMR (150.90 MHz, DMSO-d6): d = 157.8 (C-2), 152.9
(C-6), 144.2 (C-4 in 4-MeC6H4), 137.9 (C-1 in 4-MeC6H4), 137.0 (C-4), 136.7,
136.6 (C-1 in Ph, C-3), 129.4, 129.2, 127.4, 127.1 (C-2, C-3, C-5, C-6 in Ph and 4-
MeC6H4), 128.5 (C-4 in Ph), 123.1 (C-5), 20.9 (CH3). Anal. Calcd for C18H15NO2S:
C, 69.88; H, 4.89; N, 4.53. Found: C, 69.76; H, 5.01; N, 4.75.
m
4
DMSO-d6): d = 7.07 (1H, d, JN(3)H,N(1)H = 1.8 Hz, N(3)H), 6.55 (1H, d,
4
4JN(1)H,N(3)H = 1.8 Hz, N(1)H), 5.71 (1H, d, JOH,5-H = 0.7 Hz, OH), 3.92 (1H, ddd,
3
3
3J6-H,5-H = 11.7, J6-H,CH(A) = 7.4, J6-H,CH(B) = 2.9 Hz, 6-H), 3.41–3.57 (2H, m,
3
4
CH2N3), 2.45 (1H, dd, J5-H,6-H = 11.7, J5-H,OH = 0.7 Hz, 5-H), 2.18 (3H, s, CH3 in
Ac), 1.40–1.66 (2H, m, CH2CH2N3), 1.28 (3H, s, 4-CH3). 13C NMR (75.48 MHz,
DMSO-d6): d = 207.6 (C=O in Ac), 154.5 (C-2), 78.0 (C-4), 61.0 (C-5), 46.4
(CH2CH2N3), 45.9 (C-6), 32.0 (CH2CH2N3), 30.4 (CH3 in Ac), 27.5 (4-CH3). Anal.
Calcd for C9H15N5O3: C, 44.81; H, 6.27; N, 29.03. Found: C, 45.01; H, 6.26; N,
29.16.
14. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 891696. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 (0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
15. Shutalev, A. D.; Komarova, E. N.; Ignatova, L. A. Chem. Heterocycl. Compd. 1993,
29, 1182–1191.
11. Synthesis of 6-phenyl-5-tosyl-4-ureido-1,2,3,4-tetrahydropyridine (9a): To
a
mixture of 6a (0.360 g, 0.87 mmol) and PPh3 (0.231 g, 0.88 mmol) was added
dry THF (4 mL) and the obtained mixture was refluxed under stirring for 3 h.
The clear solution formed at the beginning of reflux and after 20 min the
product precipitated to give the dense suspension. After the reaction was
complete, the mixture was cooled (–10 °C), the precipitate was filtered on cold
(–10 °C) filter, washed with cold (–10 °C) THF (3 ꢂ 2 mL), cold (–10 °C) Et2O
(4 ꢂ 4 mL), petroleum ether, and dried to give 9a (0.291 g, 90%). Mp 131–
16. Synthesis of 2-phenyl-3-tosyl-4-ureidopiperidine (11): To a stirred, cooled in an
ice-bath suspension of finely powdered NaBH4 (0.621 g, 16.41 mmol) and
tetrahydropyridine 9a (0.777 g, 2.09 mmol) in dry THF (6 mL), was added
CF3COOH (13 mL) dropwise over 25 min with protection from air moisture
(CaCl2-tube). The obtained solution was stirred at rt for 6 h, the solvents were
removed in vacuum (temperature of bath about 40–45 °C), the resulting oil
was co-evaporated with toluene (2 ꢂ 10 mL). The residue was dissolved in H2O
(5 mL), neutralized with solid Na2CO3, the resulting solution was extracted
with CHCl3 (6 ꢂ 10 mL), the combined extracts were washed with water to pH
7, brine, and dried over Na2SO4. The solvent was removed in vacuum, the
residual foam was triturated with cold Et2O (3 mL) until crystallization was
complete. The obtained suspension was cooled (ꢁ10 °C), the precipitate was
filtered, washed with cold (ꢁ10 °C) Et2O (3 ꢂ 5 mL), petroleum ether, and dried
to give 11 (0.512 g, 66%) as a mixture of three diastereomers in a ratio of
70:25:5. After crystallization from MeCN, the major isomer with (2R⁄,3R⁄,4S⁄)-
configuration was obtained. Mp 204ꢁ204.5 °C (decomp., MeCN). IR (Nujol):
132 °C (decomp., MeCN). IR (Nujol):
(sh), 3185 (s) ( NH), 1667 (vs) (amide-I), 1617 (m), 1607 (m) (
(s) ( C@C), 1515 (s), 1500 (vs) (amide-II), 1294 (s) ( as SO2), 1139 (vs) (
809 (m) (d CHarom in Ts), 762 (s), 701 (s) (d CH in Ph) cmꢁ1 1H NMR
m
= 3434 (s), 3382 (sh), 3364 (br s), 3303
CCarom), 1569
s SO2),
m
m
m
m
m
.
(300.13 MHz, DMSO-d6): d = 7.17–7.40 (7H, m, C6H4 and C(3)H, C(4)H, C(5)H in
3
Ph), 7.18 (1H, d, J1-H,2-He = 4.6 Hz, 1-H), 7.03–7.09 (2H, m, C(2)H and C(6)H in
3
Ph), 6.07 (1H, d, JNH,4-H = 6.6 Hz, NH), 5.40 (2H, s, NH2), 4.71 (1H, dddd,
3
3
4
3J4-H,NH = 6.6, J4-H,3-Ha = 3.3, J4-H,3-He = 2.8, J4-H,2-He = 1.3 Hz, 4-H), 3.17–3.27
3
2
3
(1H, m, 2-He), 3.07 (1H, ddd, J2-Ha,3-Ha = 13.6, J2-Ha,2-He = 12.9, J2-Ha,3-He
=
3.6 Hz, 2-Ha), 2.33 (3H, s, CH3), 1.83–1.92 (1H, m, 3-He), 1.38 (1H, dddd,
2
3
3
3J3-Ha,2-Ha = 13.6, J3-Ha,3-He = 12.9, J3-Ha,2-He = 4.9, J3-Ha,4-H = 3.3 Hz, 3-Ha). 13C
NMR (75.48 MHz, DMSO-d6): d = 157.4 (C@O), 155.6 (C-6), 142.7 (C-4 in
4-MeC6H4), 141.3 (C-1 in 4-MeC6H4), 136.2 (C-1 in Ph), 128.9, 128.6 (br), 127.2,
126.0 (C-2, C-3, C-5, C-6 in Ph and 4-MeC6H4), 128.5 (C-4 in Ph), 99.1 (C-5),
42.5 (C-4), 36.0 (C-2), 27.3 (C-3), 20.9 (CH3). Anal. Calcd for C19H21N3O3S: C,
61.44; H, 5.70; N, 11.31. Found: C, 61.07; H, 6.07; N, 11.55.
m
= 3468 (s), 3407 (s), 3356 (br m), 3339 (s), 3213 (m) (
(w), 3018 (w) ( CHarom), 1646 (s), 1620 (s) (amide-I), 1594 (w) (
(s) (amide-II), 1295 (s) (
(s), 701 (s) (d CHarom in Ph) cmꢁ1
m
NH), 3057 (w), 3037
m
m
CCarom), 1514
m
as SO2), 1130 (s) (ms SO2), 811 (m) (d CHarom in Ts), 754
.
1H NMR of (2R⁄,3R⁄,4S⁄)-11 (600.13 MHz,
3
DMSO-d6): d = 6.97–7.07 (9H, m, Ph and C6H4), 6.75 (1H, d, JNH,4-H = 7.1 Hz,
3
3
NH), 5.55 (2H, s, NH2), 4.72 (1H, dddd, J4-H,NH = 7.1, J4-H,5-Ha = 4.2,
3
3
12. Synthesis of 5-acetyl-6-methyl-4-ureido-1,2,3,4-tetrahydropyridine (9b): To
a
3J4-H,5-He = 3.1, J4-H,3-H = 2.7 Hz, 4-H), 4.34 (1H, d, J2-H,3-H = 3.3 Hz, 2-H), 3.88
3 3 4
mixture of 7b (0.268 g, 1.11 mmol) and PPh3 (0.294 g, 1.12 mmol) was added
dry THF (4 mL), the obtained mixture was refluxed under stirring for 2 h, and
the solvent was removed in vacuum. The solid residue was triturated with
diethyl ether until the crystallization was complete, the precipitate was
filtered, washed with Et2O, Et2O–THF (6 mL, 1:1 v/v), Et2O (2 ꢂ 4 mL),
petroleum ether, and dried to give 9b (0.153 g, 70%). Note: filtration and
washings were performed without cooling to remove POPh3 completely. Mp
(1H, ddd, J3-H,2-H = 3.3, J3-H,4-H = 2.7, J3-H,5-He = 1.0 Hz, 3-H), 3.16 (1H, ddd,
3 3
2J6-He,6-Ha = 14.0, J6-He,5-Ha = 5.1, J6-He,5-He = 1.9 Hz, 6-He), 2.92 (1H, ddd,
2J6-Ha,6-He = 14.0, J6-Ha,5-Ha = 13.2, J6-Ha,5-He = 2.8 Hz, 6-Ha), 2.58 (1H, br s,
3
3
2
3
1-H), 2.28 (3H, s, CH3), 1.99 (1H, dddd, J5-Ha,5-He = 14.1, J5-Ha,6-Ha = 13.2,
3J5-Ha,6-He = 5.1, J5-Ha,4-H = 4.2 Hz, 5-Ha), 1.53 (1H, ddddd, J5-He,5-Ha = 14.1,
3
2
3J5-He,4-H = 3.1, J5-He,6-Ha = 2.8, J5-He,6-He = 1.9, J5-He,3-H = 1.0 Hz, 5-He). 13C
NMR of (2R⁄,3R⁄,4S⁄)-11 (150.90 MHz, DMSO-d6): d = 157.8 (C@O), 142.9 (C-4
in 4-MeC6H4), 139.3 (C-1 in 4-MeC6H4), 138.5 (C-1 in Ph), 129.0, 127.4, 126.6,
126.3 (C-2, C-3, C-5, C-6 in Ph and 4-MeC6H4), 126.1 (C-4 in Ph), 64.5 (C-3),
54.9 (C-2), 43.9 (C-4), 41.0 (C-6), 27.8 (C-5), 20.9 (CH3). Anal. Calcd for
3
3
4
168–168.5 °C (decomp., EtOH). IR (Nujol):
3217 (sh), 3100 (s) ( NH), 1646 (s) ( C@O and amide-I), 1591 (s) (
1516 (vs) (amide-II) cmꢁ1 1H NMR (300.13 MHz, DMSO-d6): d = 7.22 (1H, d,
3J1-H,2-He = 4.6 Hz, 1-H), 5.97 (1H, d, 3JNH,4-H = 6.9 Hz, NH), 5.32 (2H, s, NH2), 4.48
m
= 3417 (s), 3344 (s), 3270 (vs),
m
m
m
C@C),
.
C
19H23N3O3S: C, 61.10; H, 6.21; N, 11.25. Found: C, 61.08; H, 6.44; N, 11.32.
3
3
3
4
(1H, dddd, J4-H,NH = 6.9, J4-H,3-Ha = 3.4, J4-H,3-He = 2.8, J4-H,2-He = 1.4 Hz, 4-H),
17. Arndt, F.; Martius, C. Liebigs Ann. Chem. 1932, 499, 228–287.
3.14 (1H, ddddd, 2J2-He,2-Ha = 12.8, 3J2-He,3-Ha = 4.8, 3J2-He,1-H = 4.6, 3J2-He,3-He = 2.1,