A novel access to pyrido[4,3-d]pyrimidine scaffold via Staudinger/intramolecular aza-Wittig reaction of 5-acyl-4-(β-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones

Article abstract of DOI:10.1016/j.tet.2014.06.128

A general four-step approach to 1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-ones via Staudinger/intramolecular aza-Wittig reaction of 5-acyl-4-(β-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones promoted by PPh was developed. Synthesis of the starting pyrimidinones included preparation of 3-azidoaldehydes by the addition of hydrazoic acid to α,β-unsaturated aldehydes, transformation of 3-azidoaldehydes into N-[(3-azido-1-tosyl)alkyl]ureas followed by the reaction with enolates of dibenzoylmethane, benzoylacetone, acetylacetone, or ethyl 2,4-dioxo-4-phenylbutanoate and dehydration of the resulting products under acidic conditions.

Full text of DOI:10.1016/j.tet.2014.06.128

Tetrahedron 70 (2014) 5398e5414
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel access to pyrido[4,3-d]pyrimidine scaffold via
Staudinger/intramolecular aza-Wittig reaction
of 5-acyl-4-(
b
-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones
*
Anastasia A. Fesenko, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow State University of Fine Chemical Technologies, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A general four-step approach to 1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-ones via Staudinger/
Received 29 April 2014
Received in revised form 18 June 2014
Accepted 30 June 2014
intramolecular aza-Wittig reaction of 5-acyl-4-(
moted by PPh3 was developed. Synthesis of the starting pyrimidinones included preparation of 3-
azidoaldehydes by the addition of hydrazoic acid to -unsaturated aldehydes, transformation of 3-
azidoaldehydes into N-[(3-azido-1-tosyl)alkyl]ureas followed by the reaction with enolates of di-
benzoylmethane, benzoylacetone, acetylacetone, or ethyl 2,4-dioxo-4-phenylbutanoate and dehydration
of the resulting products under acidic conditions.
b-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones pro-
a,b
Available online 3 July 2014
Keywords:
Azidoaldehydes
Tetrahydropyrimidines
Pyrido[4,3-d]pyrimidines
Ureidoalkylation
Ó 2014 Elsevier Ltd. All rights reserved.
Staudinger reaction
Aza-Wittig reaction
1. Introduction
Staudinger/aza-Wittig sequence (Scheme 1). The synthesis of py-
rimidines B could include ureidoalkylation of enolates of 1,3-
Pyridopyrimidines are of current interest due to their multi-
faceted pharmacological profiles.1 Among them, pyrido[4,3-d]py-
rimidines remain relatively less explored in spite of their
interesting applications. For example, they manifest remarkable
inhibitory properties against epidermal growth factor receptor ty-
rosine kinase2 and dihydrofolate reductase.3 These compounds
possess antioxidant,4 antitumor,5 antiulcer,6 antibacterial,7 and
pesticidal activities.8 The described syntheses of pyrido[4,3-d]py-
rimidines mainly start with either pyridine or pyrimidine pre-
cursor, which is modified to annulate the other ring.1 However, to
the best of our knowledge, Staudinger/intramolecular aza-Wittig
reaction,9 a powerful strategy for nitrogen heterocycles construc-
tion has never been applied to pyrido[4,3-d]pyrimidines synthesis.
Previously, we developed a completely general and flexible
approach to the synthesis of various 5-functionalized 1,2,3,4-
diketones with N-(3-azido-1-tosylalkyl)ureas C followed by de-
hydration of the resulting products. Azides C could be obtained by
three-component condensation of 3-azidoaldehydes D, p-toluene-
sulfinic acid, and ureas.
tetrahydropyrimidin-2-ones/thiones,
substituted ones, based on ureidoalkylation of ketone enolates with
-tosyl-substituted N-alkylureas or N-alkylthioureas.10 We have
hypothesized that pyrido[4,3-d]pyrimidin-2-one scaffold A could
be assembled from 5-acyl-4-(2-azidoalkyl)pyrimidines B using
specifically,
5-acyl-
Scheme 1. Retrosynthesis of pyrido[4,3-d]pyrimidin-2-ones via ureidoalkylation/
Staudinger/aza-Wittig reactions.
a
Successful application of this methodology has been reported
in our preliminary communication.11 Here, we describe full
details of hexahydropyrido[4,3-d]pyrimidines synthesis via
Staudinger/aza-Wittig reaction of 5-acyl-4-(
tetrahydropyrimidin-2-ones promoted by PPh3.
preparation of the starting pyrimidines using transformation of 3-
b
-azidoalkyl)-1,2,3,4-
A
three-step
* Corresponding author. Tel.: þ7 495 936 8908; fax: þ7 495 936 8909; e-mail
addresses: shutalev@orc.ru, anatshu@gmail.com (A.D. Shutalev).
http://dx.doi.org/10.1016/j.tet.2014.06.128
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5399
azidoaldehydes into N-[(3-azido-1-tosyl)alkyl]ureas followed by
reaction with enolates of dibenzoylmethane, benzoylacetone, ace-
tylacetone, or ethyl 2,4-dioxo-4-phenylbutanoate and dehydration
of resulting products under acidic conditions is described. The
procedure for preparative synthesis of 3-azidoaldehydes by the
more thoroughly using 1H NMR spectroscopy. The selected data are
given in Table 1.
Table 1
1H NMR study of the reaction of aldehydes 1bee with NaN3 in aqueous AcOH at
25 ꢁC
addition of hydrazoic acid to
reported.
a,b-unsaturated aldehydes is also
b
Entry
1
1/NaN3
2
Molar ratio of 2/1a after:
1 h
2 h
3 h
Work-up
1
2
3
4
5
1b
1b
1c
1d
1e
1:1.5
1:2.5
1:1.5
1:2.5
1:2.5
2b
2b
2c
2d
2e
92:8
96:4
d
92:8
96:4
90:10
87:13
84:16
92:8
96:4
92:8
d
97:3
98:2
94:6
98:2
95:5
2. Results and discussion
2.1. Synthesis of 3-azidoaldehydes and N-[(3-azido-1-tosyl)
alk-1-yl]ureas
74:26
69:31
d
According to 1H NMR spectroscopy for samples of reaction mixtures after 1, 2,
3 h (entries 1, 2, 4, 5: extracts in CDCl3; entry 3: solutions in D2O), and for crude
products after work-up (in CDCl3).
a
3-Azidoaldehydes served as starting compounds for the syn-
thesis of pyrido[4,3-d]pyrimidines. The described methods of their
preparation include oxidation of 3-azido alkohols,12 reduction of 3-
azido esters,13 reaction of 3-tosyloxy aldehydes with sodium
b
Molar ratio.
Table 1 shows that the addition of HN3 to crotonaldehyde (1b)
proceeded rapidly (<1 h) at room temperature to give a 92:8
equilibrium mixture of 2b and 1b, respectively (entry 1). A greater
excess of NaN3 only slightly shifted this equilibrium to 2b (entry 2).
Compared with 1b, the rate of the addition decreased in-
significantly when pent-2-enal (1c) was used (entry 1 vs entry 3). In
azide,14 and addition of hydrazoic acid to
a,b-unsaturated alde-
hydes.15 However, 3-azidoaldehydes were prepared only on a small
scale (<1 g) and usually used in further reactions without purifi-
cation.16 Our initial task focused on preparation of pure 3-
azidoaldehydes on a multigram scale. We used the method based
on the reaction of sodium azide with a,b-unsaturated aldehydes
contrast to aldehydes 1aec,
a-alkyl-substituted aldehydes 1d,e
1aee in aqueous acetic acid, which seems to be the most promising.
3-Azidopropanal (2a) was prepared by the addition of aqueous
solution of NaN3 (1.5 equiv) to a cooled (ꢀ12 ꢁC) solution of acrolein
in acetic acid (Scheme 2). The product was isolated from the re-
action 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 under re-
duced pressure. We failed to remove diethyl ether completely and
achieve constant mass of the residue due to high volatility of azide
2a. According to 1H NMR data, the crude 2a always contained
a small quantity of diethyl ether. Previously, we described the use of
azide 2a prepared in this way in the synthesis of functionalized
pyridine derivatives17 and two pyrido[4,3-d]pyrimidines.11 In the
current work, we attempted to purify the crude 2a by fast vacuum
distillation at 48e59 ꢁC/15e20 mmHg collecting the main fraction
in an ice-cooled flask.18 As a result, azide 2a was obtained as
a colorless transparent liquid (53% yield from acrolein). However,
the distilled 2a was unstable and decomposed in the receiving flask
already during distillation. After some time, we observed slow gas
evolution (probably HN3) from the main fraction and a minor de-
crease in vacuum.19 Therefore, 3-azidopropanal (2a) was used im-
mediately after distillation.
reacted much more slowly even if 2.5 equiv of NaN3 was used
(entries 4 and 5).
Based on 1H NMR experiments, we developed a simple medium-
scale procedure for preparation of azidoaldehydes 2bee. According
to this procedure, an aqueous solution of NaN3 (1.5e2.5 equiv) was
added to a solution of aldehydes 1bee in AcOH followed by stirring
of the resulting reaction mixture for 3e4 h at room temperature.
Azidoaldehydes 2bee were obtained in 51e71% yield after extrac-
tive work-up, neutralization, drying, and distillation18 of crude
products. Compared with 2a, compounds 2bee were stable upon
distillation but gradually decomposed during storage at room
temperature (slowly in CDCl3 solutions, faster in liquid phase)
(NMR spectroscopy data). Stability of azides 2bee, especially in
CDCl3 solutions, significantly increased upon storage at ꢀ18 ꢁC.
We used freshly distilled 3-azidoaldehydes 2aee as starting
materials for the synthesis of the required ureidoalkylation re-
agents. The synthesis involved three-component condensation of
2aee, p-toluenesulfinic acid (3), and urea (4a) or N-methylurea (4b)
to give the corresponding N-[(3-azido-1-tosyl)alk-1-yl]ureas 5aef
(Scheme 3).
Scheme 2. Synthesis of 3-azidoaldehydes 2aee.
Scheme 3. Synthesis of ureidoalkylation reagents, N-[(3-azido-1-tosyl)alk-1-yl]ureas
5aef.
We extended this method to the preparation of other 3-
azidoaldehydes 2bee. In contrast to acrolein, crotonaldehyde (1b)
reacted with NaN3 (1.5 equiv) in aqueous acetic acid more slowly
affording only 72% conversion after 4.25 h at ꢀ12 ꢁC according to 1H
NMR spectroscopic analysis of a sample of the reaction mixture
dissolved in D2O. Increase in the reaction temperature improved
conversion, which changed to 83% after additional 55 min at 0 ꢁC,
and then to 93% after 1.5 h at 25 ꢁC. The work-up of the reaction
mixture as described above for 2a gave practically pure azide 2b
containing only 3% of the starting material. The obtained results
prompted us to examine the addition of HN3 to aldehydes 2bee
Optimized reaction conditions for preparation of ureas 5aef and
their yields are summarized in Table 2.
Three-component condensation of 3-azidopropanal (2a), sul-
finic acid 3, and urea (5 equiv) or N-methylurea (1.5 equiv)
smoothly proceeded in water at room temperature for 24 h to give
substituted ureas 5a,b as white solids in 84 and 90% yields, re-
spectively (entries 1 and 2).20 In contrast, the reactions of other
azidoaldehydes 2bee with acid 3 and urea in water at room tem-
perature afforded only gummy materials containing the expected
azidoalkyl ureas 5cef along with considerable amount of various

5400
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
Table 2
The reaction of sulfone 5a with the Na-enolate of 6a readily
proceeded at room temperature in 7 h 45 min to give a product of
nucleophilic substitution of the tosyl group, the corresponding
ureido ketone 7a, which spontaneously and completely cyclized
into hydroxypyrimidinone 8a under the reaction conditions. Py-
rimidine 8a was isolated in 75% yield as a single diastereomer
(Table 3, entry 1). According to 1H NMR data, this diastereomer had
Reaction of 3-azidoaldehydes 2aee with p-toluenesulfinic acid (3) and ureas 4a,b
Entry
2
4
Reaction conditionsa
5
Yieldb (%)
Isomer ratioc
1
2
3
4
5
6
2a
2a
2b
2c
2d
2e
4a
4b
4a
4a
4a
4a
H2O, 24 h
H2O, 24 h
25% Aq HCOOH, 8 h
30% Aq EtOH, 16 h
30% Aq EtOH, 19 h
30% Aq EtOH, 18 h
5a
5b
5c
5d
5e
5f
84
90
92
92
79
83
d
d
55:45
58:42
82:18
63:37
(4R
*
,5R
*
,6R )-configuration with equatorial orientation of the sub-
*
stituents at C-5 and C-6 (3J5-H,6-H¼11.7, 3JN(1)H,6-Hz0 Hz)21 and axial
orientation of the hydroxyl group (4J5-H,OH¼0.7 Hz) in DMSO-d6.
In contrast to the reaction of 5a with the Na-enolate of 6a, all
other reactions of 5aec with Na-enolates of 6aec (MeCN or THF, rt,
8e8.33 h) gave only the corresponding acyclic ureido ketones 7beg
in 54e91% yield (Scheme 4; Table 3, entries 2e7).
a
Room temperature; 1:1:5 molar ratio of 2/3/4 for the synthesis of 5a,cef and
1:1:1.5 molar ratio of 2/3/4 for the synthesis of 5b.
b
Isolated yields.
c
According to 1H NMR spectra of the crude products.
byproducts (NMR spectroscopy data). Compound 5c was success-
fully prepared in a yield of 92% by sequential addition of acid 3 and
a fivefold excess of urea to a solution of 3-azidobutanal (2b) in 25%
aqueous HCOOH (entry 3). However, only complex mixtures
formed in the reactions of aldehydes 2cee with 3 and 4a when
aqueous HCOOH was used in various concentrations. Condensation
of these aldehydes with 3 and 4a cleanly proceeded in 30% aqueous
EtOH to give the expected products 5def in 79e92% yield (entries
4e6). Under optimal conditions (Table 2), sulfones 5aef pre-
cipitated from the reaction mixtures formed after the addition of all
reagents as white solids. They were isolated by filtration with >95%
purity according to 1H NMR spectra of the crude products and used
in the ureidoalkylation step without additional purification. Com-
pounds 5cef were obtained as mixtures of two diastereomers
(Table 2).
The products 8a, 7beg were readily isolated after removal of
solvent followed by aqueous NaHCO3 work-up and filtration with
>95% purity (1H NMR spectroscopy data) and were used in further
syntheses without additional purification. Their yields were good,
except compound 7d (54%). The moderate yield of 7d can be
explained by partial loss of the product during aqueous work-up
because of enhanced solubility of 7d in water. Our attempt to im-
prove yield of 7d using extractive work-up of a mother liquor with
CHCl3 failed. Compounds 7b,e,g were obtained as diastereomeric
mixtures (Table 3).
We also attempted to react sulfone 5e with the Na-enolate of 6b
in MeCN (rt, 8 h) and sulfone 5a with the Na-enolate of 6d (Scheme
4; R3¼Ph, R4¼COOEt) in THF (rt, 8 h). However, after removal of
solvent and addition of saturated aqueous NaHCO3 to the resulting
residues, only gummy materials were obtained that did not solidify
even upon prolonged manipulations. Therefore, it became evident
2.2. Synthesis of 5-acyl-4-(b-azidoalkyl)-1,2,3,4-
that in these and similar cases the synthesis of 5-acyl-4-(b-azi-
tetrahydropyrimidin-2-ones
doalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones should be performed
using a one-pot procedure directly from sulfones 5 without iso-
lation of the ureidoalkylation products 7, 8 from the reaction
mixtures. Previously, we demonstrated that this one-pot procedure
is often very effective for the pyrimidine synthesis.10f,g,i
According to the retrosynthetic plan (Scheme 1), the next step of
the pyrido[4,3-d]pyrimidin-2-one scaffold synthesis involved two-
step transformation of sulfones 5 into the corresponding 5-acyl-4-
(b-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones using our pre-
Thus, we developed two different synthetic methods for prep-
aration of tetrahydropyrimidines 9aep (Scheme 5). First, we
viously developed methodology for pyrimidine ring construction.10
First, we studied ureidoalkylation of sodium enolates of acetyla-
cetone, benzoylacetone, and dibenzoylmethane with sulfones 5aec
in dry MeCN or THF (Scheme 4, Table 3). The enolates were gen-
erated by treatment of the corresponding CH-acids 6aec with NaH.
Scheme 5. Synthesis of 5-acyl-4-(
9aep.
b-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones
Scheme 4. Ureidoalkylation of Na-enolates of 1,3-diketones 6aec with sulfones 5aec.
Table 3
Reaction of azidoalkyl ureas 5aec with 1,3-diketones 6aec in the presence of NaH at room temperature
Entry
5
6
R
R1
R2
R3
R4
NaH/6 molar ratioa
Solvent
Reaction time (h)
Product
Yieldb (%)
Isomer ratioc
d
1
2
3
4
5
6
7
5a
5a
5a
5b
5b
5b
5c
6a
6b
6c
6a
6b
6c
6b
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
H
Me
Ph
Ph
Me
Ph
Ph
Ph
Me
Me
Ph
Me
Me
Ph
1.10:1.11
1.00:1.02
1.05:1.01
1.00:1.02
1.02:1.05
1.05:1.00
1.01:1.02
MeCN
MeCN
THF
MeCN
MeCN
THF
7.75
8.33
8
8a
7b
7c
7d
7e
7f
75
79
90
54
82
91
75
52:48
d
8
d
8.25
8.08
8
59:41
d
Me
MeCN
7g
27:28:19:26
a
The amount of the corresponding sulfone 5 is 1.00 equiv.
Isolated yields.
b
c
According to 1H NMR spectra of the crude products.
d
A single diastereomer with (4R
*
,5R
*
*
,6R )-configuration.

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5401
examined the transformation of hydroxypyrimidine 8a and ureido
ketones 7b,c,g into the corresponding tetrahydropyrimidines
9a,f,g,k. It was found that dehydration of 8a cleanly proceeded in
refluxing EtOH for 1 h in the presence of TsOH (0.19 equiv) to give
pyrimidine 9a in 77% yield (Table 4, entry 1). The yield of 9a de-
creased to 63% when this reaction was carried out under similar
conditions but in refluxing MeCN.
pyrimidines 9 varied from moderate to high (47e82%) with the
exception of compounds 9o,p. The latter were isolated by silica
gel column chromatography in only 19 and 14% yields, re-
spectively (entries 16 and 17). Notably, the yield of pyrimidine 9a
obtained from 5a and 6a in the one-pot procedure was slightly
higher (61%) than the overall yield in two steps (58%) (entry 2 vs
entry 1).
Table 4
Synthesis of 5-acyl-4-(b-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-ones 9aep
Entry
Starting
material
R
R1
R3
R4
Reaction conditions
Product
Yielda (%)
Isomer ratiob
1
2
8a
5aþ6a
H
H
H
H
Me
Me
Me
Me
TsOH (0.19 equiv), EtOH, reflux, 1 h
9a
9a
77
61
d
d
(i) 6a (1.03 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.32 equiv), THF, reflux, 1.67 h
(i) 6a (1.04 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.32 equiv), THF, reflux, 1.92 h
(i) 6a (1.06 equiv), NaH (1.02 equiv), THF, rt, 8 h
(ii) TsOH (1.30 equiv), THF, reflux, 1.92 h
(i) 6a (1.06 equiv), NaH (1.02 equiv), THF, rt, 8 h
(ii) TsOH (1.30 equiv), THF, reflux, 1.92 h
(i) 6a (1.03 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.31 equiv), THF, reflux, 1.83 h
TsOH (0.20 equiv), EtOH, reflux, 1 h
3
4
5
6
5cþ6a
5dþ6a
5eþ6a
5fþ6a
Me
Et
H
H
Me
Me
Me
Me
Me
Me
Me
Me
9b
9c
9d
9e
47
74
63
76
86:14
65:35
56:44
69:31
H
Me
Et
H
7
8
9
7b
7g
5dþ6b
H
Me
Et
H
H
H
Ph
Ph
Ph
Me
Me
Me
9f
9g
9h
89
88
82
d
TsOH (0.21 equiv), EtOH, reflux, 45 min
(i) 6b (1.02 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.31 equiv), THF, reflux, 1.5 h
55:45
55:45
10
11
5eþ6b
5fþ6b
H
H
Me
Et
Ph
Ph
Me
Me
(i) 6b (1.06 equiv), NaH (1.03 equiv), THF, rt, 8 h
(ii) TsOH (1.30 equiv), THF, reflux, 1.58 h
(i) 6b (1.02 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.30 equiv), THF, reflux, 1.83 h
TsOH (1.01 equiv), EtOH, reflux, 2.25 h
(i) 6d (1.03 equiv), NaH (1.01 equiv), THF, rt, 8.17 h
(ii) TsOH (1.32 equiv), THF, reflux, 3.17 min
(i) 6d (1.03 equiv), NaH (1.02 equiv), THF, rt, 8 h
(ii) TsOH (1.30 equiv), THF, reflux, 2.5 h
(i) 6d (1.03 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.40 equiv), THF, reflux, 2.33 h
(i) 6d (1.03 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.43 equiv), THF, reflux, 2.33 h
(i) 6d (1.03 equiv), NaH (1.01 equiv), THF, rt, 8 h
(ii) TsOH (1.40 equiv), THF, reflux, 2.33 h
9i
9j
79
73
50:50
67:33
12
13
7c
5aþ6d
H
H
H
H
Ph
Ph
Ph
COOEt
9k
9l
21
60
d
d
14
15
16
17
5cþ6d
5dD6d
5eþ6d
5fþ6d
Me
Et
H
H
Ph
Ph
Ph
Ph
COOEt
COOEt
COOEt
COOEt
9m
9n
9o
9p
62
73
19
14
63:37
62:38
60:40
50:50
H
Me
Et
H
a
Isolated yields.
b
According to 1H NMR spectra of the crude products.
Ureido ketones 7b and 7g smoothly underwent cycliza-
2.3. Synthesis of pyrido[4,3-d]pyrimidin-2-ones
tionedehydration in refluxing EtOH in the presence of TsOH to
give the corresponding pyrimidines 9f and 9g in high yields (en-
tries 7 and 8). In contrast, the reduced electrophilicity of the
benzoyl carbonyl groups in dibenzoylmethane derivative 7c ex-
tremely hampered the cyclizationedehydration of this compound
to afford pyrimidine 9k. In this case greater amounts of TsOH
(>0.5 equiv) and longer reaction times were required for com-
pletion of conversion of the starting material in refluxing EtOH or
MeCN. These conditions led to formation of a significant amount
of various byproducts that complicated isolation of 9k and sharply
decreased its yield. Compound 9k was obtained in pure form only
in 21% yield by refluxing 7c in EtOH in the presence of 1.01 equiv
of TsOH for 2 h 15 min followed by isolation of 9k using silica gel
column chromatography (entry 12). In this experiment diben-
zoylmethane (6c) was isolated in a 30% yield as one of the
byproducts.
The final step of the synthesis of pyrido[4,3-d]pyrimidin-2-ones
10 was intramolecular Staudinger/aza-Wittig reaction of 5-acyl-4-
(b-azidoalkyl)pyrimidines 9 promoted by PPh3 (Scheme 6).
Next, we developed a convenient one-pot synthesis of tetra-
hydropyrimidines 9aee,hej,lep based on the reaction of sulfones
5a,cef with Na-enolates of 6a,b,d in THF (rt, 8e8.17 h) followed
by the addition of 1.30e1.43 equiv of TsOH and heating at reflux
for 1.5e3.17 h (Table 4, entries 2e6, 9e11, 13e17). The completion
of the second step was monitored by TLC. Tetrahydropyrimidines
9 were isolated from the reaction mixtures after removal of the
solvent, aqueous NaHCO3 work-up of the resulting residues, and
filtration of the obtained solids. Generally, the yields of
Scheme 6. Synthesis of pyrido[4,3-d]pyrimidin-2-ones 10aeh from 5-acyl-4-(b-azi-
doalkyl)pyrimidines 9a,b,deg,i,m via intramolecular Staudinger/aza-Wittig reaction.
Initially, we studied the reaction of 9a with PPh3 (1.1 equiv) in
various solvents (THF, MeCN, and 1,4-dioxane) at reflux for 1.5 h. The
obtained reaction mixtures were evaporated in vacuo to dryness,
and the composition of residues dissolved in DMSO-d6 was

5402
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
determined using 1H NMR spectroscopy. The starting material
disappeared in all cases, and the expected pyridopyrimidine 10a
formed as the main heterocyclic product. However, the reaction in
THF, besides 45% of 10a, gave two other compounds in a ratio of
30:25 that seem to be intermediates of incomplete conversion of
9a into 10a. According to 1H NMR spectrum, one of them (30%)
was iminophosphorane 11a. These intermediates were absent in
refluxing 1,4-dioxane, but significant amount of side products
formed along with 10a. Refluxing MeCN gave the better result fur-
nishing pyridopyrimidine 10a plus the above intermediates in a ra-
tio of 83:13:4, respectively. An increase in the reaction time to 6 h
was necessary to achieve complete conversion of 9a into 10a in
MeCN at reflux (1H NMR spectroscopy data).
The reaction of 5-benzoyl-substituted pyrimidine 9f with PPh3
(1.1 equiv) in refluxing THF for 6 h was studied. Although the
starting material was consumed, no traces of the bicyclic product
10e were detected in the 1H NMR spectrum of the crude reaction
mixture.
Therefore, the results obtained show that the transformation of
pyrimidines 9 into bicycles 10 is controlled predominantly by the
intramolecular aza-Wittig reaction. Specifically, the rate of this step
depends on electrophilicity of carbonyl group and steric factors in
iminophosphoranes 11. Based on these data, further we carried out
all the pyrido[4,3-d]pyrimidines syntheses in refluxing MeCN for
5.5e8 h (Table 5).
that both the protons are bonded to the ureido nitrogens. Therefore,
we concluded that the obtained pyridopyrimidines in DMSO-d6
solutions exist predominantly in the form of tautomer 10. This
conclusion is supported by a high geminal coupling constant be-
tween the 7-HA and 7-HB protons in 10a,c,e,g (14.8e17.9 Hz), in-
dicating that these protons are located at a-position to a double
bond.23 In addition, structures 10aeh are confirmed by the absence
of spinespin coupling between one of the NH protons and the 7-H
proton(s), which could be expected in the case of structures 12aeh.
It should be noted that the signal of the
N(3)H proton
(8.39e8.76 ppm) in 1H NMR spectra of 10aeh in DMSO-d6 solutions
appeared as an unusually broad singlet. In addition, 13C NMR
spectra of these compounds (except 10h) demonstrated a notice-
able broadening of the signal of the C-4 carbon (135.7e138.5 ppm).
These features of the NMR spectra could be explained by an ex-
changing process between tautomers 10 and 12. To confirm this
suggestion we performed ab initio calculations (B3LYP/6-
311þG(d,p))24 for pyridopyrimidines 10a,e and 12a,e in the gas
phase and in DMSO solution using the polarizable continuum
model (PCM). According to these calculations, in the gas phase,
10a,e are considerably more stable tautomers than 12a,e
(6.94e10.23 kcal/mol). However, the computed difference in en-
ergies of tautomers 10a,e and 12a,e in DMSO solution becomes
quite small (0.27e0.79 kcal/mol), suggesting that tautomeric
equilibrium between 10a,e and 12a,e in favor of 10a,e could take
place in solutions.
Table 5
The relative configurations of compounds 10bed,feh were de-
termined by 1H NMR spectroscopy. Large values of two vicinal
coupling constants between 7-H, 8-H, and 8a-H protons in 1H NMR
spectra of the major isomers of 10bed,f,h and the minor isomer of
10g (7.3e11.9 Hz) allowed us to conclude that the tetrahydropyr-
idine cycle of these compounds adopts a flattened chair confor-
mation with a pseudo axial orientation of the 8a-H proton and
a pseudo equatorial position of the alkyl group at C-7 (for 10b,d,f,h)
or C-8 (for 10c,g). Therefore, the above mentioned diastereomers
Synthesis of pyrido[4,3-d]pyrimidin-2-ones 10aeh via intramolecular Staudinger/
aza-Wittig reaction of 5-acyl-4-(
by PPh3
b
-azidoalkyl)pyrimidines 9a,b,deg,i,m promoted
a
Entry Starting Isomer
materialb ratio
R
R1 R3 R4
Time Product Yieldc Isomer
(h)
(%)
ratiod
1
2
3
4
5
6
7
8
9a
9b
9d
9e
9f
9g
9i
9m
d
H
H
H
Me Me
Me Me
5.5
7
6
6
7
8
6
6
10a
10b
10c
10d
10e
10f
94
84
87
55
95
96
90
26
d
86:14 Me
56:44
69:31 Et
90:10
57:43
65:35
d
H
Me Me Me
H
H
H
Me Me
Ph Me
Ph Me
d
H
had (7R
*
,8aS )-configuration. The relative configuration of the mi-
*
55:45 Me
50:50
67:37 Me
54:46
nor isomers of 10bed,f and the major isomer of 10g was (7R
*
,8aR ).
*
H
Me Ph Me
Ph COOEt
10g
10h
49:51
e
H
3. Conclusion
a
Reactions were carried out in refluxing MeCN in the presence of 1.13e1.18 equiv
of PPh3.
A general four-step approach to 1,2,3,7,8,8a-hexahydropyrido
[4,3-d]pyrimidin-2-ones via Staudinger/intramolecular aza-Wittig
reaction of 5-acyl-4-(b-azidoalkyl)-1,2,3,4-tetrahydropyrimidin-2-
b
Crude starting materials were used.
Isolated yields.
c
d
e
(7R
*
,8aS
*
)-10/(7R
*
,8aR
*
)-10. According to 1H NMR spectra of the crude products.
,8aS )-configuration was isolated by column
A single diastereomer with (7R
*
*
ones promoted by PPh3 was developed. Synthesis of the starting
pyrimidinones included transformation of 3-azidoaldehydes into
N-[(3-azido-1-tosyl)alkyl]ureas followed by reaction with enolates
of dibenzoylmethane, benzoylacetone, acetylacetone, or ethyl 2,4-
dioxo-4-phenylbutanoate and dehydration of the resulting prod-
ucts under acidic conditions. We believe that this approach to
pyrido[4,3-d]pyrimidine scaffold is very promising since both
components of the amidoalkylation reaction can be widely varied.
Furthermore, the prepared hexahydropyrido[4,3-d]pyrimidin-2-
ones can be aromatized or reduced by routine procedures
expanding the synthetic utility of the method.
Medium-scale synthesis of 3-azidoaldehydes based on the re-
action of a,b-unsaturated aldehydes with hydrazoic acid generated
from sodium azide and aqueous acetic acid was also developed.
High availability of 3-azidoaldehydes provides an opportunity for
wider application of these compounds in organic synthesis.
chromatography.
Since compounds 10aec were slightly soluble in MeCN, they
precipitated from the reaction mixtures and were isolated in pure
form in 84e94% yield by filtration. Compounds 10deh were iso-
lated in up to 96% yield using silica gel column chromatography of
the residues obtained after evaporation of the reaction mixtures.
Low yield of ethyl carboxylate 10h (26%) is caused by formation of
a huge amount of various byproducts (1H NMR spectroscopy data).
According to NMR data, pyrido[4,3-d]pyrimidines 10bed,f,g
formed as mixtures of two diastereomers in ratios that are close to
isomer ratios in the starting pyrimidines 9b,d,e,g,i (Table 5). Only
compound 10h was obtained as a single diastereomer indicating
that the second isomer of 10h did not form in the intramolecular
aza-Wittig reaction of intermediate 11h.
The structure of the obtained pyridopyrimidines was estab-
lished by NMR spectroscopy. First, we determined in which tauto-
meric form these compounds exist, namely, in the form of
4. Experimental section
4.1. General
1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-ones
10
or
1,2,6,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-ones 12 (Scheme
5).22 The values of 1H NMR chemical shifts for the two NH pro-
tons (6.88e7.21 and 8.39e8.76 ppm) in DMSO-d6 clearly indicated
All solvents were distilled before use. Petroleum ether had
a distillation range of 40e70 ꢁC. Dry solvents (MeCN, THF, 1,4-

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5403
dioxane) were obtained according to standard procedures. p-Tol-
uenesulfinic acid (3) was synthesized by treatment of saturated
aqueous solution of sodium p-toluenesulfinate25 with hydrochloric
acid at 0 ꢁC, dried over P2O5, and stored at 0 ꢁC. Sodium hydride
(60% suspension in mineral oil) was thoroughly washed with dry
pentane and dried under vacuum prior to use. 2-Ethylprop-2-enal
(1e) with bp 91e93.5 ꢁC/760 mmHg and 2-methylprop-2-enal
(1d) with bp 67e68 ꢁC/760 mmHg were used. Acrolein (1a) (90%,
Aldrich) was used without distillation since it had no effect on the
yield of 3-azidopropanal. Ethyl 2,4-dioxo-4-phenylbutanoate (6d)
was prepared as described in the literature26 and used without
crystallization. All other reagents were purchased from commercial
sources and used without additional purification. FTIR spectra were
recorded using a Bruker Vector 22 spectrophotometer in Nujol for
solid samples or in film for liquid samples. Band characteristics in
the IR spectra are defined as very strong (vs), strong (s), medium
(m), weak (w), shoulder (sh), and broad (br). 1H NMR and proton-
decoupled 13C NMR spectra (solutions in DMSO-d6 or CDCl3) were
acquired using a Bruker DPX 300 spectrometer at 300.13 MHz (1H)
and 75.48 MHz (13C). 1H NMR chemical shifts are referenced to the
residual proton signal in DMSO-d6 (2.50 ppm) or CDCl3 (7.25 ppm).
In 13C NMR spectra, central signals of DMSO-d6 (39.50 ppm) or
CDCl3 (77.00 ppm) were used as references. Multiplicities are re-
ported as singlet (s), doublet (d), triplet (t), quartet (q), and some
combinations of these, multiplet (m). Selective 1He1H decoupling
and DEPT-135 experiments were used to aid in the assignment of
1H and 13C NMR signals. Elemental analyses (CHN) were performed
by using a Thermo Finnigan Flash EA1112 apparatus. Thin-layer
chromatography was carried out on Aldrich silica gel 60 F254 alu-
minum backed plates in chloroform/methanol (9:1, v/v) and chlo-
roform/methanol (5:1, v/v) as solvent systems. Spots were
visualized with UV light or iodine vapors. Column chromatography
59 ꢁC/15 mmHg (the pressure slightly decreased during distilla-
tion). The distilled 2a (16.62 g, 53%) was very unstable and began to
decompose (slow gas evolution) in the receiving flask at the time of
distillation.19 Therefore, 3-azidopropanal (2a) was used in the next
step immediately after distillation. 1H NMR (300.13 MHz, DMSO-d6)
d
: 9.68 (1H, t, 3J¼1.2 Hz, CH]O), 3.58 (2H, t, 3J¼6.2 Hz, CH2N3), 2.76
(2H, dt, 3J¼6.2, 3J¼1.2 Hz, CH2C]O); 13C NMR (75.48 MHz, DMSO-
d6) d: 201.3 (C]O), 44.2 (CH2N3), 42.1 (CH2C]O).
4.2.2. 3-Azidobutanal (2b). A solution of NaN3 (16.05 g, 0.247 mol)
in H2O (60 mL) was added dropwise to a stirred solution of but-2-
enal (1b) (11.53 g, 0.164 mol) in AcOH (23 mL) cooled in an ice bath.
After the addition was complete, cooling was removed, the
resulting emulsion was warmed to room temperature (water bath),
stirred for 4 h, and extracted with diethyl ether (100 mL, 4ꢂ50 mL).
Combined extracts were washed with 7% aqueous solution of
Na2CO3 (3ꢂ50 mL, 25 mL), H2O (3ꢂ50 mL), brine (3ꢂ25 mL), and
dried overnight over Na2SO4 at þ4 ꢁC (transparent slightly yellow
liquid). Then the solvent was removed under reduced pressure, and
the residue was subjected to vacuum distillation to give 2b (13.30 g,
72%) as a colorless liquid, which was immediately used in the next
step. Bp 58e59.5 ꢁC/18 mmHg. n2D0 1.4490. 1H NMR (300.13 MHz,
CDCl3)
d
: 9.72 (1H, dd, 3J¼1.7, 3J¼1.3 Hz, CH]O), 4.02 (1H, ddq,
3J¼7.6, 3J¼6.6, 3J¼5.6 Hz, CHN3), 2.62 (1H, ddd, 2J¼17.4, 3J¼7.6,
3J¼1.7 Hz, HA in CH2C]O), 2.52 (1H, ddd, 2J¼17.4, 3J¼5.6, 3J¼1.3 Hz,
HB in CH2C]O), 1.30 (3H, d, 3J¼6.6 Hz, CH3); 13C NMR (75.48 MHz,
CDCl3) d: 199.3 (C]O), 52.1 (CHN3), 49.4 (CH2), 19.3 (CH3); IR (neat)
n
, cmꢀ1: 2978 (m), 2936 (w), 2905 (w), 2877 (w) (CH2, CH3), 2836
(m), 2734 (m) (HeCO), 2118 (vs) (N3), 1726 (s) (C]O), 1456 (m)
(CH2, CH3), 1381 (m) (CH3), 1265 (s) (N3).
4.2.3. 3-Azidopentanal (2c). Compound 2c was prepared from
pent-2-enal (1c) (9.569 g, 113.75 mmol), NaN3 (18.504 g,
284.55 mmol), H2O (60 mL), and AcOH (18 mL) as described for 2b.
The resulting emulsion was extracted with diethyl ether (2ꢂ25 mL,
2ꢂ20 mL). Combined extracts were washed with 7% aqueous so-
lution of Na2CO3 (3ꢂ30 mL, 15 mL), H2O (2ꢂ30 mL), brine
(3ꢂ15 mL), and dried for 1.5 h over Na2SO4 at room temperature
(transparent slightly yellow liquid). Then the solvent was removed
under reduced pressure, and the residue was subjected to vacuum
distillation collecting the main fraction (a colorless liquid) in the
receiving flask cooled in an ice bath. The distilled 2c (10.292 g, 71%)
was immediately used in the next step. Bp 32e35 ꢁC/0.1 mmHg. nD20
was performed
with MachereyeNagel silica
gel 60
(0.063e0.200 mm). All yields refer to isolated, spectroscopically
and TLC pure compounds. The color of substances was white, if not
otherwise mentioned. Evaporation of solvent from all the reaction
mixtures formed after one-pot syntheses of pyrimidines 9 (from 5)
was carried out, at the beginning, upon cooling (temperature of
water bath about 5e10 ꢁC), and low vacuum (about 100 mmHg),
otherwise the vigorous foaming complicated evaporation. Distil-
lation of 3-azidoaldehydes 2aec was performed without protecting
atmosphere since it had no effect on purity, yield or stability of
products. All 3-azidoaldehydes started to decompose during the
distillation if boiling temperature was higher than 70 ꢁC. The ge-
ometry optimizations of compounds 10a,e and 12a,e were carried
out at the B3LYP level of theory using Gaussian 09 suite24 of
quantum chemical programs. Pople’s basis sets, 6-311þG(d,p), were
employed for geometry optimization in both the gas phase and
DMSO solution. The effect of continuum solvation was incorporated
by using the polarizable continuum model (PCM).
1.4506. 1H NMR (300.13 MHz, CDCl3)
d
: 9.74 (1H, dd, 3J¼1.6,
3J¼1.3 Hz, CH]O), 3.79 (1H, dddd, 3J¼7.6, 3J¼6.5, 3J¼6.5, 3J¼5.4 Hz,
CHN3), 2.60 (1H, ddd, 2J¼17.5, 3J¼7.6, 3J¼1.6 Hz, HA in CH2C]O),
2.56 (1H, ddd, 2J¼17.5, 3J¼5.4, 3J¼1.3 Hz, HB in CH2C]O), 1.53e1.63
(2H, m, CH2 in Et), 0.96 (3H, t, 3J¼7.4 Hz, CH3); 13C NMR (75.48 MHz,
CDCl3)
d: 199.4 (C]O), 58.3 (CHN3), 47.6 (CH2CH]O), 27.4 (CH2 in
Et), 10.2 (CH3); IR (neat)
n
, cmꢀ1: 2972 (m), 2936 (m), 2881
(m) (CH2, CH3), 2836 (m), 2733 (m) (HeCO), 2102 (vs) (N3), 1726 (s)
(C]O), 1463 (m) (CH2, CH3), 1385 (m) (CH3), 1269 (s) (N3).
4.2. Synthesis of 3-azidoaldehydes
4.2.1. 3-Azidopropanal (2a). A solution of NaN3 (30.75 g, 0.473 mol)
in H2O (115 mL) was added dropwise to a stirred, cooled (internal
temperature ꢀ12 ꢁC) solution of acrolein (1a) (17.68 g, 0.315 mol) in
AcOH (45 mL). After the addition was completed, cooling was re-
moved, the resulting emulsion was stirred for additional 30 min,
and extracted with diethyl ether (2ꢂ100 mL, 3ꢂ50 mL). Combined
extracts were washed with 7% aqueous solution of Na2CO3
(3ꢂ50 mL, 2ꢂ30 mL), H2O (2ꢂ50 mL), brine (3ꢂ50 mL, 2ꢂ30 mL),
and dried overnight over Na2SO4 at þ4 ꢁC (transparent yellow
liquid). Then the solvent was removed under reduced pressure, and
the residue was subjected to fast vacuum distillation collecting the
main fraction (a colorless liquid) in the receiving flask cooled in an
ice bath. The collection began at bp 48 ꢁC/20 mmHg and finished at
4.2.4. 3-Azido-2-methylpropanal (2d). A solution of NaN3 (11.582 g,
178.10 mmol) in H2O (35 mL) was added dropwise to a stirred so-
lution of 2-methylprop-2-enal (1d) (4.993 g, 71.25 mmol) in AcOH
(12 mL) cooled in an ice bath. After the addition was complete,
cooling was removed, the resulting emulsion was warmed to room
temperature (water bath), stirred for 3 h, and extracted with diethyl
ether (4ꢂ20 mL). Combined extracts were washed with 7% aqueous
solution of Na2CO3 (3ꢂ20 mL, 10 mL), H2O (2ꢂ30 mL), brine
(3ꢂ15 mL), and dried for 1.5 h over Na2SO4 at room temperature
(transparent slightly yellow liquid). The solvent was removed under
reduced pressure, and the residue was subjected to vacuum distil-
lation, collecting the main fraction (a colorless liquid) in the re-
ceiving flask cooled in an ice bath. The distilled 2d (4.465 g, 55%) was

5404
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
immediately used in the next step. Bp 66e67 ꢁC/22 mmHg;
triturated until the fine suspension formed, H2O (10 mL) was added,
and the suspension was stirred at room temperature for 20 min.
Then N-methylurea (18.699 g, 252.42 mmol) and H2O (50 mL) were
added and the reaction mixture was stirred for 24 h. After 2, 4, and
6 h from the beginning of the reaction, the solid was triturated to
obtain the fine suspension. After about 3 h from the beginning of
the reaction the suspension became extremely dense, but after
trituration it was fluid enough to be stirred normally. When the
reaction was completed, the obtained mixture was cooled to 0 ꢁC,
the precipitate was filtered, washed with ice-cold water, petroleum
ether, and dried to give 5b (47.223 g, 90%), which was used without
further purification. Mp 114.5e115 ꢁC (decomp., MeCN); 1H NMR
34e39 ꢁC/1 mmHg. nD20 1.4514. 1H NMR (300.13 MHz, CDCl3)
d: 9.67
(1H, d, 3J¼0.9 Hz, CH]O), 3.59 (1H, dd, 2J¼12.5, 3J¼6.5 Hz, HA in
CH2N3), 3.47 (1H, dd, 2J¼12.5, 3J¼5.7 Hz, HB in CH2N3), 2.62 (1H,
dddq, 3J¼7.3, 3J¼6.5, 3J¼5.7, 3J¼0.9 Hz, CHC]O), 1.20 (3H, d,
3J¼7.3 Hz, CH3); 13C NMR (75.48 MHz, CDCl3)
d: 202.1 (C]O), 51.1
(CH2N3), 45.9 (CH),11.3 (CH3); IR (neat) n
, cmꢀ1: 2978 (m), 2937 (m),
2878 (m) (CH2, CH3), 2825 (m), 2728 (m) (HeCO), 2104 (vs) (N3),
1728 (s) (C]O), 1459 (m) (CH2, CH3), 1375 (w) (CH3), 1281 (s) (N3).
4.2.5. 3-Azido-2-ethylpropanal (2e). Compound 2e was prepared
from freshly distilled 2-ethylprop-2-enal (1e) (8.127 g,
96.61 mmol), NaN3 (15.708 g, 241.55 mmol), H2O (50 mL), and
AcOH (15 mL) as described for 2d. The resulting emulsion was
extracted with diethyl ether (2ꢂ25 mL, 2ꢂ20 mL). Combined ex-
tracts were washed with 7% aqueous solution of Na2CO3 (3ꢂ35 mL,
2ꢂ15 mL), H2O (2ꢂ35 mL), brine (3ꢂ15 mL), and dried for 1.5 h over
Na2SO4 at room temperature (transparent slightly yellow liquid).
The solvent was removed under reduced pressure, and the residue
was subjected to vacuum distillation, collecting the main fraction (a
colorless liquid) in the receiving flask cooled in an ice bath. The
distilled 2e (6.210 g, 51%) was immediately used in the next step. Bp
(300.13 MHz, DMSO-d6) d: 7.66e7.71 (2H, m, ArH), 7.39e7.45 (2H,
m, ArH), 6.88 (1H, d, 3J¼10.2 Hz, NHCH), 5.84 (1H, q, 3J¼4.7 Hz,
NHMe), 5.04 (1H, ddd, 3J¼10.2, 3J¼11.1, 3J¼3.3 Hz, CHSO2), 3.51 (1H,
ddd, 2J¼12.4, 3J¼6.7, 3J¼4.8 Hz, HA in CH2N3), 3.31 (1H, ddd, 2J¼12.4,
3J¼9.0, 3J¼6.0 Hz, HB in CH2N3), 2.41 (3H, s, CH3 in Ts), 2.40 (3H, d,
3J¼4.7 Hz, NCH3), 2.17 (1H, dddd, 2J¼13.9, 3J¼9.0, 3J¼6.7, 3J¼3.3 Hz,
HC in CH2CH2N3), 1.78 (1H, dddd, 2J¼13.9, 3J¼11.1, 3J¼6.0, 3J¼4.8 Hz,
H
D in CH2CH2N3); 13C NMR (75.48 MHz, DMSO-d6)
d: 156.6 (C]O),
144.4 (C), 133.8 (C), 129.5 (2CH), 128.9 (2CH), 68.4 (CHSO2), 46.9
(CH2N3), 26.7 (CH2CH2N3), 26.2 (NCH3), 21.0 (CH3 in Ts); IR (Nujol) n,
34e35 ꢁC/0.1 mmHg. nD20 1.4530. 1H NMR (300.13 MHz, CDCl3)
d:
cmꢀ1: 3373 (s), 3262 (s), 3179 (m) (NH), 3088 (w) (CHarom), 2110 (s)
(N3), 1657 (s) (amide-I), 1595 (w) (CCarom), 1560 (s) (amide-II), 1494
(w) (CCarom), 1298 (s), 1124 (s) (SO2), 820 (m) (CHarom). Anal. Calcd
for C12H17N5O3S: C, 46.29; H, 5.50; N, 22.49. Found: C, 46.59; H,
5.65; N, 22.10.
9.66 (1H, d, 3J¼1.5 Hz, CH]O), 3.58 (1H, dd, 2J¼12.6, 3J¼7.0 Hz, HA
in CH2N3), 3.48 (1H, dd, 2J¼12.6, 3J¼5.2 Hz, HB in CH2N3), 2.45 (1H,
3
ddddd, J¼7.0, 3J¼6.8, 3J¼6.6, 3J¼5.2, 3J¼1.5 Hz, CHC]O), 1.76 (1H,
ddq, 2J¼14.1, 3J¼7.5, 3J¼6.8 Hz, HC in CH2CH3),1.59 (1H, ddq, 2J¼14.1,
3J¼7.5, 3J¼6.6 Hz, HD in CH2CH3), 0.96 (3H, t, 3J¼7.5 Hz, CH3); 13C
NMR (75.48 MHz, CDCl3)
d
: 202.3 (C]O), 52.5 (CH), 49.2 (CH2N3),
4.3.3. N-[(3-Azido-1-tosyl)but-1-yl]urea (5c). Freshly distilled 3-
azidobutanal (2b) (6.588 g, 58.24 mmol) was dissolved in 80%
formic acid (29 mL) and H2O (29 mL), and to the resulting colorless
solution were subsequently added p-toluenesulfinic acid (9.099 g,
58.25 mmol) and H2O (20 mL). The mixture was stirred for 10 min,
then urea (17.485 g, 291.13 mmol) and H2O (9 mL) were added. The
resulting oily material partially dissolved, and new solid pre-
cipitated in 5 min. Then H2O (29 mL) was added, and the obtained
suspension was stirred for 8 h, cooled to 0 ꢁC, the precipitate was
filtered, washed with ice-cold water until the smell of HCOOH
disappeared, petroleum ether, and dried to give 5c (16.758 g, 92%)
as a 55:45 mixture of two diastereomers, which was used without
further purification. After crystallization from MeCN the di-
astereomeric ratio changed to 60:40, respectively. Mp 119e120 ꢁC
(decomp., MeCN); 1H NMR of the major isomer (300.13 MHz,
19.7 (CH2 in Et), 11.0 (CH3); IR (neat) n
, cmꢀ1: 2970 (m), 2937 (m),
2878 (m) (CH2, CH3), 2824 (m), 2724 (m) (HeCO), 2104 (vs) (N3),
1727 (s) (C]O), 1460 (m) (CH2, CH3), 1271 (s) (N3).
4.3. Synthesis of N-[(3-azido-1-tosyl)alk-1-yl]ureas
4.3.1. N-[(3-Azido-1-tosyl)prop-1-yl]urea (5a). To
a solution of
freshly distilled 3-azidopropanal (2a) (12.32 g, 0.124 mol) in H2O
(100 mL) at room temperature was added p-toluenesulfinic acid
(19.43 g, 0.124 mol) under vigorous stirring followed by the addition
of H2O (50 mL), and the resulting suspension was stirred for 30 min.
Thenurea(37.31 g, 0.621 mol) and H2O (100 mL)were added, and the
reaction mixture was stirred at room temperature for 24 h. The
obtained suspension was cooled to 0 ꢁC, the precipitate was filtered,
washed with ice-cold water, petroleum ether, and dried to give 5a
(30.89 g, 84%), which was used without further purification. Mp
DMSO-d6) d: 7.67e7.73 (2H, m, ArH, overlap with signals of anal-
ogous protons of the minor isomer), 7.39e7.45 (2H, m, ArH, overlap
with signals of analogous protons of the minor isomer), 7.04 (1H, d,
3J¼10.2 Hz, NH), 5.71 (2H, br s, NH2), 5.02 (1H, ddd, 3J¼10.7, 3J¼10.2,
3J¼3.8 Hz, CHSO2, partly overlap with signals of analogous proton of
the minor isomer), 3.70 (1H, ddq, 3J¼7.8, 3J¼6.5, 3J¼5.6 Hz, CHN3),
2.40 (3H, s, CH3 in Ts), 2.10 (1H, ddd, 2J¼13.8, 3J¼7.8, 3J¼3.8 Hz, HA in
CH2CH), 1.83 (1H, ddd, 2J¼13.8, 3J¼10.7, 3J¼5.6 Hz, HB in CH2CH),
1.18 (3H, d, 3J¼6.5 Hz, CH3CH); 1H NMR of the minor isomer
108.5e110 ꢁC (decomp., MeCN). 1H NMR (300.13 MHz, DMSO-d6)
d:
7.67e7.72 (2H, m, ArH), 7.39e7.45 (2H, m, ArH), 6.97 (1H, d,
3J¼10.2 Hz, NH), 5.72 (2H, s, NH2), 5.01 (1H, ddd, 3J¼11.1, 3J¼10.2,
3J¼3.2 Hz, CHSO2), 3.54 (1H, ddd, 2J¼12.4, 3J¼6.5, 3J¼4.7 Hz, HA in
CH2N3), 3.31 (1H, ddd, 2J¼12.4, 3J¼9.2, 3J¼5.8 Hz, HB in CH2N3), 2.19
(1H, dddd, 2J¼14.0, 3J¼9.2, 3J¼6.5, 3J¼3.2 Hz, HC in CH2CH2N3), 2.40
(3H, s, CH3), 1.76 (1H, dddd, 2J¼14.0, 3J¼11.1, 3J¼5.8, 3J¼4.7 Hz, HD in
CH2CH2N3); 13C NMR (75.48 MHz, DMSO-d6)
d: 156.6 (C]O), 144.5
(300.13 MHz, DMSO-d6) d: 7.67e7.73 (2H, m, ArH, overlap with
(C), 133.9 (C), 129.7 (2CH), 129.0 (2CH), 67.9 (CHSO2), 46.9 (CH2N3),
signals of analogous protons of the major isomer), 7.39e7.45 (2H,
m, ArH, overlap with signals of analogous protons of the major
isomer), 6.96 (1H, d, 3J¼10.2 Hz, NH), 5.73 (2H, br s, NH2), 5.02 (1H,
ddd, 3J¼11.7, 3J¼10.2, 3J¼2.6 Hz, CHSO2, partly overlap with signals
of analogous proton of the major isomer), 3.57 (1H, ddq, 3J¼10.5,
3J¼6.5, 3J¼3.1 Hz, CHN3), 2.40 (3H, s, CH3 in Ts), 2.00 (1H, ddd,
2J¼14.0, 3J¼10.5, 3J¼2.6 Hz, HA in CH2CH), 1.70 (1H, ddd, 2J¼14.0,
26.6 (CH2CH2N3), 21.2 (CH3); IR (Nujol)
n
, cmꢀ1: 3463 (br s), 3351 (bs
s), 3332 (br s), 3195 (br w) (NH), 3067 (w), 3056 (w), 3002 (w)
(CHarom), 2162 (m), 2123 (s), 2107 (s) (N3), 1667 (vs) (amide-I), 1593
(m) (CCarom), 1523 (s) (amide-II), 1283 (s), 1143 (s) (SO2), 813 (m)
(CHarom). Anal. Calcd for C11H15N5O3S: C, 44.44; H, 5.09; N, 23.55.
Found: C, 44.60; H, 5.41; N, 23.38.
3J¼11.7, 3J¼3.1 Hz, HB in CH2CH), 1.28 (3H, d, 3J¼6.5 Hz, CH3CH); 13
C
4.3.2. N-[(3-Azido-1-tosyl)prop-1-yl]-N0-methylurea (5b). To a solu-
tion of freshly distilled 3-azidopropanal (2a) (16.617 g,
167.70 mmol) in H2O (100 mL) was added p-toluenesulfinic acid
(26.199 g, 167.72 mmol) under vigorous stirring followed by the
addition of H2O (50 mL). After 2 min, the resulting solid was
NMR of the major isomer (75.48 MHz, DMSO-d6) d: 156.4 (C]O),
144.51 (C), 133.8 (C), 129.66 (2CH), 129.1 (2CH), 67.6 (CHSO2), 54.5
(CHN3), 32.9 (CH2), 21.2 (CH3 in Ts), 18.4 (CH3CH); 13C NMR of the
minor isomer (75.48 MHz, DMSO-d6)
d: 156.6 (C]O), 144.47 (C),
133.9 (C),129.68 (2CH),129.0 (2CH), 68.0 (CHSO2), 54.1 (CHN3), 33.2

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5405
(CH2), 21.2 (CH3 in Ts), 19.5 (CH3CH); IR (Nujol)
n
, cmꢀ1: 3452 (s),
3J¼8.3 Hz, HB in CH2N3), 2.56 (1H, dddq, 3J¼8.3, 3J¼6.9, 3J¼5.8,
3J¼2.7 Hz, CHCH3), 2.40 (3H, s, CH3 in Ts), 1.04 (3H, d, 3J¼6.9 Hz,
3388 (s), 3358 (br w), 3324 (br m), 3273 (m), 3217 (m) (NH), 2114
(s), 2085 (s) (N3), 1698 (s), 1668 (s) (amide-I), 1626 (w), 1598 (w)
(CCarom), 1520 (s) (amide-II), 1288 (s), 1144 (s) (SO2), 816 (m)
(CHarom). Anal. Calcd for C12H17N5O3S: C, 46.29; H, 5.50; N, 22.49.
Found: C, 46.36; H, 5.72; N, 22.54.
CH3CH); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6)
d:
7.67e7.73 (2H, m, ArH, overlap with signals of analogous protons of
the major isomer), 7.38e7.44 (2H, m, ArH, overlap with signals of
analogous protons of the major isomer), 6.96 (1H, d, 3J¼10.8 Hz,
NHCO), 5.69 (2H, br s, NH2), 4.98 (1H, dd, 3J¼10.8, 3J¼5.3 Hz, CHSO2),
3.73 (1H, dd, 2J¼12.3, 3J¼4.4 Hz, HA in CH2N3), 3.35 (1H, dd, 2J¼12.3,
3J¼7.7 Hz, HB in CH2N3), 2.46 (1H, dddq, 3J¼7.7, 3J¼6.9, 3J¼5.3,
3J¼4.4 Hz, CHCH3), 2.40 (3H, s, CH3 in Ts), 1.10 (3H, d, 3J¼6.9 Hz,
4.3.4. N-[(3-Azido-1-tosyl)pent-1-yl]urea (5d). Freshly distilled 3-
azidopentanal (2c) (7.826 g, 61.56 mmol) was dissolved in EtOH
(30 mL), and to the resulting colorless stirred solution were sub-
sequently added p-toluenesulfinic acid (9.631 g, 61.65 mmol) and
H2O (15 mL). p-Toluenesulfinic acid dissolved in 5 min. After
that urea (18.486 g, 307.79 mmol) and H2O (15 mL) were added.
After 5 min to the resulting solution was gradually added 60 mL of
H2O. After the addition of about 10e15 vol % of H2O the solid started
to precipitate from the solution. As soon as the precipitation began,
the addition of water was stopped, and the suspension was stirred
for 10e15 min, then the remaining H2O was added. The obtained
suspension was stirred at room temperature for 16 h, cooled to 0 ꢁC,
the precipitate was filtered, washed with ice-cold water, petroleum
ether, and dried to give 5d (18.488 g, 92%) as a 58:42 mixture of two
diastereomers, which was used without further purification. After
crystallization from MeCN the diastereomeric ratio changed to
55:45, respectively. Mp 117e117.5 ꢁC (decomp., MeCN). 1H NMR of
CH3CH); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
156.6 (C]O), 144.3 (C), 135.0 (C), 129.6 (2CH), 128.5 (2CH), 69.8
(CHSO2), 53.7 (CH2N3), 31.8 (CHCH3), 21.0 (CH3 in Ts), 12.2 (CH3CH);
13C NMR of the minor isomer (75.48 MHz, DMSO-d6)
d: 156.4 (C]O),
144.2 (C), 135.2 (C), 129.4 (2CH), 128.6 (2CH), 71.7 (CHSO2), 53.1
(CH2N3), 33.3 (CHCH3), 21.0 (CH3 in Ts), 15.3 (CH3CH); IR (Nujol) n,
cmꢀ1: 3466 (s), 3375 (s), 3261 (br s), 3197 (m), 3054 (m) (NH), 2100
(s) (N3), 1689 (m), 1660 (s) (amide-I), 1609 (m), 1592 (w) (CCarom),
1542 (s) (amide-II), 1298 (s), 1149 (s) (SO2), 821 (m) (CHarom). Anal.
Calcd for C12H17N5O3S: C, 46.29; H, 5.50; N, 22.49. Found: C, 46.55;
H, 5.58; N, 22.51.
4.3.6. N-[(3-Azido-2-ethyl-1-tosyl)prop-1-yl]urea (5f). Compound
5f (12.515 g, 83%) as a 63:37 mixture of two diastereomers was
prepared from freshly distilled aldehyde 2e (5.906 g, 46.45 mmol),
p-toluenesulfinic acid (7.269 g, 46.53 mmol), and urea (13.948 g,
232.24 mmol) in EtOH (23 mL) and H2O (92 mL) (18 h, rt) as de-
scribed for 5d. After crystallization from MeCN the diastereomeric
ratio changed to 65:35, respectively. Mp 102e102.5 ꢁC (decomp.,
the major isomer (300.13 MHz, DMSO-d6) d: 7.68e7.73 (2H, m, ArH,
overlap with signals of analogous protons of the minor isomer),
7.39e7.45 (2H, m, ArH, overlap with signals of analogous protons of
the minor isomer), 6.96 (1H, d, 3J¼10.2 Hz, NH), 5.69 (2H, br s, NH2),
5.06 (1H, ddd, 3J¼11.7, 3J¼10.2, 3J¼2.6 Hz, CHSO2), 3.29e3.38 (1H,
m, CHN3), 2.40 (3H, s, CH3 in Ts), 1.99 (1H, ddd, 2J¼14.1, 3J¼10.6,
3J¼2.6 Hz, HA in CH2CH), 1.75 (1H, ddd, 2J¼14.1, 3J¼11.7, 3J¼2.9 Hz,
HB in CH2CH), 1.35e1.67 (2H, m, CH2 in Et, overlap with signals of
analogous protons of the minor isomer), 0.94 (3H, t, 3J¼7.4 Hz, CH3
MeCN). 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d:
7.66e7.74 (2H, m, ArH, overlap with signals of analogous protons of
the minor isomer), 7.38e7.44 (2H, m, ArH, overlap with signals of
analogous protons of the minor isomer), 6.90 (1H, d, 3J¼10.8 Hz,
NHCO), 5.76 (2H, br s, NH2), 5.07 (1H, dd, 3J¼10.8, 3J¼3.8 Hz,
CHSO2), 3.81 (1H, dd, 2J¼12.6, 3J¼4.2 Hz, HA in CH2N3), 3.42 (1H, dd,
2J¼12.6, 3J¼7.3 Hz, HB in CH2N3), 2.39 (3H, s, CH3 in Ts), 2.20e2.35
(1H, m, CHCH2CH3, overlap with signals of analogous proton of the
minor isomer), 1.48e1.62 (1H, m, HC in CH2CH3), 1.31e1.46 (1H, m,
HD in CH2CH3), 0.88 (3H, t, 3J¼7.4 Hz, CH2CH3); 1H NMR of the
in Et); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6)
d:
7.68e7.73 (2H, m, ArH, overlap with signals of analogous protons of
the major isomer), 7.39e7.45 (2H, m, ArH, overlap with signals of
analogous protons of the major isomer), 7.01 (1H, d, 3J¼10.2 Hz,
NH), 5.67 (2H, br s, NH2), 5.04 (1H, ddd, 3J¼10.2, 3J¼10.2, 3J¼4.0 Hz,
CHSO2), 3.50e3.58 (1H, m, CHN3), 2.40 (3H, s, CH3 in Ts), 2.19 (1H,
ddd, 2J¼14.1, 3J¼7.0, 3J¼4.0 Hz, HA in CH2CH), 1.80 (1H, ddd, 2J¼14.1,
3J¼10.2, 3J¼6.2 Hz, HB in CH2CH), 1.35e1.67 (2H, m, CH2 in Et,
overlap with signals of analogous protons of the major isomer),
0.89 (3H, t, 3J¼7.4 Hz, CH3 in Et); 13C NMR of the major isomer
minor isomer (300.13 MHz, DMSO-d6) d: 7.66e7.74 (2H, m, ArH,
overlap with signals of analogous protons of the major isomer),
7.38e7.44 (2H, m, ArH, overlap with signals of analogous protons of
the major isomer), 6.91 (1H, d, 3J¼10.8 Hz, NHCO), 5.74 (2H, br s,
NH2), 5.11 (1H, dd, 3J¼10.8, 3J¼3.4 Hz, CHSO2), 3.66 (1H, dd, 2J¼12.6,
3J¼4.4 Hz, HA in CH2N3), 3.17 (1H, dd, 2J¼12.6, 3J¼8.6 Hz, HB in
CH2N3), 2.39 (3H, s, CH3 in Ts), 2.20e2.35 (1H, m, CHCH2CH3,
overlap with signals of analogous proton of the major isomer),
1.72e1.86 (1H, m, HC in CH2CH3), 1.09e1.28 (1H, m, HD in CH2CH3),
0.94 (3H, t, 3J¼7.4 Hz, CH2CH3); 13C NMR of the major isomer
(75.48 MHz, DMSO-d6) d: 156.5 (C]O), 144.36 (C), 133.9 (C), 129.6
(2CH), 128.88 (2CH), 68.0 (CHSO2), 60.2 (CHN3), 31.0 (CH2CHN3),
27.3 (CH2CH3), 21.1 (CH3 in Ts), 10.1 (CH3CH2); 13C NMR of the minor
isomer (75.48 MHz, DMSO-d6) d: 156.3 (C]O), 144.39 (C), 133.8 (C),
129.5 (2CH), 128.93 (2CH), 67.6 (CHSO2), 60.7 (CHN3), 31.1
(CH2CHN3), 25.9 (CH2CH3), 21.1 (CH3 in Ts), 9.7 (CH3CH2); IR (Nujol)
n
, cmꢀ1: 3455 (s), 3384 (s), 3337 (br m), 3272 (m), 3218 (m) (NH),
(75.48 MHz, DMSO-d6) d: 156.5 (C]O), 144.30 (C), 135.0 (C), 129.56
3046 (w) (CHarom), 2096 (s) (N3), 1696 (s), 1665 (s) (amide-I), 1624
(w), 1598 (w) (CCarom), 1517 (s) (amide-II), 1287 (s), 1142 (s) (SO2),
817 (m) (CHarom). Anal. Calcd for C13H19N5O3S: C, 47.99; H, 5.89; N,
21.52. Found: C, 48.12; H, 6.11; N, 21.55.
(2CH), 128.6 (2CH), 69.86 (CHSO2), 50.87 (CH2N3), 38.66
(CHCH2CH3), 22.1 (CH2 in Et), 21.1 (CH3 in Ts), 10.9 (CH3 in Et); 13C
NMR of the minor isomer (75.48 MHz, DMSO-d6) d: 156.6 (C]O),
144.26 (C), 135.1 (C), 129.57 (2CH), 128.5 (2CH), 69.94 (NCH), 50.85
(CH2N3), 38.67 (CHCH2CH3), 19.5 (CH2 in Et), 21.1 (CH3 in Ts), 11.3
4.3.5. N-[(3-Azido-2-methyl-1-tosyl)prop-1-yl]urea (5e). Compound
5e (23.870 g, 79%) as an 82:18 mixture of two diastereomers was
prepared from freshly distilled aldehyde 2d (10.953 g, 96.83 mmol),
p-toluenesulfinic acid (15.153 g, 97.01 mmol), and urea (29.070 g,
484.02 mmol) in EtOH (48.5 mL) and H2O (145.5 mL) (19 h, rt) as
described for 5d. After crystallization from MeCN the diastereomeric
ratio changed to 85:15, respectively. Mp 104.5 ꢁC (decomp., MeCN).
(CH3 in Et); IR (Nujol) n
, cmꢀ1: 3500 (s), 3392 (s), 3249 (m), 3189 (br
m), 3041 (m) (NH), 2105 (s) (N3), 1686 (w), 1659 (s) (amide-I), 1598
(m) (CCarom), 1552 (s) (amide-II), 1496 (w) (CCarom), 1305 (s), 1142
(s) (SO2), 818 (m) (CHarom). Anal. Calcd for C13H19N5O3S: C, 47.99; H,
5.89; N, 21.52. Found: C, 48.20; H, 5.97; N, 21.62.
4.4. Synthesis of 4-hydroxyhexahydropyrimidin-2-one 8a and
N-(g-oxoalkyl)ureas 7beh
1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d: 7.67e7.73
(2H, m, ArH), 7.38e7.44 (2H, m, ArH), 6.94 (1H, d, 3J¼10.8 Hz,
NHCO), 5.75 (2H, br s, NH2), 5.10 (1H, dd, 3J¼10.8, 3J¼2.7 Hz, CHSO2),
3.34 (1H, dd, 2J¼12.2, 3J¼5.8 Hz, HA in CH2N3), 3.15 (1H, dd, 2J¼12.2,
4.4.1. 5-Acetyl-6-(2-azidoethyl)-4-hydroxy-4-methylhexahydropyri-
midin2-one (8a). To stirred suspension of NaH (0.289 g,
a

5406
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
12.04 mmol) in dry MeCN (8 mL) cooled in an ice-cold bath was
added a solution of acetylacetone (6a) (1.218 g, 12.17 mmol) in
MeCN (10 mL), and the resulting mixture was stirred for 25 min.
The ice bath was removed, and to the obtained solution were
added sulfone 5a (3.252 g, 10.84 mmol) and MeCN (3 mL). The
suspension was stirred at room temperature for 7 h 45 min, and
solvent was removed under reduced pressure. The residue was
triturated with petroleum ether (15 mL) and saturated aqueous
solution of NaHCO3 (9 mL), the obtained mixture was left over-
night at room temperature and cooled to 0 ꢁC. The precipitate was
filtered, washed with ice-cold water, and petroleum ether. The
obtained solid was dried in a vacuum desiccator (over P2O5) on the
filter, cooled (ꢀ10 ꢁC), washed with cold (ꢀ10 ꢁC) diethyl ether
(3ꢂ4 mL), and dried to give 8a (1.974 g, 75%) as a single
(CHarom). Anal. Calcd for C14H17N5O3: C, 55.44; H, 5.65; N, 23.09.
Found: C, 55.56; H, 5.71; N, 23.02.
4.4.3. N-[(5-Azido-2-benzoyl-1-oxo-1-phenyl)pent-3-yl]urea
(7c). To a mixture of dibenzoylmethane (6c) (1.214 g, 5.41 mmol)
and NaH (0.122 g, 5.07 mmol) was added dry THF (11 mL), the
mixture was stirred in an ice-cold bath for 12 min, and to the
resulting solution were added sulfone 5a (1.492 g, 5.02 mmol) and
THF (7 mL). The reaction mixture was stirred at room temperature
for 8 h, and the solvent was removed under reduced pressure. To
a solid residue were added saturated aqueous solution of NaHCO3
(6 mL) and petroleum ether (10 mL), the obtained mixture was
triturated until complete crystallization, and the resulting sus-
pension was left overnight at room temperature and cooled to 0 ꢁC.
The precipitate was filtered, washed with ice-cold water and pe-
troleum ether. The obtained solid was dried in a vacuum desiccator
(over P2O5) on the filter, cooled (ꢀ10 ꢁC), washed with cold (ꢀ10 ꢁC)
diethyl ether (3ꢂ5 mL), and dried to give 7c (1.654 g, 90%). Mp
(4R
*
,5R
*
,6R
)-diastereomer. Mp 160.5 ꢁC (decomp., EtOH). 1H NMR
*
(300.13 MHz, DMSO-d6)
d
: 7.07 (1H, d, 4J¼1.8 Hz, N(3)H), 6.55 (1H,
d, 4J¼1.8 Hz, N(1)H), 5.71 (1H, d, 4J¼0.7 Hz, OH), 3.92 (1H, ddd,
3J¼11.7, 3J¼7.4, 3J¼2.9 Hz, 6-H), 3.41e3.57 (2H, m, CH2N3), 2.45
(1H, dd, 3J¼11.7, 4J¼0.7 Hz, 5-H), 2.18 (3H, s, CH3 in Ac), 1.40e1.66
(2H, m, CH2CH2N3), 1.28 (3H, s, 4-CH3); 13C NMR (75.48 MHz,
154.5 ꢁC (decomp., EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d:
7.93e8.05 (4H, m, ArH), 7.47e7.71 (6H, m, ArH), 6.20 (1H, d,
3J¼9.4 Hz, NH), 6.08 (1H, d, 3J¼4.8 Hz, CHC]O), 5.56 (2H, br s, NH2),
4.46 (1H, dddd, 3J¼10.1, 3J¼9.4, 3J¼4.8, 3J¼3.9 Hz, CHN), 3.41 (1H,
ddd, 2J¼12.4, 3J¼7.1, 3J¼5.2 Hz, HA in CH2N3), 3.30 (1H, ddd, 2J¼12.4,
3J¼8.2, 3J¼6.7 Hz, HB in CH2N3), 1.77e2.00 (2H, m, CH2CH2N3); 13C
DMSO-d6)
46.4 (CH2N3), 45.9 (C-6), 32.0 (CH2CH2N3), 30.4 (CH3 in Ac), 27.5
(4-CH3); IR (Nujol)
, cmꢀ1: 3298 (s), 3266 (s), 3100 (br s) (OH,
d: 207.6 (C]O in Ac), 154.5 (C-2), 78.0 (C-4), 61.0 (C-5),
n
NH), 2148 (m), 2108 (s), 2088 (s) (N3), 1714 (s) (C]O in Ac), 1653
(vs) (amide-I), 1501 (s) (amide-II), 1135 (s) (CeO). Anal. Calcd for
C9H15N5O3: C, 44.81; H, 6.27; N, 29.03. Found: C, 45.01; H, 6.26; N,
29.16.
NMR (75.48 MHz, DMSO-d6) d: 196.3 (C]O in Bz), 195.6 (C]O in
Bz), 158.0 (CONH2), 136.2 (C), 135.7 (C), 133.73 (CH), 133.67 (CH),
129.0 (2CH), 128.9 (2CH), 128.5 (2CH), 128.2 (2CH), 58.4 (CHC]O),
48.1 (CH2N3), 47.3 (CHN), 32.3 (CH2CH2N3); IR (Nujol) n
, cmꢀ1: 3414
4.4.2. N-[(1-Azido-4-benzoyl-5-oxo)hex-3-yl]urea (7b). To a mix-
ture of benzoylacetone (6b) (1.083 g, 6.68 mmol) and NaH (0.158 g,
6.58 mmol) was added dry MeCN (12 mL), the mixture was stirred
at room temperature for 26 min, and to the resulting suspension
were added sulfone 5a (1.945 g, 6.54 mmol) and MeCN (6 mL). The
suspension was stirred at room temperature for 8 h, and the sol-
vent was removed under reduced pressure. To a solid residue were
added saturated aqueous solution of NaHCO3 (2 mL) and petro-
leum ether (10 mL), the obtained mixture was triturated until
complete crystallization, and the resulting suspension was left
overnight at room temperature and cooled to 0 ꢁC. The precipitate
was filtered, washed with ice-cold water, and petroleum ether. The
obtained solid was dried in a vacuum desiccator (over P2O5) on the
filter, cooled (ꢀ10 ꢁC), washed with cold (ꢀ10 ꢁC) diethyl ether
(3ꢂ5 mL), and dried to give 7b (2.222 g, 79%) as a mixture of two
diastereomers (52:48). After two crystallizations from EtOH the
diastereomeric ratio changed to 48:52, respectively. Mp
124.5e125.0 ꢁC (decomp., EtOH). 1H NMR of the 48:52 di-
astereomeric mixture (after two crystallizations) (300.13 MHz,
(s), 3360 (s), 3197 (br s) (NH), 3060 (w) (CHarom), 2097 (s) (N3), 1691
(s) (C]O), 1658 (s) (amide-I), 1625 (w), 1595 (w), 1578 (w) (CCarom),
1542 (s) (amide-II), 763 (m), 688 (m) (CHarom). Anal. Calcd for
C19H19N5O3: C, 62.46; H, 5.24; N, 19.17. Found: C, 62.41; H, 5.30; N,
19.00.
4.4.4. N-[(4-Acetyl-1-azido-5-oxo)hex-3-yl]-N0-methylurea
(7d). Compound 7d (1.167 g, 54%) was prepared from acetylacetone
(6a) (0.866 g, 8.65 mmol), NaH (0.203 g, 8.45 mmol), and sulfone 5b
(2.630 g, 8.45 mmol) in dry MeCN (20 mL) (8 h, rt) as described for
8a. Mp 118e118.5 ꢁC (decomp., EtOH). 1H NMR (300.13 MHz,
DMSO-d6)
d
: 5.93 (1H, d, 3J¼9.6 Hz, NH), 5.93 (1H, q, 3J¼4.7 Hz,
NHCH3), 4.36 (1H, dddd, 3J¼9.6, 3J¼8.0, 3J¼6.8, 3J¼5.7 Hz, CHN),
4.14 (1H, d, 3J¼6.8 Hz, CHC]O), 3.20e3.37 (2H, m, CH2N3), 2.51 (3H,
d, 3J¼4.7 Hz, NCH3), 2.19 (3H, s, CH3 in Ac), 2.09 (3H, s, CH3 in Ac),
1.53e1.68 (2H, m, CH2CH2N3); 13C NMR (75.48 MHz, DMSO-
d6)
(CHC]O), 47.9 (CH2N3), 46.4 (CHN), 32.6 (CH2CH2N3), 30.15 (CH3 in
Ac), 30.08 (CH3 in Ac), 26.2 (NCH3); IR (Nujol)
, cmꢀ1: 3352 (s)
d: 204.6 (C]O in Ac), 204.1 (C]O in Ac), 158.0 (CONH), 69.8
n
DMSO-d6)
d
: 7.94e8.01 (2H, m, ArH in both isomers), 7.63e7.72
(NH), 2105 (s) (N3), 1722 (s), 1701 (m) (C]O), 1638 (s) (amide-I),
1566 (s), 1531 (m) (amide-II). Anal. Calcd for C10H17N5O3: C, 47.05;
H, 6.71; N, 27.43. Found: C, 46.98; H, 6.80; N, 27.12.
(1H, m, ArH in both isomers), 7.50e7.60 (2H, m, ArH in both iso-
mers), 6.19 (0.52H, d, 3J¼9.7 Hz, NH in the major isomer), 6.05
(0.48H, d, 3J¼9.6 Hz, NH in the minor isomer), 5.65 (1.04H, br s,
NH2 in the major isomer), 5.59 (0.96H, br s, NH2 in the minor
isomer), 5.20 (0.52H, d, 3J¼4.9 Hz, CHC]O in the major isomer),
5.04 (0.48H, d, 3J¼7.7 Hz, CHC]O in the minor isomer), 4.43e4.56
(1H, m, CHN in both isomers), 3.22e3.43 (2H, m, CH2N3 in both
isomers), 2.26 (1.56H, s, CH3 in the major isomer), 2.13 (1.44H, s,
CH3 in the minor isomer), 1.56e1.82 (2H, m, CH2CH2N3 in both
isomers); 13C NMR of the 48:52 diastereomeric mixture
4.4.5. N-[(1-Azido-4-benzoyl-5-oxo)hex-3-yl]-N0-methylurea
(7e). Compound 7e (1.616 g, 82%) as a mixture of two di-
astereomers (59:41) was prepared from benzoylacetone (6b)
(1.054 g, 6.50 mmol), NaH (0.152 g, 6.33 mmol), and sulfone 5b
(1.934 g, 6.21 mmol) in dry MeCN (18 mL) (8 h 15 min, rt) as de-
scribed for 7b. After crystallization from MeCN the diastereomeric
ratio did not change. Mp 123.5e124 ꢁC (decomp., MeCN). 1H NMR of
(75.48 MHz, DMSO-d6)
d: 204.5, 203.7 (C]O in Ac), 197.2, 195.4
the 59:41 diastereomeric mixture (300.13 MHz, DMSO-d6) d:
(C]O in Bz), 158.2, 158.0 (CONH2), 136.7, 136.2 (C), 133.9, 133.6
(CH), 129.0, 128.8 (2CH), 128.5, 128.2 (2CH), 65.5, 63.3 (CHC]O),
48.1, 47.8 (CH2N3), 47.0, 46.6 (CHN), 32.7, 32.5 (CH2CH2N3), 29.5,
7.94e8.01 (2H, m, ArH in both isomers), 7.62e7.72 (1H, m, ArH in
both isomers), 7.50e7.60 (2H, m, ArH in both isomers), 6.08 (0.59H,
d, 3J¼9.6 Hz, NH in the major isomer), 6.02 (0.59H, q, 3J¼4.7 Hz,
NHCH3 in the major isomer), 5.97 (0.41H, d, 3J¼9.5 Hz, NH in the
minor isomer), 5.89 (0.41H, q, 3J¼4.6 Hz, NHCH3 in the minor iso-
mer), 5.19 (0.59H, d, 3J¼5.0 Hz, CHC]O in the major isomer), 5.04
(0.41H, d, 3J¼8.0 Hz, CHC]O in the minor isomer), 4.45e4.57 (1H,
28.7 (CH3); IR (Nujol) n
, cmꢀ1: 3420 (s), 3404 (s), 3366 (s), 3212 (br
s) (NH), 3087 (w) (CHarom), 2151 (m), 2104 (vs) (N3), 1717 (s), 1708
(s) (C]O), 1662 (s), 1651 (vs) (amide-I), 1617 (m), 1610 (m), 1595
(m), 1578 (m) (CCarom), 1542 (s), 1522 (s) (amide-II), 771 (s), 697 (s)

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5407
m, CHN in both isomers), 3.21e3.41 (2H, m, CH2N3 in both isomers),
2.51 (1.23H, d, 3J¼4.6 Hz, NCH3 in the minor isomer), 2.50 (1.77H, d,
3J¼4.7 Hz, NCH3 in the major isomer), 2.25 (1.77H, s, CH3C]O in the
major isomer), 2.12 (1.23H, s, CH3C]O in the minor isomer),
1.55e1.84 (2H, m, CH2CH2N3 in both isomers); 13C NMR of the major
(CH2), 29.59, 29.55, 28.7 (CH3 in Ac), 19.8, 18.5, 18.4 (CH3); IR (Nujol)
, cmꢀ1: 3411 (s), 3374 (m), 3203 (br s) (NH), 3086 (w), 3060
n
(w) (CHarom), 2111 (s) (N3), 1712 (s) (C]O in Ac), 1667 (sh), 1654 (s)
(C]O in Bz and amide-I), 1622 (w), 1596 (w), 1579 (w) (CCarom),
1534 (sh),1523 (s) (amide-II), 766 (m), 690 (m) (CHarom). Anal. Calcd
for C15H19N5O3: C, 56.77; H, 6.03; N, 22.07. Found: C, 56.94; H, 6.22;
N, 21.77.
isomer (75.48 MHz, DMSO-d6) d: 204.3 (C]O in Ac), 197.1 (C]O in
Bz), 158.1 (CONH), 136.7 (C), 133.6 (CH), 128.8 (2CH), 128.2 (2CH),
63.4 (CHC]O), 48.0 (CH2N3), 46.9 (CHN), 32.4 (CH2CH2N3), 29.5
(CH3 in Ac), 26.1 (NCH3); 13C NMR of the minor isomer (75.48 MHz,
4.5. Synthesis of 5-acyl-4-(azidoalkyl)-1,2,3,4-
tetrahydropyrimidin-2-ones
DMSO-d6) d: 203.5 (C]O in Ac), 195.4 (C]O in Bz), 158.0 (CONH),
136.3 (C), 133.8 (CH), 128.9 (2CH), 128.5 (2CH), 65.6 (CHC]O), 47.7
(CH2N3), 47.3 (CHN), 32.5 (CH2CH2N3), 28.6 (CH3 in Ac), 26.2
4 . 5 .1. 5 - A c e t y l - 4 - ( 2 - a z i d o e t h y l ) - 6 - m e t h y l - 1, 2 , 3 , 4 -
tetrahydropyrimidin-2-one (9a). Method A: a solution of compound
8a (1.737 g, 7.20 mmol) and p-TsOH$H2O (0.263 g, 1.38 mmol) in
EtOH (20 mL) was heated at reflux for 1 h under stirring, and then
the solvent was removed in vacuum. The oily residue was triturated
with saturated aqueous solution of NaHCO3 (3 mL) and petroleum
ether (10 mL), and the obtained suspension was cooled to 0 ꢁC. The
precipitate was filtered, washed with ice-cold water, petroleum
ether, cold (ꢀ10 ꢁC) diethyl ether (2ꢂ5 mL), and dried to give 9a
(1.231 g, 77%) as a white solid. Mp 150.0e150.5 ꢁC (decomp.,
(NCH3); IR (Nujol) n
, cmꢀ1: 3379 (s), 3303 (br s) (NH), 3064 (w)
(CHarom), 2098 (s) (N3), 1712 (s) (C]O in Ac), 1666 (s) (C]O in Bz),
1626 (s) (amide-I), 1598 (w) (CCarom), 1565 (s) (amide-II), 1508 (w)
(CCarom), 771 (m) (CHarom). Anal. Calcd for C15H19N5O3: C, 56.77; H,
6.03; N, 22.07. Found: C, 56.88; H, 5.94; N, 22.23.
4.4.6. N-[(5-Azido-2-benzoyl-1-oxo-5-phenyl)pent-3-yl]-N0-methyl-
urea (7f). Compound 7f (3.375 g, 91%) was prepared from diben-
zoylmethane (6c) (2.346 g, 10.25 mmol), NaH (0.234 g, 9.76 mmol),
and sulfone 5b (3.033 g, 9.74 mmol) in dry THF (18 mL) (8 h 5 min,
rt) as described for 7c. Mp 139 ꢁC (decomp., EtOH). 1H NMR
MeCN). 1H NMR (300.13 MHz, DMSO-d6)
d
: 9.05 (1H, br d, 4J¼1.9 Hz,
N
(1)H), 7.55 (1H, br dd, 3J¼3.9, 4J¼1.9 Hz, N(3)H), 4.20 (1H, ddd,
(300.13 MHz, DMSO-d6)
d
: 7.95e8.03 (4H, m, ArH), 7.61e7.70 (2H,
3J¼7.8, 3J¼4.1, 3J¼3.9 Hz, 4-H), 3.30e3.44 (2H, m, CH2N3), 2.21 (3H,
m, ArH), 7.48e7.58 (4H, m, ArH), 6.11 (1H, d, 3J¼9.0 Hz, NH), 6.09
(1H, d, 3J¼5.1 Hz, CHC]O), 5.94 (1H, q, 3J¼4.7 Hz, NHCH3), 4.49 (1H,
dddd, 3J¼10.4, 3J¼9.0, 3J¼5.1, 3J¼3.8 Hz, CHN), 3.40 (1H, ddd,
2J¼12.4, 3J¼7.3, 3J¼5.2 Hz, HA in CH2N3), 3.29 (1H, ddd, 2J¼12.4,
3J¼8.3, 3J¼6.6 Hz, HB in CH2N3), 2.44 (3H, d, 3J¼4.7 Hz, NCH3), 1.95
(1H, dddd, 2J¼13.8, 3J¼10.4, 3J¼6.6, 3J¼5.2 Hz, HC in CH2CH2N3),1.81
s, CH3 in Ac), 2.19 (3H, s, 6-CH3), 1.49e1.67 (2H, m, CH2CH2N3). 13
C
NMR (75.48 MHz, DMSO-d6)
(C-6), 110.0 (C-5), 47.9 (C-4), 46.6 (CH2N3), 35.1 (CH2CH2N3), 30.3
(CH3 in Ac),18.9 (6-CH3). IR (Nujol)
, cmꢀ1: 3364 (w), 3230 (s), 3113
d: 193.9 (C]O in Ac),152.6 (C-2), 148.1
n
(s) (NH), 2172 (m), 2122 (m), 2095 (s) (N3), 1713 (vs) (amide-I), 1669
(s) (C]O), 1598 (s) (C]C). Anal. Calcd for C9H13N5O2, %: C, 48.42; H,
5.87; N, 31.37. Found: C, 48.40; H, 5.86; N, 31.47.
(1H, dddd, 2J¼13.8, 3J¼8.3, 3J¼7.3, 3J¼3.8 Hz, HD in CH2CH2N3); 13
C
NMR (75.48 MHz, DMSO-d6)
d
: 196.3 (C]O in Bz), 195.5 (C]O in
Method B: to a stirred suspension of NaH (0.337 g, 14.04 mmol)
in dry THF (10 mL) cooled in an ice-cold bath was added a solution
of acetylacetone (6a) (1.437 g, 14.35 mmol) in THF (10 mL), and the
resulting mixture was stirred for 25 min. The ice bath was removed,
and to the obtained solution were added sulfone 5a (4.129 g,
13.88 mmol) and THF (5 mL). The suspension was stirred at room
temperature for 8 h, p-TsOH$H2O (3.481 g, 18.30 mmol) was added,
and the reaction mixture was heated at reflux under stirring for 1 h
40 min. Vigorous foaming occurred for about 30 min from the be-
ginning of reflux and then faded away (use of a straight condenser
and periodic shaking of the flask during foaming are recom-
mended). The solvent was removed under reduced pressure. The
residue was triturated with petroleum ether (3ꢂ15 mL), petroleum
ether was decanted, saturated aqueous solution of NaHCO3 (10 mL),
solid NaHCO3 (1.500 g, 17.85 mmol), and petroleum ether (15 mL)
were added, the obtained mixture was triturated until crystalliza-
tion was complete, left overnight at room temperature, and cooled
to 0 ꢁC. The precipitate was filtered, washed with ice-cold
water and petroleum ether. The obtained solid was dried in a vac-
uum desiccator (over P2O5) on the filter, cooled (ꢀ10 ꢁC), washed
with cold (ꢀ10 ꢁC) diethyl ether (3ꢂ4 mL), and dried to give 9a
(1.879 g, 61%) as a white solid.
Bz), 158.0 (CONH2), 136.1 (C), 135.8 (C), 133.73 (CH), 133.70 (CH),
129.0 (2CH), 128.9 (2CH), 128.4 (2CH), 128.3 (2CH), 58.5 (CHC]O),
48.1 (CH2N3), 47.7 (CHN), 32.1 (CH2CH2N3), 26.1 (NCH3); IR (Nujol) n,
cmꢀ1: 3421 (m), 3366 (m), 3308 (br m) (NH), 3057 (w) (CHarom),
2097 (s) (N3), 1692 (s) (C]O), 1664 (s), 1638 (m) (amide-I),1592 (w)
(CCarom), 1550 (s) (amide-II), 762 (m), 688 (s) (CHarom). Anal. Calcd
for C20H21N5O3: C, 63.31; H, 5.58; N, 18.46. Found: C, 63.44; H, 5.57;
N, 18.46.
4.4.7. N-[(6-Azido-3-benzoyl-2-oxo)hept-4-yl]urea (7g). Compound
7g (1.399 g, 75%) as a mixture of four diastereomers (27:28:19:26)
was prepared from benzoylacetone (6b) (0.983 g, 6.06 mmol), NaH
(0.143 g, 5.96 mmol), and sulfone 5c (1.839 g, 5.91 mmol) in dry
MeCN (19 mL) (8 h, rt) as described for 7b. Recrystallization from
AcOEt or MeCN gave compound 7g with isomer ratios of
21:50:10:19 or 42:27:22:9, respectively. Mp 131.5e132 ꢁC
(decomp., MeCN). 1H NMR the 42:27:22:9 diastereomeric mixture
(300.13 MHz, DMSO-d6) d: 7.93e8.01 (2H, m, ArH), 7.62e7.72 (1H,
m, ArH), 7.50e7.60 (2H, m, ArH), 6.22 (0.42H, 3J¼9.8 Hz, NH), 6.19
(0.27H, 3J¼9.5 Hz, NH), 6.09 (0.22H, 3J¼9.8 Hz, NH), 6.03 (0.09H,
3J¼9.4 Hz, NH), 5.63 (1.38H, br s, NH2), 5.59 (0.44H, br s, NH2), 5.56
(0.18H, br s, NH2), 5.20 (0.27H, d, 3J¼4.7 Hz, CHC]O), 5.19 (0.42H, d,
3J¼4.9 Hz, CHC]O), 5.03 (0.22H, d, 3J¼7.8 Hz, CHC]O), 5.01 (0.09H,
d, 3J¼7.6 Hz, CHC]O), 4.47e4.60 (1H, m, CHN), 3.45e3.60 (1H, m,
CHN3), 2.27 (2.07H, s, CH3 in Ac), 2.13 (0.27H, s, CH3 in Ac), 2.12
(0.66H, s, CH3 in Ac), 1.35e1.84 (2H, m, CH2), 1.23 (0.66H, d,
3J¼6.4 Hz, CH3), 1.21 (2.07H, d, 3Jz6.5 Hz, CH3), 1.18 (0.27H, d,
3Jz6.5 Hz, CH3); 13C NMR of the 42:27:22:9 diastereomeric mixture
(signals of only three isomers are presented; signals of the 42%
4.5.2. 5-Acetyl-4-(2-azidoprop-1-yl)-6-methyl-1,2,3,4-
tetrahydropyrimidin-2-one (9b). Pyrimidine 9b (1.267 g, 47%) as
a mixture of two diastereomers (86:14) was prepared from acety-
lacetone (6a) (1.193 g, 11.91 mmol), NaH (0.279 g, 11.61 mmol), and
sulfone 5c (3.569 g, 11.46 mmol) in dry THF (25 mL) (rt, 8 h), fol-
lowed by treatment with p-TsOH$H2O (2.875 g, 15.12 mmol) (THF,
reflux, 1 h 55 min) as described for 9a in method B. After crystal-
lization from MeCN the diastereomeric ratio changed to 97:3, re-
spectively. Mp 191e192 ꢁC (decomp., MeCN). 1H NMR of the major
isomer are in italics) (75.48 MHz, DMSO-d6) d: 204.6, 204.4, 203.7
(C]O in Ac), 197.31, 197.27, 195.4 (C]O in Bz), 158.2, 158.0, 157.9
(CONH2), 136.74, 136.68, 136.2 (C), 133.9, 133.63, 133.59 (CH), 128.9,
128.84, 128.81 (2CH), 128.6, 128.25, 128.22 (2CH), 65.7, 63.5, 63.3
(CHC]O), 55.2, 55.0, 54.6 (CHN3), 46.6, 46.5, 46.1 (CHN), 39.7, 39.4
isomer (300.13 MHz, DMSO-d6)
d
: 9.04 (1H, d, 4J¼2.1 Hz, N(1)H),
7.67 (1H, dd, 3J¼4.1, 4J¼2.1 Hz, N(3)H), 4.23 (1H, ddd, 3J¼9.8, 3J¼4.1,
3J¼2.7 Hz, 4-H), 3.73 (1H, ddq, 3J¼10.8, 3J¼6.5, 3J¼2.9 Hz, CHN3),

5408
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
2.18 (6H, s, 6-CH3 and CH3 in Ac), 1.51 (1H, ddd, 2J¼14.1, 3J¼9.8,
3J¼2.9 Hz, CHA in CH2), 1.31 (1H, ddd, 2J¼14.1, 3J¼10.8, 3J¼2.7 Hz,
CHB in CH2), 1.23 (3H, d, 3J¼6.5 Hz, CH3CHN3); 1H NMR of the minor
DMSO-d6)
d
: 9.02 (1H, br d, 4J¼2.0 Hz, N(1)H), 7.53 (1H, br dd, 3J¼3.8,
4J¼2.0 Hz, N(3)H), 4.17 (1H, dd, 3J¼5.0, 3J¼3.8 Hz, 4-H), 3.38 (1H, dd,
2J¼12.2, 3J¼4.9 Hz, CHA in CH2N3), 3.10 (1H, dd, 2J¼12.2, 3J¼7.9 Hz,
CHB in CH2N3), 2.24 and 2.21 (3H and 3H, two s, 6-CH3 and CH3 in
Ac), 1.58e1.79 (1H, m, CHCH3, signals overlap with signals of the
analogous proton of the major isomer), 0.86 (3H, d, 3J¼7.0 Hz,
isomer (300.13 MHz, DMSO-d6) d: 9.08 (1H, br s, N(1)H), 7.48 (1H, br
s, N(3)H), 3.50e3.62 (1H, m, CHN3), 1.62e1.71 (1H, m, CHA in CH2),
signals of other protons partly or completely overlap with signals of
analogous protons of the major isomer; 13C NMR of the major
CHCH3); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
isomer (75.48 MHz, DMSO-d6)
148.0 (C-6), 110.3 (C-5), 53.3 (CHN3), 47.6 (C-4), 42.4 (CH2), 30.1
(CH3 in Ac), 19.6 (CH3), 18.9 (6-CH3); IR (Nujol)
, cmꢀ1: 3230 (br s),
d
: 193.7 (C]O in Ac), 152.6 (C-2),
194.3 (C]O in Ac), 152.9 (C-2), 148.3 (C-6), 108.3 (C-5), 52.8
(CH2N3), 51.6 (C-4), 39.74 (CHCH3), 30.2 (CH3 in Ac), 18.9 (6-CH3),
11.0 (CH3CH); 13C NMR of the minor isomer (75.48 MHz, DMSO-d6)
n
3188 (sh), 3111 (br s) (NH), 2110 (s), 2078 (m) (N3),1713 (vs) (amide-
I), 1675 (s) (C]O), 1606 (s) (C]C). Anal. Calcd for C10H15N5O2: C,
50.62; H, 6.37; N, 29.52. Found: C, 50.74; H, 6.31; N, 29.42.
d
: 194.4 (C]O in Ac),152.7 (C-2), 148.1 (C-6), 108.9 (C-5), 52.9 (C-4),
52.6 (CH2N3), 39.66 (CHCH3), 30.5 (CH3 in Ac), 19.0 (6-CH3), 14.1
(CH3CH); IR (Nujol)
, cmꢀ1: 3276 (br vs), 3123 (br s) (NH), 2095 (vs)
(N3), 1704 (vs) (amide-I), 1603 (vs) (C]O, C]C). Anal. Calcd for
10H15N5O2: C, 50.62; H, 6.37; N, 29.52. Found: C, 50.78; H, 6.38; N,
n
4.5.3. 5-Acetyl-4-(2-azidobut-1-yl)-6-methyl-1,2,3,4-tetrahydro-
pyrimidin-2-one (9c). Pyrimidine 9c (1.496 g, 74%) as a mixture of
two diastereomers (65:35) was prepared from acetylacetone (6a)
(0.853 g, 8.52 mmol), NaH (0.197 g, 8.22 mmol), and sulfone 5d
(2.628 g, 8.08 mmol) in dry THF (20 mL) (rt, 8 h), followed by
treatment with p-TsOH$H2O (2.038 g, 10.71 mmol) (THF, reflux, 1 h
55 min) as described for 9a in method B. After crystallization from
EtOH the diastereomeric ratio changed to 80:20, respectively. Mp
172e173 ꢁC (decomp., EtOH). 1H NMR of the 80:20 diastereomeric
C
29.57.
4.5.5. 5-Acetyl-4-(1-azidobut-2-yl)-6-methyl-1,2,3,4-tetrahydro-
pyrimidin-2-one (9e). Pyrimidine 9e (2.240 g, 76%) as a mixture of
two diastereomers (69:31) was prepared from acetylacetone (6a)
(1.203 g, 12.01 mmol), NaH (0.282 g, 11.77 mmol), and sulfone 5f
(3.793 g, 11.66 mmol) in THF (25 mL) (rt, 8 h), followed by
treatment with p-TsOH$H2O (2.914 g, 15.32 mmol) (THF, reflux,
1 h 50 min) as described for 9a in method B. After crystallization
from EtOH the diastereomeric ratio changed to 73:27, re-
spectively. Mp 144e145 ꢁC (decomp., EtOH). 1H NMR of the major
mixture (300.13 MHz, DMSO-d6)
d
: 9.05 (0.2H, d, 4J¼2.0 Hz, N(1)H in
the minor isomer), 9.02 (0.8H, d, 4J¼2.0 Hz, N(1)H in the major
isomer), 7.66 (0.8H, dd, 3J¼4.0, 4J¼2.0 Hz, N(3)H in the major iso-
mer), 7.45 (0.2H, dd, 3J¼3.9, 4J¼2.0 Hz, N(3)H in the minor isomer),
4.25 (0.8H, ddd, 3J¼9.8, 3J¼4.0, 3J¼2.7 Hz, 4-H in the major isomer),
4.18e4.24 (0.2H, m, 4-H in the minor isomer, signals partly overlap
with the 4-H proton signals of the major isomer), 3.48e3.57 (0.8H,
m, CHN3 in the major isomer), 3.34e3.42 (0.2H, m, CHN3 in the
minor isomer), 2.23 and 2.21 (0.6H and 0.6H, two s, 6-CH3 and
COCH3 in the minor isomer), 2.190 and 2.186 (2.4H and 2.4H, two s,
6-CH3 and COCH3 in the major isomer), 1.36e1.72 (3.2H, m, CHA of
the CH2CHN3 fragment and CH2CH3 in the major isomer, CH2CHCH2
in the minor isomer), 1.30 (0.8H, ddd, 2J¼14.1, 3J¼10.8, 3J¼2.7 Hz,
CHB of the CH2CHN3 fragment in the major isomer), 0.92 (0.6H, t,
3J¼7.3 Hz, CH3 in the minor isomer), 0.91 (2.4H, t, 3J¼7.3 Hz, CH3 in
the major isomer); 13C NMR of the major isomer (75.48 MHz,
isomer (300.13 MHz, DMSO-d6)
d
: 8.97 (1H, br d, 4J¼2.0 Hz,
N
(1)H), 7.45 (1H, br dd, 3J¼4.1, 4J¼2.0 Hz, N(3)H), 4.32 (1H, dd,
3J¼4.1, 3J¼3.6 Hz, 4-H), 3.41 (1H, dd, 2J¼12.5, 3J¼4.5 Hz, CHA in
CH2N3), 3.20 (1H, dd, 2J¼12.5, 3J¼6.3 Hz, CHB in CH2N3), 2.23 and
2.21 (3H and 3H, two s, 6-CH3 and CH3 in Ac), 1.28e1.47 (3H, m,
CHCH2CH3, overlap with signals of the CH2 protons of the minor
isomer), 0.89 (3H, t, 3J¼7.2 Hz, CH3 in Et); 1H NMR of the minor
isomer (300.13 MHz, DMSO-d6)
d
: 8.92 (1H, br d, 4J¼2.0 Hz,
N
(1)H), 7.40 (1H, br dd, 3J¼3.8, 4J¼2.0 Hz, N(3)H), 4.38 (1H, dd,
3J¼3.8, 3J¼2.8 Hz, 4-H), 3.41 (1H, dd, 2J¼12.5, 3J¼5.1 Hz, CHA in
CH2N3), 3.36 (1H, dd, 2J¼12.5, 3J¼8.6 Hz, CHB in CH2N3), 2.21 and
2.18 (3H and 3H, two s, 6-CH3 and CH3 in Ac), 1.28e1.47 (2H, m,
CH2 in Et, overlap with signals of the CHCH2 protons of the major
isomer), 1.00e1.11 (1H, m, CHEt), 0.84 (3H, t, 3J¼7.3 Hz, CH3 in
DMSO-d6) d: 193.7 (C]O in Ac), 152.5 (C-2), 147.9 (C-6), 110.3 (C-5),
59.2 (CHN3), 47.7 (C-4), 40.1 (CH2), 30.0 (CH3 in Ac), 27.4 (CH2 in Et),
Et); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d: 194.2
18.8 (6-CH3), 10.1 (CH3 in Et); 13C NMR of the minor isomer
(C]O in Ac), 152.6 (C-2), 148.3 (C-6), 108.9 (C-5), 50.9 (C-4), 50.5
(CH2N3), 45.8 (CHeEt), 30.5 (CH3 in Ac), 20.5 (CH2 in Et), 19.0 (6-
CH3), 11.4 (CH3 in Et); 13C NMR of the minor isomer (75.48 MHz,
DMSO-d6)
5), 51.3 (C-4), 50.1 (CH2N3), 46.3 (CHeEt), 30.1 (CH3 in Ac), 18.3
(CH2 in Et), 18.9 (6-CH3), 11.6 (CH3 in Et); IR (Nujol)
, cmꢀ1: 3350
(75.48 MHz, DMSO-d6)
6), 110.6 (C-5), 59.9 (CHN3), 47.8 (C-4), 39.9 (CH2), 30.4 (CH3 in Ac),
26.4 (CH2 in Et), 19.0 (6-CH3), 9.8 (CH3 in Et); IR (Nujol)
, cmꢀ1
d: 193.8 (C]O in Ac), 152.6 (C-2), 148.0 (C-
n
:
d: 194.4 (C]O in Ac), 152.7 (C-2), 148.1 (C-6), 108.5 (C-
3353 (m), 3236 (br s), 3117 (br s) (NH), 2103 (vs) (N3), 1711 (vs)
(amide-I), 1675 (s) (C]O), 1607 (s) (C]C). Anal. Calcd for
n
C
11H17N5O2: C, 52.58; H, 6.82; N, 27.87. Found: C, 52.79; H, 6.82; N,
(m), 3230 (br s), 3111 (br s) (NH), 2098 (vs) (N3), 1708 (vs)
27.81.
(amide-I), 1675 (s) (C]O), 1606 (s) (C]C). Anal. Calcd for
C
11H17N5O2: C, 52.58; H, 6.82; N, 27.87. Found: C, 52.62; H, 6.84;
4.5.4. 5-Acetyl-4-(1-azidoprop-2-yl)-6-methyl-1,2,3,4-tetrahydro-
pyrimidin-2-one (9d). Pyrimidine 9d (1.110 g, 63%) as a mixture of
two diastereomers (56:44) was prepared from acetylacetone (6a)
(0.789 g, 7.88 mmol), NaH (0.181 g, 7.52 mmol), and sulfone 5e
(2.307 g, 7.41 mmol) in THF (20 mL) (rt, 8 h), followed by treatment
with p-TsOH$H2O (1.866 g, 9.81 mmol) (THF, reflux, 1 h 55 min) as
described for 9a in method B. After crystallization from MeCN the
diastereomeric ratio changed to 60:40, respectively. Mp
162e165 ꢁC (decomp., MeCN). 1H NMR of the major isomer
N, 27.88.
4.5.6. 4-(2-Azidoethyl)-5-benzoyl-6-methyl-1,2,3,4-tetrahydro-
pyrimidin-2-one (9f). Pyrimidine 9e (0.700 g, 89%) as a slightly
yellow solid was prepared from urea 7b (0.835 g, 2.75 mmol) and p-
TsOH$H2O (0.109 g, 0.57 mmol) in EtOH (13 mL) (reflux, 1 h) as
described for 9a in method A. Mp 186.0e186.5 ꢁC (decomp., EtOH).
1H NMR (300.13 MHz, DMSO-d6)
d
: 9.10 (1H, br d, 4J¼1.9 Hz, N(1)H),
7.43e7.59 (6H, m, Ph and N(3)H), 4.25 (1H, dt, 3J¼6.0, 3J¼3.7 Hz, 4-
H), 3.31e3.44 (2H, m, CH2N3), 1.68 (2H, ddd, 3J¼7.2, 3J¼6.6,
3J¼6.0 Hz, CH2CH2N3), 1.61 (3H, s, 6-CH3); 13C NMR (75.48 MHz,
(300.13 MHz, DMSO-d6)
d
: 8.95 (1H, br d, 4J¼1.9 Hz, N(1)H), 7.40 (1H,
br dd, 3J¼3.8, 4J¼1.9 Hz, N(3)H), 4.31 (1H, dd, 3J¼3.8, 3J¼2.7 Hz, 4-H),
3.35 (1H, dd, 2J¼12.3, 3J¼8.6 Hz, CHA in CH2N3), 3.23 (1H, dd,
2J¼12.3, 3J¼6.6 Hz, CHB in CH2N3), 2.21 and 2.19 (3H and 3H, two s,
6-CH3 and CH3 in Ac), 1.58e1.79 (1H, m, CHCH3, signals overlap
with signals of the analogous proton of the minor isomer), 0.75 (3H,
d, 3J¼6.9 Hz, CHCH3); 1H NMR of the minor isomer (300.13 MHz,
DMSO-d6) d: 194.2 (C]O in Bz), 152.5 (C-2), 146.7 (C-6), 141.1 (C),
131.3 (CH), 128.6 (2CH), 127.8 (2CH), 108.0 (C-5), 49.1 (C-4), 46.5
(CH2N3), 35.3 (CH2), 18.6 (6-CH3); IR (Nujol)
3175 (br m) (NH), 3056 (w) (CHarom), 2100 (sh), 2086 (s) (N3), 1710
(s) (amide-I), 1678 (vs), 1653 (m) (C]O), 1601 (s), 1591 (s), 1572 (s)
n
, cmꢀ1: 3291 (br vs),

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5409
(C]C, CCarom), 743 (s), 712 (m) (CHarom). Anal. Calcd for
14H15N5O2$0.07C2H5OH: C, 58.86; H, 5.39; N, 24.27. Found: C,
58.89; H, 5.57; N, 23.95.
(w) (CHarom), 2100 (s) (N3), 1701 (vs) (amide-I), 1650 (s), 1629 (s)
(C]O, C]C), 1599 (m), 1577 (w) (CCarom), 738 (m), 703 (m)
(CHarom). Anal. Calcd for C16H19N5O2: C, 61.33; H, 6.11; N, 22.35.
Found: C, 61.04; H, 6.03; N, 22.34.
C
4.5.7. 4-(2-Azidoprop-1-yl)-5-benzoyl-6-methyl-1,2,3,4-
tetrahydropyrimidin-2-one (9g). Pyrimidine 9g (1.410 g, 88%) as
a mixture of two diastereomers (55:45) was prepared from urea 7g
(1.683 g, 5.30 mmol) and p-TsOH$H2O (0.207 g, 1.09 mmol) in EtOH
(15 mL) (reflux, 45 min) as described for 9a in method A. After
crystallization from MeCN the diastereomeric ratio did not change.
Mp 168.5e171 ꢁC (decomp., MeCN). 1H NMR of the major isomer
4.5.9. 4-(1-Azidoprop-1-yl)-5-benzoyl-6-methyl-1,2,3,4-
tetrahydropyrimidin-2-one (9i). Pyrimidine 9i (0.991 g, 79%) as
a mixture of two diastereomers (50:50) was prepared from ben-
zoylacetone (6b) (0.727 g, 4.48 mmol), NaH (0.104 g, 4.33 mmol),
and sulfone 5e (1.312 g, 4.21 mmol) in THF (18 mL) (rt, 8 h), fol-
lowed by treatment with p-TsOH$H2O (1.076 g, 5.66 mmol) (THF,
reflux, 1 h 35 min) as described for 9a in method B. After crystal-
lization from MeCN the diastereomeric ratio changed to 51:49. Mp
177.5e178.5 ꢁC (decomp., MeCN). 1H NMR of the first isomer (49%)
(300.13 MHz, DMSO-d6)
d
: 9.08 (1H, br d, 4J¼1.8 Hz, N(1)H), 7.70 (1H,
br dd, 3J¼3.8, 4J¼1.8 Hz, N(3)H), 7.43e7.59 (5H, m, Ph, overlap with
the Ph and N(3)H proton signals of the minor isomer), 4.25 (1H, ddd,
3J¼9.7, 3J¼3.8, 3J¼3.1 Hz, 4-H), 3.71 (1H, ddq, 3J¼10.4, 3J¼6.5,
3J¼3.2 Hz, CHN3), 1.60 (3H, s, 6-CH3), 1.51e1.72 (1H, m, CHA in CH2,
overlap with the CH2 proton signals of the minor isomer), 1.43 (1H,
ddd, 2J¼14.1, 3J¼10.4, 3J¼3.2 Hz, CHB in CH2), 1.21 (3H, d, 3J¼6.5 Hz,
(300.13 MHz, DMSO-d6)
d
: 8.94 (1H, br d, 4J¼1.9 Hz, N(1)H),
7.44e7.61 (5H, m, Ph, overlap with the Ph and N(3)H proton signals
of the second isomer), 7.40 (1H, br dd, 3J¼3.6, 4J¼1.9 Hz, N(3)H), 4.39
(1H, dd, 3J¼3.6, 3J¼3.0 Hz, 4-H), 3.32 (1H, dd, 2J¼12.4, 3J¼8.1 Hz,
CHA in CH2N3), 3.22 (1H, dd, 2J¼12.4, 3J¼6.6 Hz, CHB in CH2N3), 1.65
(3H, s, 6-CH3), 1.62e1.85 (1H, m, CHCH3, overlap with signals of the
analogous proton of the second isomer and signals of the 6-Me
groups of both isomers), 0.84 (3H, d, 3J¼6.9 Hz, CHCH3); 1H NMR
CH3CHN3); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6)
d:
9.14 (1H, br d, 4Jz1.6 Hz, N(1)H), 7.43e7.59 (6H, m, Ph and N(3)H,
overlap with the Ph proton signals of the major isomer), 4.20 (1H,
ddd, 3J¼7.5, 3J¼5.1, 3J¼3.8 Hz, 4-H), 3.56 (1H, ddq, 3J¼6.8, 3J¼6.8,
3J¼6.5 Hz, CHN3), 1.66 (3H, s, 6-CH3), 1.51e1.72 (2H, m, CH2, overlap
with the CHA proton signals of the major isomer), 1.16 (3H, d,
3J¼6.5 Hz, CH3CHN3); 13C NMR of the major isomer (75.48 MHz,
of the second isomer (51%) (300.13 MHz, DMSO-d6) d: 9.02 (1H, br
d, 4J¼1.9 Hz, N(1)H), 7.44e7.61 (6H, m, Ph and N(3)H, overlap with
the Ph proton signals of the first isomer), 4.23 (1H, dd, 3J¼4.9,
3J¼3.9 Hz, 4-H), 3.37 (1H, dd, 2J¼12.3, 3J¼5.1 Hz, CHA in CH2N3), 3.13
(1H, dd, 2J¼12.3, 3J¼7.5 Hz, CHB in CH2N3), 1.69 (3H, s, 6-CH3),
1.62e1.85 (1H, m, CHCH3, overlap with signals of the analogous
proton of the first isomer and signals of the 6-Me groups of both
isomers), 0.86 (3H, d, 3J¼6.9 Hz, CHCH3); 13C NMR of the 49:51
DMSO-d6) d: 194.1 (C]O in Bz), 152.56 (C-2), 146.6 (C-6), 141.1 (C),
131.28 (CH), 128.54 (2CH), 127.7 (2CH), 109.5 (C-5), 53.2 (CHN3),
48.8 (C-4), 42.6 (CH2), 19.5 (CH3CHN3), 18.6 (6-CH3); 13C NMR of the
minor isomer (75.48 MHz, DMSO-d6) d: 194.2 (C]O in Bz), 152.63
(C-2), 146.8 (C-6), 140.9 (C), 131.33 (CH), 128.52 (2CH), 127.7 (2CH),
109.3 (C-5), 53.8 (CHN3), 49.0 (C-4), 42.6 (CH2), 19.0 (CH3CHN3),
diastereomeric mixture (75.48 MHz, DMSO-d6) d: 194.6, 194.6 (C]
18.4 (6-CH3); IR (Nujol)
n
, cmꢀ1: 3255 (sh), 3235 (br s), 3114 (br s)
O in Bz),152.9,152.8 (C-2),146.3,146.1 (C-6),140.9,140.6 (C),131.50,
131.45 (CH), 128.6, 128.6 (2CH), 127.9, 127.8 (2CH), 107.59, 107.55 (C-
5), 54.0, 52.9 (C-4), 52.59, 52.56 (CH2N3), 40.3, 39.8 (CHCH3), 18.24,
(NH), 3026 (w) (CHarom), 2113 (s), 2091 (m), (N3), 1704 (vs) (amide-
I), 1649 (m), 1625 (s) (C]O, C]C), 1594 (m), 1573 (w) (CCarom), 739
(m), 702 (m) (CHarom). Anal. Calcd for C15H17N5O2: C, 60.19; H, 5.72;
N, 23.40. Found: C, 60.24; H, 5.66; N, 23.35.
18.17 (6-CH3), 13.7, 11.3 (CH3CH); IR (Nujol) n
, cmꢀ1: 3228 (br s),
3104 (br s) (NH), 2102 (s) (N3), 1702 (vs) (amide-I), 1648 (m), 1628
(s) (C]C, C]O), 1595 (w), 1578 (w) (CCarom), 739 (m), 704 (m)
(CHarom). Anal. Calcd for C15H17N5O2: C, 60.19; H, 5.72; N, 23.40.
Found: C, 60.12; H, 5.83; N, 23.29.
4.5.8. 4-(2-Azidobut-1-yl)-5-benzoyl-6-methyl-1,2,3,4-
tetrahydropyrimidin-2-one (9h). Pyrimidine 9h (2.290 g, 82%) as
a mixture of two diastereomers (55:45) was prepared from ben-
zoylacetone (6b) (1.476 g, 9.10 mmol), NaH (0.215 g, 8.94 mmol),
and sulfone 5d (2.893 g, 8.89 mmol) in dry THF (22 mL) (rt, 8 h),
followed by treatment with p-TsOH$H2O (2.214 g, 11.64 mmol)
(THF, reflux, 1 h 30 min) as described for 9a in method B. After
crystallization from MeCN the diastereomeric ratio did not change.
Mp 164e165.5 ꢁC (decomp., MeCN). 1H NMR of the major isomer
4.5.10. 4-(1-Azidobut-2-yl)-5-benzoyl-6-methyl-1,2,3,4-
tetrahydropyrimidin-2-one (9j). Pyrimidine 9j (1.927 g, 73%) as
a mixture of two diastereomers (67:33) was prepared from ben-
zoylacetone (6b) (1.394 g, 8.59 mmol), NaH (0.203 g, 8.45 mmol),
and sulfone 5f (2.733 g, 8.40 mmol) in THF (25 mL) (rt, 8 h), fol-
lowed by treatment with p-TsOH$H2O (2.092 g, 10.99 mmol) (THF,
reflux, 1 h 50 min) as described for 9a in method B. After crystal-
lization from MeCN the diastereomeric ratio changed to 76:24,
respectively. Mp 163.5e165.5 ꢁC (decomp., MeCN). 1H NMR of the
(300.13 MHz, DMSO-d6)
d
: 9.10 (1H, br d, 4J¼1.9 Hz, N(1)H), 7.73 (1H,
dd, 3J¼3.8, 4J¼1.9 Hz, N(3)H), 7.42e7.59 (5H, m, Ph, overlap with the
Ph and N(3)H proton signals of the minor isomer), 4.27 (1H, ddd,
3J¼9.6, 3J¼3.8, 3J¼2.8 Hz, 4-H), 3.46e3.55 (1H, m, CHN3), 1.61 (3H, s,
6-CH3), 1.33e1.67 (4H, m, CH2CHCH2, overlap with signals of anal-
ogous protons of the minor isomer), 0.90 (3H, t, 3J¼7.4 Hz, CH3 in
major isomer (300.13 MHz, DMSO-d6)
d
: 9.03 (1H, br d, 4J¼1.8 Hz,
N(1)H), 7.42e7.60 (6H, m, Ph and N(3)H, overlap with signals of
analogous protons of the minor isomer), 4.37 (1H, t, 3J1þ3J2¼7.3 Hz,
4-H), 3.48 (1H, dd, 2J¼12.5, 3J¼4.7 Hz, CHA in CH2N3), 3.25 (1H, dd,
2J¼12.5, 3J¼6.4 Hz, CHB in CH2N3),1.70 (3H, s, 6-CH3),1.02e1.52 (3H,
m, CHCH2CH3, overlap with signals of analogous protons of the
minor isomer), 0.75 (3H, t, 3J¼7.3 Hz, CH3 in Et); 1H NMR of the
Et); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6)
d: 9.15
(1H, br d, 4J¼1.9 Hz, N(1)H), 7.42e7.59 (6H, m, Ph and N(3)H, overlap
with the Ph proton signals of the major isomer), 4.22 (1H, ddd,
3J¼6.4, 3J¼6.4, 3J¼3.8 Hz, 4-H), 3.35e3.43 (1H, m, CHN3), 1.65 (3H, s,
6-CH3), 1.33e1.67 (4H, m, CH2CHCH2, overlap with signals of anal-
ogous protons of the major isomer), 0.87 (3H, t, 3J¼7.4 Hz, CH3 in
minor isomer (300.13 MHz, DMSO-d6)
d
: 8.96 (1H, br d, 4J¼1.8 Hz,
N
(1)H), 7.42e7.60 (6H, m, Ph and N(3)H, overlap with signals of
Et); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d: 194.1
analogous protons of the major isomer), 4.44 (1H, t, 3J1þ3J2¼6.7 Hz,
4-H), 3.32e3.43 (2H, m, CH2N3), 1.66 (3H, s, 6-CH3), 1.02e1.52 (3H,
m, CHCH2CH3, overlap with signals of analogous protons of the
major isomer), 0.84 (3H, t, 3J¼7.3 Hz, CH3 in Et); 13C NMR of the
(C]O in Bz), 152.6 (C-2), 146.7 (C-6), 141.2 (C), 131.3 (CH), 128.6
(2CH), 127.75 (2CH), 109.5 (C-5), 59.1 (CHN3), 48.9 (C-4), 40.3 (CH2),
27.4 (CH2 in Et), 18.6 (6-CH3), 10.2 (CH3 in Et); 13C NMR of the minor
isomer (75.48 MHz, DMSO-d6)
d: 194.2 (C]O in Bz), 152.7 (C-2),
major isomer (75.48 MHz, DMSO-d6) d: 194.6 (C]O in Bz),152.7 (C-
146.9 (C-6),141.0 (C),131.4 (CH),128.6 (2CH),127.77 (2CH),109.3 (C-
5), 59.8 (CHN3), 49.1 (C-4), 40.2 (CH2), 26.5 (CH2 in Et), 18.5 (6-CH3),
2), 146.5 (C-6), 140.8 (C), 131.5 (CH), 128.58 (2CH), 127.9 (2CH), 107.8
(C-5), 52.2 (C-4), 50.5 (CH2N3), 46.4 (CHeEt), 20.3 (CH2 in Et), 18.3
(6-CH3), 11.2 (CH3 in Et); 13C NMR of the minor isomer (75.48 MHz,
9.8 (CH3 in Et); IR (Nujol) n
, cmꢀ1: 3236 (br s), 3100 (br s) (NH), 3030

5410
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
DMSO-d6)
d
: 194.7 (C]O in Bz), 152.9 (C-2), 145.8 (C-6), 140.7 (C),
180e181 ꢁC (decomp., MeCN). 1H NMR of the major isomer
131.6 (CH), 128.64 (2CH), 127.9 (2CH), 107.7 (C-5), 52.5 (C-4), 50.0
(300.13 MHz, DMSO-d6)
d
: 8.98 (1H, d, 4J¼1.9 Hz, N(3)H), 7.77 (1H,
(CH2N3), 46.6 (CHeEt), 18.8 (CH2 in Et), 18.2 (6-CH3), 11.7 (CH3 in
dd, 3J¼3.5, 4J¼1.9 Hz, N(1)H), 7.46e7.74 (5H, m, Ph), 4.23 (1H, ddd,
3J¼9.9, 3J¼3.5, 3J¼2.8 Hz, 6-H), 3.82 (1H, ddq, 3J¼10.9, 3J¼6.5,
3J¼2.8 Hz, CHN3), 3.64 (2H, q, 3J¼7.1 Hz, OCH2), 1.73 (1H, ddd,
2J¼14.1, 3J¼9.9, 3J¼2.8 Hz, CHA in CH2), 1.48 (1H, ddd, 2J¼14.1,
3J¼10.9, 3J¼2.8 Hz, CHB in CH2), 1.24 (3H, d, 3J¼6.5 Hz, CH3CHN3),
0.86 (3H, t, 3J¼7.1 Hz, CH3 in COOEt); 1H NMR of the minor isomer
Et); IR (Nujol) n
, cmꢀ1: 3229 (br s), 3103 (br s) (NH), 3028 (w)
(CHarom), 2097 (s) (N3), 1701 (vs) (amide-I), 1649 (m), 1631 (s) (C]
O, C]C), 1598 (w), 1578 (w) (CCarom), 740 (m), 703 (m) (CHarom).
Anal. Calcd for C16H19N5O2: C, 61.33; H, 6.11; N, 22.35. Found: C,
61.35; H, 6.20; N, 22.19.
(300.13 MHz, DMSO-d6)
d
: 9.08 (1H, d, 4J¼1.9 Hz, N(3)H), 7.46e7.74
4. 5.11. 4-(2-Azidoethyl)-5-benzoyl-6-phenyl-1, 2, 3, 4-
tetrahydropyrimidin-2-one (9k). A solution of compound 7c
(0.981 g, 2.68 mmol) and p-TsOH$H2O (0.516 g, 2.71 mmol) in EtOH
(20 mL) was heated at reflux for 2 h 15 min under stirring, and then
the solvent was removed in vacuum. The residue was dissolved in
CHCl3 (10 mL) and subsequently washed with saturated aqueous
solution of NaHCO3 (5 mL, 3ꢂ3 mL), H2O (2ꢂ5 mL), brine (2ꢂ5 mL),
and dried over Na2SO4. After removal of solvent, the residue was
purified using column chromatography on silica gel 60 (6.9 g)
eluting with CHCl3/MeOH (from 1:0 to 100:1) to give 9k (0.191 g,
21%). Mp 171.5e173 ꢁC (decomp., AcOEt/hexane, 1:1). 1H NMR
(6H, m, Ph and N(1)H, overlap with the Ph proton signals of the
major isomer), 4.21e4.27 (1H, m, 6-H, overlap with signals of
analogous proton of the major isomer), 3.64 (2H, q, 3J¼7.1 Hz,
OCH2), 3.59e3.69 (1H, m, CHN3, overlap with signals of the OCH2
protons of both isomers), 1.64e1.83 (2H, m, CH2CHN3, partly over-
lap with signals of the CHA proton of the major isomer), 1.19 (3H, d,
3J¼6.5 Hz, CH3CHN3), 0.88 (3H, t, 3J¼7.1 Hz, CH3 in COOEt); 13C NMR
of the major isomer (75.48 MHz, DMSO-d6) d: 193.15 (C]O in Bz),
161.2 (C]O in COOEt), 152.2 (C-2), 137.9 (C-4), 134.0 (C), 132.8 (CH),
128.62 (2CH), 128.1 (2CH), 114.8 (C-5), 61.70 (OCH2), 52.9 (CHN3),
49.6 (C-6), 41.7 (CH2CHN3), 19.4 (CH3CHN3), 13.0 (CH3 in COOEt);
(300.13 MHz, DMSO-d6)
d
: 9.35 (1H, d, 4J¼1.8 Hz, N(1)H), 7.68 (1H,
13C NMR of the minor isomer (75.48 MHz, DMSO-d6)
d: 193.12 (C]
dd, 3J¼3.8, 4J¼1.8 Hz, N(3)H), 7.26e7.32 (2H, m, ArH), 6.98e7.18 (8H,
m, ArH), 4.28 (1H, ddd, 3J¼7.3, 3J¼4.7, 3J¼3.8 Hz, 4-H), 3.46e3.61
(2H, m, CH2N3), 1.85e2.02 (2H, m, CH2CH2N3); 13C NMR
O in Bz), 161.3 (C]O in COOEt), 152.3 (C-2), 138.0 (C-4), 134.7 (C),
132.7 (CH), 128.59 (2CH), 128.1 (2CH), 114.4 (C-5), 61.72 (OCH2),
53.6 (CHN3), 49.7 (C-6), 41.7 (CH2CHN3), 18.9 (CH3CHN3), 13.0 (CH3
(75.48 MHz, DMSO-d6)
d
: 194.7 (C]O in Bz), 152.8 (C-2), 148.9 (C-
in COOEt); IR (Nujol) n
, cmꢀ1: 3222 (br s), 3115 (br s) (NH), 2119 (s),
6), 139.5 (C), 133.4 (C), 130.6 (CH), 129.7 (2CH), 129.6 (CH), 128.5
(2CH), 127.6 (2CH), 127.4 (2CH), 108.7 (C-5), 49.9 (C-4), 46.7
2099 (s) (N3), 1736 (s) (C]O in COOEt), 1706 (vs) (amide-I), 1679
(m), 1649 (s) (C]O in Bz, C]C), 1595 (w), 1577 (w) (CCarom), 1254
(s), 1217 (s), 1085 (m) (CeO), 715 (s) (CHarom). Anal. Calcd for
(CH2N3), 35.1 (CH2CH2N3); IR (Nujol) n
, cmꢀ1: 3208 (br s), 3116 (br s)
(NH), 3031 (w) (CHarom), 2091 (s) (N3), 1704 (vs) (amide-I), 1618
(sh), 1597 (s), 1569 (s) (C]O, C]C), 1492 (w) (CCarom), 730 (s), 700
(m) (CHarom). Anal. Calcd for C19H17N5O2: C, 65.70; H, 4.93; N, 20.16.
Found: C, 65.38; H, 4.93; N, 19.82.
C17H19N5O4: C, 57.14; H, 5.36; N, 19.60. Found: C, 57.19; H, 5.36; N,
19.61.
4.5.14. Ethyl 6-(2-azidobut-1-yl)-5-benzoyl-2-oxo-1,2,3,6-
tetrahydropyrimidine-4-carboxylate (9n). Pyrimidine 9n (1.483 g,
73%) as a mixture of two diastereomers (62:38) was prepared from
6d (1.245 g, 5.66 mmol), NaH (0.133 g, 5.55 mmol), and sulfone 5d
(1.791 g, 5.50 mmol) in THF (19 mL) (rt, 8 h), followed by treatment
with p-TsOH$H2O (1.478 g, 7.77 mmol) (THF, reflux, 2 h 20 min) as
described for 9a in method B. The analytically pure sample (0.223 g;
mixture of two diastereomers, 65:35) was obtained by purification
of 0.405 g of crude 9n using column chromatography on silica gel
60 (4.2 g) eluting with MeOH/CHCl3 (from 0:1 to 1:100) followed by
crystallization from EtOH (3 mL). Mp 123e124 ꢁC (decomp., EtOH).
1H NMR of the 65:35 diastereomeric mixture (300.13 MHz, DMSO-
4.5.12. Ethyl 6-(2-azidoethyl)-5-benzoyl-2-oxo-1,2,3,6-
tetrahydropyrimidine-4-carboxylate (9l). Pyrimidine 9l (1.093 g,
60%) was prepared from 6d (1.202 g, 5.46 mmol), NaH (0.129 g,
5.37 mmol), and sulfone 5a (1.577 g, 5.30 mmol) in THF (20 mL) (rt,
8 h 10 min), followed by treatment with p-TsOH$H2O (1.334 g,
5.90 mmol) (THF, reflux, 3 h 10 min) as described for 9a in method
B. The analytically pure sample (0.273 g) was obtained by purifi-
cation of 0.355 g of crude 9l using column chromatography on silica
gel 60 (4.1 g) eluting with MeOH/CHCl3 (from 0:1 to 1:95) followed
by crystallization from EtOH (18 mL). Mp 174.5e175 ꢁC (decomp.,
EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d
: 8.99 (1H, br s, N(3)H),
d6) d: 9.14 (0.35H, br s, N(3)H in the minor isomer), 9.05 (0.65H, br s,
7.70e7.75 (2H, m, ArH), 7.62 (1H, br d, 3J¼3.4 Hz, N(1)H), 7.58e7.64
(1H, m, ArH), 7.47e7.53 (2H, m, ArH), 4.25 (1H, ddd, 3J¼7.2, 3J¼4.8,
3J¼3.4 Hz, 6-H), 3.58e3.72 (2H, m, OCH2), 3.39e3.52 (2H, m,
CH2N3), 1.69e1.85 (2H, m, CH2CH2N3), 0.87 (3H, t, 3J¼7.1 Hz, CH3);
N(3)H in the major isomer), 7.82 (0.65H, d, 3J¼3.6 Hz, N(1)H in the
major isomer), 7.46e7.74 (5.35H, m, Ph in both isomers and N(1)H in
the minor isomer), 4.24 (0.65H, ddd, 3J¼9.9, 3J¼3.6, 3J¼2.6 Hz, 6-H
in the major isomer), 4.22e4.28 (0.35H, m, 6-H in the minor isomer,
overlap with signals of analogous proton of the major isomer),
3.55e3.69 (2.65H, m, OCH2 in both isomers and CHN3 in the major
isomer), 3.42e3.50 (0.35H, m, CHN3 in the minor isomer),
1.36e1.80 (4H, m, CH2CHCH2 in both isomers), 0.91 (1.95H, t,
3J¼7.3 Hz, CH3CH2CH in the major isomer), 0.87 (1.05H, t, 3J¼7.1 Hz,
CH3CH2O in the minor isomer), 0.87 (1.05H, t, 3J¼7.3 Hz, CH3CH2CH
in the minor isomer), 0.86 (1.95H, t, 3J¼7.1 Hz, CH3CH2O in the
major isomer); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
13C NMR (75.48 MHz, DMSO-d6)
d: 193.2 (C]O in Bz),161.2 (C]O in
COOEt), 152.2 (C-2), 137.8 (C-4), 134.0 (C), 132.8 (CH), 128.6 (2CH),
128.1 (2CH), 114.5 (C-5), 61.7 (OCH2), 49.9 (C-6), 46.2 (CH2N3), 34.5
(CH2CH2N3), 13.0 (CH3); IR (Nujol) n
, cmꢀ1: 3216 (br s), 3112 (br s)
(NH), 2138 (m), 2097 (s) (N3), 1731 (s) (C]O in COOEt), 1708 (vs)
(amide-I), 1643 (s) (C]O in Bz, C]C), 1596 (w), 1578 (w) (CCarom),
1292 (s), 1217 (s), 1079 (s) (CeO), 714 (s) (CHarom). Anal. Calcd for
C
16H17N5O4: C, 55.97; H, 4.99; N, 20.40. Found: C, 55.87; H, 4.95; N,
20.06.
d: 193.2 (C]O in Bz), 161.3 (C]O in COOEt), 152.3 (C-2), 138.0 (C-4),
134.2 (C), 132.81 (CH), 128.66 (2CH), 128.1 (2CH), 114.8 (C-5), 61.76
(OCH2), 58.7 (CHN3), 49.6 (C-6), 39.5 (CHCH2CH), 27.4 (CH3CH2CH),
13.0 (CH3 in COOEt), 10.1 (CH3CH2CH); 13C NMR of the major isomer
4.5.13. Ethyl 6-(2-azidoprop-1-yl)-5-benzoyl-2-oxo-1,2,3,6-
tetrahydropyrimidine-4-carboxylate (9m). Pyrimidine 9m (1.093 g,
60%) as a mixture of two diastereomers (63:37) was prepared from
6d (1.676 g, 7.61 mmol), NaH (0.180 g, 7.50 mmol), and sulfone 5c
(2.300 g, 7.39 mmol) in THF (20 mL) (rt, 8 h), followed by treatment
with p-TsOH$H2O (1.859 g, 9.77 mmol) (THF, reflux, 2 h 30 min) as
described for 9a in method B. After crystallization from MeCN the
diastereomeric ratio changed to 78:22, respectively. Mp
(75.48 MHz, DMSO-d6) d: 193.2 (C]O in Bz), 161.4 (C]O in COOEt),
152.4 (C-2), 138.1 (C-4), 135.0 (C), 132.75 (CH), 128.63 (2CH), 128.1
(2CH), 114.3 (C-5), 61.77 (OCH2), 59.6 (CHN3), 49.8 (C-6), 39.5
(CHCH2CH), 26.5 (CH3CH2CH), 13.0 (CH3 in COOEt), 9.8
(CH3CH2CH); IR (Nujol)
(NH), 2098 (s) (N3), 1721 (s) (C]O in COOEt), 1702 (vs) (amide-I),
n
, cmꢀ1: 3230 (br s), 3125 (m), 3094 (m)

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5411
1658 (s) (C]O in Bz, C]C), 1595 (w), 1578 (w) (CCarom), 1293 (m),
1213 (s), 1073 (m) (CeO), 718 (s) (CHarom). Anal. Calcd for
analogous protons of the second isomer), 0.87 (3H, t, 3J¼7.1 Hz,
CHCH2CH3), 0.87 (3H, t, 3J¼7.1 Hz, CH3 in COOEt); 1H NMR of the
second isomer (35% in analytically pure form) (300.13 MHz, DMSO-
C
18H21N5O4: C, 58.21; H, 5.70; N, 18.86. Found: C, 58.22; H, 5.72; N,
18.77.
d6) d: 9.07 (1H, br s, N(3)H), 7.46e7.75 (6H, m, Ph and N(1)H, overlap
with signals of analogous protons of the first isomer), 4.40 (1H, dd,
3J¼3.5, 3J¼3.4 Hz, 6-H), 3.55e3.79 (2H, m, OCH2, overlap with sig-
nals of analogous protons of the first isomer), 3.51 (1H, dd, 2J¼12.6,
3J¼5.4 Hz, CHA in CH2N3), 3.32 (1H, dd, 2J¼12.6, 3J¼6.3 Hz, CHB in
CH2N3), 1.07e1.64 (3H, m, CHCH2CH3, overlap with signals of
analogous protons of the first isomer), 0.89 (3H, t, 3J¼7.1 Hz, CH3 in
COOEt), 0.80 (3H, t, 3J¼7.3 Hz, CHCH2CH3); 13C NMR of the first
4.5.15. Ethyl 6-(1-azidoprop-2-yl)-5-benzoyl-2-oxo-1,2,3,6-
tetrahydropyrimidine-4-carboxylate (9o). Pyrimidine 9o (two di-
astereomers, 60:40) along with unidentified byproducts was
prepared from 6d (1.276 g, 5.79 mmol), NaH (0.136 g, 5.68 mmol),
and sulfone 5e (1.744 g, 5.60 mmol) in THF (18 mL) (rt, 8 h), fol-
lowed by treatment with p-TsOH$H2O (1.520 g, 7.99 mmol) (THF,
reflux, 2 h 20 min) as described for 9a in method B. Pure 9o
(0.387 g, 19%) was isolated from the crude product (1.174 g) using
column chromatography on silica gel 60 (18 g) eluting with CHCl3/
petroleum ether (from 2:1 to 1:0), then CHCl3/MeOH (100:1). After
crystallization from EtOH the diastereomeric ratio was 64:36, re-
spectively. Mp 155.5e156.5 ꢁC (decomp., EtOH). 1H NMR of the
isomer (65% in analytically pure form) (75.48 MHz, DMSO-d6) d:
193.4 (C]O in Bz), 161.2 (C]O in COOEt), 152.6 (C-2), 137.6 (C-4),
134.3 (C), 133.1 (CH), 128.8 (2CH), 128.1 (2CH), 113.9 (C-5), 61.80
(OCH2), 53.4 (C-6), 49.5 (CH2N3), 45.8 (CH3CH2CH), 18.8
(CH3CH2CH), 13.04 (CH3 in COOEt), 11.6 (CH3CH2CH); 13C NMR of
the second isomer (35% in analytically pure form) (75.48 MHz,
major isomer (300.13 MHz, DMSO-d6)
d
: 8.89 (1H, br s, N(3)H),
DMSO-d6) d: 193.3 (C]O in Bz), 161.4 (C]O in COOEt), 152.5 (C-2),
7.47e7.76 (6H, m, Ph and N(1)H, overlap with signals of analogous
protons of the minor isomer), 4.37 (1H, dd, 3J¼3.2, 3J¼2.4 Hz, 6-H),
3.54e3.78 (2H, m, OCH2, overlap with signals of analogous protons
of the minor isomer), 3.38 (1H, dd, 2J¼12.4, 3J¼8.7 Hz, CHA in
CH2N3), 3.30 (1H, dd, 2J¼12.4, 3J¼6.4 Hz, CHB in CH2N3), 1.75 (1H,
dddq, 3J¼8.7, 3J¼6.9, 3J¼6.4, 3J¼2.4 Hz, CHCH3), 0.91 (3H, d,
3J¼6.9 Hz, CHCH3), 0.88 (3H, t, 3J¼7.1 Hz, CH3 in COOEt); 1H NMR of
137.9 (C-4), 135.6 (C), 132.8 (CH), 128.7 (2CH), 128.2 (2CH), 113.0 (C-
5), 61.79 (OCH2), 53.0 (C-6), 50.4 (CH2N3), 45.9 (CH3CH2CH), 20.3
(CH3CH2CH), 13.06 (CH3 in COOEt), 11.3 (CH3CH2CH); IR (Nujol) n,
cmꢀ1: 3213 (br s), 3092 (br s) (NH), 2102 (s) (N3), 1730 (s) (C]O in
COOEt), 1702 (vs) (amide-I), 1669 (s) (C]O in Bz, C]C), 1596 (w),
1579 (w) (CCarom), 1291 (s), 1220 (s), 1078 (m) (CeO), 717 (s)
(CHarom). Anal. Calcd for C18H21N5O4: C, 58.21; H, 5.70; N, 18.86.
Found: C, 58.50; H, 5.73; N, 18.51.
the minor isomer (300.13 MHz, DMSO-d6) d: 9.04 (1H, br s, N(3)H),
7.47e7.76 (6H, m, Ph and N(1)H, overlap with signals of analogous
protons of the major isomer), 4.28 (1H, dd, 3J¼4.3, 3J¼3.4 Hz, 6-H),
3.54e3.78 (2H, m, OCH2, overlap with signals of analogous protons
of the major isomer), 3.42 (1H, dd, 2J¼12.3, 3J¼5.4 Hz, CHA in
CH2N3), 3.20 (1H, dd, 2J¼12.3, 3J¼7.5 Hz, CHB in CH2N3), 1.87 (1H,
dddq, 3J¼7.5, 3J¼6.9, 3J¼5.4, 3J¼4.3 Hz, CHCH3), 0.92 (3H, d,
3J¼6.9 Hz, CHCH3), 0.90 (3H, t, 3J¼7.1 Hz, CH3 in COOEt); 13C NMR of
4.6. Synthesis of pyrido[4,3-d]pyrimidin-2-ones
4.6.1. 4,5-Dimethyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-2-
one (10a). To pyrimidine 9a (1.271 g, 5.69 mmol) and PPh3 (1.694 g,
6.46 mmol) was added dry MeCN (16 mL), and the obtained mix-
ture was heated at reflux under stirring for 5 h 30 min. A clear
solution formed at the beginning of reflux, and after 10 min the
product precipitated to give a suspension. After the reaction was
complete, the mixture was evaporated in vacuo to half of its vol-
ume, the resulting suspension was cooled to ꢀ10 ꢁC, and the pre-
cipitate was filtered on a cold (ꢀ10 ꢁC) filter, successively washed
with MeCN (4ꢂ4 mL, ꢀ10 ꢁC), diethyl ether (2ꢂ5 mL), petroleum
ether, and dried to give 10a (0.963 g, 94%) as a white solid. Mp
the major isomer (75.48 MHz, DMSO-d6) d: 193.32 (C]O in Bz),
161.2 (C]O in COOEt), 152.7 (C-2), 137.7 (C-4), 134.3 (C), 132.9 (CH),
128.7 (2CH), 128.1 (2CH), 113.6 (C-5), 61.7 (OCH2), 53.5 (C-6), 52.1
(CH2N3), 39.0 (CH3CH), 13.0 (CH3 in COOEt), 10.9 (CH3CH); 13C NMR
of the minor isomer (75.48 MHz, DMSO-d6) d: 193.27 (C]O in Bz),
161.3 (C]O in COOEt), 152.5 (C-2), 137.7 (C-4), 135.5 (C), 132.8 (CH),
128.6 (2CH), 128.2 (2CH), 112.7 (C-5), 61.7 (OCH2), 54.7 (C-6), 52.3
(CH2N3), 39.8 (CH3CH),13.0 (CH3 in COOEt),13.6 (CH3CH); IR (Nujol)
229.5 ꢁC (decomp.; EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d: 8.42
n
, cmꢀ1: 3230 (br s), 3126 (m), 3089 (m) (NH), 2105 (s) (N3), 1727 (s)
(1H, br s, N(3)H), 7.01 (1H, s, N(1)H), 3.99 (1H, ddq, 3J¼10.8, 3J¼4.8,
5J¼1.4 Hz, 8a-H), 3.52 (1H, dddq, 2J¼16.4, 3J¼4.7, 3J¼2.9, 5J¼1.1 Hz,
7-HA), 3.29 (1H, dddq, 2J¼16.4, 3J¼11.4, 3J¼4.2, 5J¼2.0 Hz, 7-HB),
2.13 (3H, dd, 5J¼2.0, 5J¼1.1 Hz, 5-CH3), 2.05 (3H, d, 5J¼1.4 Hz, 4-
CH3), 1.84 (1H, dddd, 2J¼12.4, 3J¼4.8, 3J¼4.2, 3J¼2.9 Hz, 8-HA),
1.41 (1H, dddd, 2J¼12.4, 3J¼11.4, 3J¼10.8, 3J¼4.7 Hz, 8-HB); 13C NMR
(C]O in COOEt), 1697 (vs) (amide-I), 1663 (s) (C]O in Bz, C]C),
1596 (w), 1579 (w), 1488 (w) (CCarom), 1291 (s), 1219 (s), 1073 (m)
(CeO), 719 (s) (CHarom). Anal. Calcd for C17H19N5O4: C, 57.14; H,
5.36; N, 19.60. Found: C, 57.18; H, 5.38; N, 19.58.
4.5.16. Ethyl 6-(1-azidobut-2-yl)-5-benzoyl-2-oxo-1,2,3,6-
tetrahydropyrimidine-4-carboxylate (9p). Pyrimidine 9p (two di-
astereomers, 50:50) along with unidentified byproducts was pre-
pared from 6d (1.367 g, 6.21 mmol), NaH (0.146 g, 6.10 mmol), and
sulfone 5f (1.959 g, 6.02 mmol) in THF (20 mL) (rt, 8 h), followed by
treatment with p-TsOH$H2O (1.627 g, 8.55 mmol) (THF, reflux, 2 h
20 min) as described for 9a in method B. Pure 9p (0.309 g, 14%) was
isolated from the crude product (1.432 g) using column chroma-
tography on silica gel 60 (18 g) eluting with CHCl3/petroleum ether
(from 20:1 to 1:0), then CHCl3/MeOH (from 200:1 to 80:1). After
crystallization from EtOH the diastereomeric ratio was 65:35. Mp
147e148 ꢁC (decomp., EtOH). 1H NMR of the first isomer (65% in
(75.48 MHz, DMSO-d6)
104.2 (C-4a), 48.9 (C-8a), 46.6 (C-7), 29.3 (C-8), 28.1 (5-CH3), 18.6
(4-CH3); IR (Nujol)
, cmꢀ1: 3213 (s), 3105 (s), 3082 (s) (NH), 1692
d: 160.3 (C-5), 154.3 (C-2), 137.4 (br) (C-4),
n
(vs) (amide-I), 1639 (s) (C]C), 1593 (s) (C]N). Anal. Calcd for
C9H13N3O: C, 60.32; H, 7.31; N, 23.45. Found: C, 60.12; H, 7.30; N,
23.58.
4.6.2. 4,5,7-Trimethyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-
2-one (10b). Compound 10b (0.393 g, 84%) as a mixture of
(7R
*
,8aS
*
)- and (7R
*
,8aR )-diastereomers (90:10) was prepared
*
from pyrimidine 9b (0.576 g, 2.43 mmol; a 86:14 isomeric mixture)
and PPh3 (0.729 g, 2.78 mmol) in MeCN (9 mL) (reflux, 7 h) as
described for 10a. After crystallization from MeCN the di-
astereomeric ratio did not change. Mp 183.5e185 ꢁC (decomp.,
analytically pure form) (300.13 MHz, DMSO-d6) d: 8.93 (1H, br s,
N
(3)H), 7.46e7.75 (6H, m, Ph and N(1)H, overlap with signals of
analogous protons of the second isomer), 4.43 (1H, dd, 3J¼3.2,
3J¼2.5 Hz, 6-H), 3.55e3.79 (2H, m, OCH2, overlap with signals of
analogous protons of the second isomer), 3.49 (1H, dd, 2J¼12.6,
3J¼4.9 Hz, CHA in CH2N3), 3.41 (1H, dd, 2J¼12.6, 3J¼9.4 Hz, CHB in
CH2N3), 1.07e1.64 (3H, m, CHCH2CH3, overlap with signals of
MeCN). 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d: 8.47
(1H, br s, N(3)H), 7.02 (1H, s, N(1)H), 4.04 (1H, ddq, 3J¼11.9, 3J¼4.6,
5J¼1.4 Hz, 8a-H), 3.22e3.35 (1H, m, 7-H, overlaps with HOD), 2.12
(3H, d, 5J¼2.1 Hz, 5-CH3), 2.06 (3H, d, 5J¼1.4 Hz, 4-CH3), 1.96 (1H,
ddd, 2J¼12.1, 3J¼4.6, 3J¼3.6 Hz, 8-HA), 1.16 (3H, d, 3J¼6.8 Hz, 7-CH3),

5412
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
1.04 (1H, ddd, 2J¼12.1, 3J¼11.9, 3J¼11.4 Hz, 8-HB); 1H NMR of the
1.27e1.61 (2H, m, CH2 in Et, overlap with the 8-H and CH2 proton
signals of the minor isomer), 1.03 (1H, ddd, 2J¼12.0, 3J¼11.9,
3J¼11.6 Hz, 8-HB), 0.92 (3H, t, 3J¼7.4 Hz, CH3 in Et); 1H NMR of the
minor isomer (300.13 MHz, DMSO-d6) d: 6.90 (1H, s, N(1)H), 3.94
(1H, ddq, 3J¼6.7, 3J¼6.2, 5J¼1.4 Hz, 8a-H), 2.13 (3H, d, 5Jz2 Hz, 5-
CH3, partly overlaps with the 5-CH3 of the major isomer), 2.02
(3H, d, 5J¼1.4 Hz, 4-CH3), 1.58 (1H, ddd, 2J¼13.1, 3J¼6.7, 3J¼4.5 Hz, 8-
HA), 1.43 (1H, ddd, 2J¼13.1, 3J¼6.2, 3J¼6.2 Hz, 8-HB), 1.12 (3H, d,
3J¼6.9 Hz, 7-CH3). Signals of the 7-H and N(3)H protons overlap
with signals of analogous protons of the major isomer; 13C NMR of
minor isomer (300.13 MHz, DMSO-d6) d: 8.45 (1H, br s, N(3)H), 6.88
(1H, s, N(1)H), 3.90 (1H, ddq, 3J¼6.3, 3J¼5.5, 5J¼1.3 Hz, 8a-H),
2.86e2.95 (1H, m, 7-H), 2.14 (3H, d, 5Jz1.7 Hz, 5-CH3, partly
overlaps with the 5-CH3 of the major isomer), 2.01 (3H, d, 5J¼1.3 Hz,
4-CH3), 1.60 (1H, ddd, 2J¼13.3, 3J¼5.5, 3J¼4.1 Hz, 8-HA), 1.27e1.61
(2H, m, CH2 in Et, overlap with the CH2 proton signals of the major
isomer), 1.38 (1H, ddd, 2J¼13.3, 3J¼7.3, 3J¼6.3 Hz, 8-HB), 0.93 (3H, t,
3J¼7.4 Hz, CH3 in Et); 13C NMR of the major isomer (75.48 MHz,
the major isomer (75.48 MHz, DMSO-d6) d: 158.8 (C-5), 154.6 (C-2),
138.5 (C-4), 103.9 (C-4a), 51.2 (C-8a), 49.2 (C-7), 36.6 (C-8), 28.0 (5-
CH3), 23.6 (7-CH3), 18.8 (4-CH3); 13C NMR of the minor isomer
(75.48 MHz, DMSO-d6)
(C-4a), 50.2 (C-8a), 45.3 (C-7), 35.3 (C-8), 27.4 (5-CH3), 22.1 (7-CH3),
18.0 (4-CH3); IR (Nujol)
, cmꢀ1: 3229 (br s), 3107 (br s) (NH), 1713
d
: 160.6 (C-5), 154.7 (C-2), 137.1 (C-4), 104.0
DMSO-d6) d: 158.7 (C-5), 154.6 (C-2), 137.8 (C-4), 104.4 (C-4a), 56.9
(C-8a), 49.4 (C-7), 34.2 (C-8), 30.0 (CH2 in Et), 28.2 (5-CH3), 18.7 (4-
n
CH3), 10.4 (CH3 in Et); 13C NMR of the minor isomer (75.48 MHz,
(vs) (amide-I),1648 (m),1631 (s) (C]C),1581 (s) (C]N). Anal. Calcd
for C10H15N3O: C, 62.15; H, 7.82; N, 21.74. Found: C, 62.14; H, 7.68; N,
21.71.
DMSO-d6)
(C-8a), 45.5 (C-7), 33.2 (C-8), 28.7 (CH2 in Et), 27.2 (5-CH3), 17.7 (4-
CH3), 11.0 (CH3 in Et); IR (Nujol)
, cmꢀ1: 3224 (br s), 3108 (br s)
d: 161.1 (C-5), 154.9 (C-2), 136.5 (C-4), 104.4 (C-4a), 56.4
n
(NH), 1699 (vs) (amide-I), 1653 (s), 1636 (s) (C]C), 1582 (s) (C]N).
Anal. Calcd for C11H17N3O: C, 63.74; H, 8.27; N, 20.27. Found: C,
63.68; H, 8.27; N, 20.38.
4.6.3. 4,5,8-Trimethyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyrimidin-
2-one (10c). Compound 10c (0.538 g, 87%) as a mixture of
(8R
*
,8aS
*
)- and (8R
*
,8aR )-diastereomers (57:43) was prepared
*
from pyrimidine 9d (0.760 g, 3.20 mmol; a 56:44 isomeric mixture)
and PPh3 (0.952 g, 3.63 mmol) in MeCN (8 mL) (reflux, 6 h) as
described for 10a. After crystallization from MeCN the di-
astereomeric ratio changed to 55:45, respectively. Mp 201.5e202 ꢁC
(decomp., MeCN). 1H NMR of the major isomer (300.13 MHz,
4.6.5. 4-Methyl-5-phenyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyr-
imidin-2-one (10e). A solution of pyrimidine 9f (0.507 g,
1.78 mmol) and PPh3 (0.529 g, 2.02 mmol) in dry MeCN (40 mL) was
heated at reflux for 7 h under stirring, and then the solvent was
removed under vacuum. The residue was purified by column
chromatography on silica gel 60 (17 g) eluting with CHCl3/MeOH
(from 1:0 to 20:1) to give compound 10e (0.403 g, 95%) as a slightly
yellow solid. Mp 197.0e197.5 ꢁC (decomp., MeCN). 1H NMR
DMSO-d6) d: 8.48 (1H, br s, N(3)H), 7.00 (1H, s, N(1)H), 3.58 (1H, dq,
3J¼10.5, 5J¼1.3 Hz, 8a-H), 3.51 (1H, ddq, 2J¼16.5, 3J¼4.5, 5J¼0.9 Hz,
7-HA), 2.90 (1H, ddq, 2J¼16.5, 3J¼10.9, 5J¼2.2 Hz, 7-HB), 2.12 (3H, dd,
5J¼2.2, 5J¼0.9 Hz, 5-CH3), 2.05 (3H, d, 5J¼1.3 Hz, 4-CH3), 1.49 (1H,
dddq, 3J¼10.9, 3J¼10.5, 3J¼6.4, 3J¼4.5 Hz, 8-H), 0.94 (3H, d,
3J¼6.4 Hz, 8-CH3); 1H NMR of the minor isomer (300.13 MHz,
(300.13 MHz, DMSO-d6) d: 8.53 (1H, br s, N(3)H), 7.05 (1H, s, N(1)H),
7.34e7.48 (5H, m, ArH), 4.14 (1H, ddq, 3J¼5.8, 3J¼5.8, 5J¼1.4 Hz, 8a-
H), 3.77 (1H, ddd, 2J¼14.8, 3J¼6.4, 3J¼4.4 Hz, 7-HA), 3.33 (1H, ddd,
2J¼14.8, 3J¼7.5, 3J¼4.4 Hz, 7-HB), 1.75 (1H, dddd, 2J¼13.3, 3J¼6.4,
3J¼5.8, 3J¼4.4 Hz, 8-HA), 1.67 (1H, dddd, 2J¼13.3, 3J¼7.5, 3J¼5.8,
3J¼4.4 Hz, 8-HB), 1.30 (3H, d, 5J¼1.4 Hz, 4-CH3); 13C NMR
DMSO-d6) d: z8.40 (1H, br s, N(3)H, partly overlaps with the N(3)H
signal of the major isomer), 6.91 (1H, s, N(1)H), 4.17 (1H, dq, 3J¼4.3,
5J¼1.3 Hz, 8a-H), 3.49 (1H, ddq, 2J¼17.2, 3J¼4.2, 5J¼2.1 Hz, 7-HA),
3.42 (1H, ddq, 2J¼17.2, 3J¼1.9, 5J¼1.2 Hz, 7-HB), 2.13 (3H, dd, 5J¼2.1,
5J¼1.2 Hz, 5-CH3), 2.05 (3H, d, 5J¼1.3 Hz, 4-CH3), 1.87 (1H, dddq,
3J¼6.9, 3J¼4.3, 3J¼4.2, 3J¼1.9 Hz, 8-H), 0.78 (3H, d, 3J¼6.9 Hz, 8-
(75.48 MHz, DMSO-d6) d: 165.7 (C-5), 154.0 (C-2), 141.4 (C), 136.3
(C-4), 128.9 (CH), 128.2 (2CH), 127.5 (2CH), 103.1 (C-4a), 47.6 (C-8a),
47.3 (C-7), 31.6 (C-8), 17.8 (CH3); IR (Nujol)
n
, cmꢀ1: 3188 (s), 3127
CH3); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
(s), 3086 (s), 3060 (sh) (NH), 1717 (vs) (amide-I), 1645 (s) (C]C),
1584 (m) (CCarom), 1557 (s) (C]N), 1490 (m) (CCarom), 702 (s)
(CHarom). Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27; N, 17.42.
Found: C, 69.49; H, 6.33; N, 17.41.
160.7 (C-5), 154.8 (C-2), 138.0 (C-4), 104.3 (C-4a), 55.4 (C-8a), 54.8
(C-7), 33.5 (C-8), 28.0 (5-CH3), 18.7 (4-CH3), 15.5 (8-CH3); 13C NMR
of the minor isomer (75.48 MHz, DMSO-d6)
2), 138.2 (C-4), 100.7 (C-4a), 53.9 (C-7), 52.8 (C-8a), 30.0 (C-8), 28.3
(5-CH3), 18.8 (4-CH3), 11.9 (8-CH3); IR (Nujol)
, cmꢀ1: 3214 (br s),
d: 159.5 (C-5), 153.6 (C-
n
4.6.6. 4,7-Dimethyl-5-phenyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]
3097 (br s) (NH), 1699 (vs) (amide-I), 1654 (s), 1631 (s) (C]C), 1595
(s) (C]N). Anal. Calcd for C10H15N3O: C, 62.15; H, 7.82; N, 21.74.
Found: C, 62.12; H, 7.93; N, 21.64.
pyrimidin-2-one (10f). A solution of pyrimidine 9g (0.509 g,
1.70 mmol;
a 55:45 isomeric mixture) and PPh3 (0.522 g,
1.99 mmol) in dry MeCN (21 mL) was heated at reflux for 8 h under
stirring, and then the solvent was removed under vacuum to give
4.6.4. 7-Ethyl-4,5-dimethyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]pyr-
a residue containing (8R
*
,8aS
*
)- and (8R
*
,8aR )-diastereomeric
*
imidin-2-one (10d). A solution of pyrimidine 9e (0.803 g,
mixture of 10f (54:46). The residue was purified by column chro-
matography on silica gel 60 (15 g) eluting with CHCl3/MeOH (from
1:0 to 20:1) to give a 51:49 diastereomeric mixture of compound
10f (0.394 g, 96%) as a slightly yellow solid. After crystallization
from MeCN the diastereomeric ratio changed to 76:24, respectively.
This compound was highly hygroscopic. 1H NMR analysis (in-
creased quantity of residual water in DMSO-d6 solution) and ele-
mental analysis data showed that immediately after purification it
contained 25 mol % of water. Further manipulations (additional
column chromatographic purification, repeated crystallizations
from MeCN, and prolonged drying under high vacuum over P2O5)
gave only gradual increase of water content (1H NMR and elemental
analysis data). Mp 119.5e122.5 (decomp., MeCN). 1H NMR of the
3.20 mmol;
a 69:31 isomeric mixture) and PPh3 (0.947 g,
3.61 mmol) in dry MeCN (9 mL) was heated at reflux under stirring
for 6 h, and the solvent was removed under vacuum to give a resi-
due containing (7R
*
,8aS
*
)- and (7R
*
,8aR )-diastereomeric mixture
*
of 10d (65:35). This residue was purified by column chromatogra-
phy on silica gel 60 (21 g) eluting with CHCl3/MeOH (from 1:0 to
10:1). The main fraction was concentrated in vacuo, the solid resi-
due was triturated with hexane (2 mL), the precipitate was filtered
and dried to give 10d (0.365 g, 55%) as a light yellow solid. An
analytical sample (two diastereomers, 62:38) was obtained by re-
crystallization from CH3CN. Mp 156.5e157.5 ꢁC (decomp., MeCN).
1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d: 8.45 (1H, br
s, N(3)H), 7.01 (1H, s, N(1)H), 4.03 (1H, ddq, 3J¼11.9, 3J¼4.7, 5J¼1.3 Hz,
8a-H), 3.01e3.13 (1H, m, 7-H), 2.13 (3H, d, 5Jz2.1 Hz, 5-CH3, partly
overlaps with the 5-CH3 of the minor isomer), 2.06 (3H, d,
5J¼1.3 Hz, 4-CH3), 1.95 (1H, ddd, 2J¼12.0, 3J¼4.7, 3J¼3.5 Hz, 8-HA),
major isomer (300.13 MHz, DMSO-d6) d: 8.47 (1H, br s, N(3)H),
7.26e7.41 (5H, m, Ph), 7.17 (1H, s, N(1)H), 4.18 (1H, ddq, 3J¼11.6,
3J¼4.3, 5J¼1.3 Hz, 8a-H), 3.63 (1H, ddq, 3J¼10.3, 3J¼6.9, 3J¼4.3 Hz, 7-
H), 2.07 (1H, ddd, 2J¼12.2, 3J¼4.3, 3J¼4.3 Hz, 8-HA), 1.27 (1H, ddd,

A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
5413
2J¼12.2, 3J¼11.6, 3J¼10.3 Hz, 8-HB), 1.26 (3H, d, 3J¼6.9 Hz, 7-CH3),
1.20 (3H, d, 5J¼1.3 Hz, 4-CH3); 1H NMR of the minor isomer
(0.554 g, 1.55 mmol; a 63:37 isomeric mixture) and PPh3 (0.462 g,
1.76 mmol) in dry MeCN (25 mL) was heated at reflux under stirring
for 6 h, and the solvent was removed under vacuum. The residue
was purified by column chromatography on silica gel 60 (10 g)
(300.13 MHz, DMSO-d6) d: 8.59 (1H, br s, N(3)H), 7.49e7.56 (2H, m,
H
arom), 7.34e7.45 (3H, m, Harom), 6.97 (1H, s, N(1)H), 4.14 (1H, ddq,
3J¼7.0, 3J¼2.1, 5J¼1.4 Hz, 8a-H), 3.12 (1H, ddq, 3J¼10.3, 3J¼6.5,
3J¼3.2 Hz, 7-H), 1.80 (1H, ddd, 2J¼13.6, 3J¼3.2, 3J¼2.1 Hz, 8-HA), 1.35
(3H, d, 5J¼1.4 Hz, 4-CH3), 1.34 (3H, d, 3J¼6.5 Hz, 7-CH3), 1.26 (1H,
ddd, 2J¼13.6, 3J¼10.3, 3J¼7.0 Hz, 8-HB); 13C NMR of the major iso-
eluting with CHCl3/MeOH (from 1:0 to 100:1) to give (7R
(0.127 g, 26%) as a slightly yellow solid. Mp 190.5e191.5 ꢁC
(decomp., MeCN). 1H NMR (300.13 MHz, DMSO-d6)
: 8.76 (1H, d,
*
,8aS
*
)-10h
d
4J¼1.7 Hz, N(3)H), 7.47e7.55 (2H, m, ArH), 7.31e7.41 (3H, m, ArH),
7.18 (1H, d, 4J¼1.7 Hz, N(1)H), 4.27 (1H, dd, 3J¼7.3, 3J¼2.1 Hz, 8a-H),
3.62 (1H, dq, 2J¼10.7, 3J¼7.1 Hz, HA in OCH2), 3.23 (1H, dq, 2J¼10.7,
3J¼7.1 Hz, HB in OCH2), 3.22 (1H, ddq, 3J¼10.3, 3J¼6.7, 3J¼3.6 Hz, 7-
H, partly overlap with the OCHB proton signals), 1.87 (1H, ddd,
2J¼13.7, 3J¼3.6, 3J¼2.1 Hz, 8-HA), 1.39 (3H, d, 3J¼6.7 Hz, 7-CH3), 1.35
(1H, ddd, 2J¼13.7, 3J¼10.3, 3J¼7.3 Hz, 8-HB), 0.79 (3H, t, 3J¼7.1 Hz,
mer (75.48 MHz, DMSO-d6) d: 162.5 (C-5), 153.8 (C-2), 142.6 (C),
137.7 (C-4), 128.1 (CH), 128.0 (2CH), 127.6 (2CH), 103.1 (C-4a), 53.1
(C-8a), 49.6 (C-7), 38.6 (C-8), 23.2 (7-CH3), 18.3 (4-CH3); 13C NMR of
the minor isomer (75.48 MHz, DMSO-d6) d: 165.3 (C-5), 154.6 (C-2),
140.5 (C), 135.8 (C-4), 129.2 (CH), 128.2 (2CH), 127.5 (2CH), 103.2 (C-
4a), 51.7 (C-8a), 46.5 (C-7), 38.5 (C-8), 22.6 (7-CH3), 17.4 (4-CH3); IR
(Nujol)
n
, cmꢀ1: 3501 (s) (H2O), 3175 (br s), 3101 (sh), 3086 (br s),
CH3 in OEt); 13C NMR (75.48 MHz, DMSO-d6)
d: 163.6 (C-5), 161.8
3067 (sh), 3030 (w) (NH), 1715 (vs) (amide-I), 1658 (m), 1622 (s)
(C]C), 1586 (w) (CCarom), 1555 (s) (C]N), 1488 (w) (CCarom), 772
(s), 699 (s) (CHarom). Anal. Calcd for C15H17N3O$0.25H2O: C, 69.34;
H, 6.79; N, 16.17. Found: C, 69.37; H, 6.83; N, 16.13.
(C]O in COOEt), 153.7 (C-2), 139.2 (C), 130.3 (C-4), 129.3 (CH), 128.0
(2CH),126.8 (2CH),108.6 (C-4a), 61.1 (OCH2), 52.0 (C-8a), 46.6 (C-7),
37.4 (C-8), 22.5 (7-CH3), 13.1 (CH3 in OEt); IR (Nujol) n
, cmꢀ1: 3312
(s), 3278 (s), 3153 (br w), 3127 (br w), 3109 (br w) (NH), 3052 (w)
(CHarom), 1727 (s) (C]O in COOEt), 1708 (s) (amide-I), 1680 (s), 1650
(s) (C]C), 1588 (w) (CCarom), 1567 (m) (C]N), 1198 (s) (CeO), 771
(s), 701 (s) (CHarom). Anal. Calcd for C17H19N3O3: C, 65.16; H, 6.11; N,
13.41. Found: C, 65.13; H, 6.14; N, 13.38.
4.6.7. 4,8-Dimethyl-5-phenyl-1,2,3,7,8,8a-hexahydropyrido[4,3-d]
pyrimidin-2-one (10g). A solution of pyrimidine 9i (0.512 g,
1.71 mmol;
a 50:50 isomeric mixture) and PPh3 (0.527 g,
2.01 mmol) in dry MeCN (26 mL) was heated at reflux for 6 h under
stirring, and then the solvent was removed under vacuum to give
Acknowledgements
a residue containing (8R
*
,8aS
*
)- and (8R
*
,8aR )-diastereomeric
*
mixture of 10g (49:51). The residue was purified by column chro-
matography on silica gel 60 (10 g) eluting with CHCl3/MeOH (from
1:0 to 12.5:1) to give a 51:49 diastereomeric mixture of compound
10g (0.395 g, 90%) as a slightly yellow solid. After two crystalliza-
tions from MeCN the diastereomeric ratio changed to 82:18, re-
spectively. According to 1H NMR analysis (increased quantity of
residual water in DMSO-d6 solution) and elemental analysis data,
this compound formed a strong solvate with water (10 mol %).
Further manipulations (repeated crystallizations from MeCN and
prolonged drying under high vacuum over P2O5) did not change
water content (1H NMR and elemental analysis data). Mp
209.5e211.5 ꢁC (decomp., MeCN). 1H NMR of the major isomer
This research was financially supported by the Ministry of Ed-
ucation and Science of the Russian Federation (project part of
government order, 4.1849.2014/K) and the Presidential Grant for
Young Scientists (MK-2956.2013.3).
Supplementary data
Copies of IR, 1H and 13C NMR spectra of all the synthesized
compounds, and computational data. Supplementary data associ-
ated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2014.06.128. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
(300.13 MHz, DMSO-d6) d: 8.39 (1H, br s, N(3)H), 7.34e7.44 (5H, m,
Ph, overlap with signals of analogous protons of the minor isomer),
6.98 (1H, br d, 3J¼1.3 Hz, N(1)H), 4.29 (1H, ddq, 3J¼4.3, 3J¼1.3,
5J¼1.3 Hz, 8a-H), 3.82 (1H, dd, 2J¼17.9, 3J¼4.9 Hz, 7-HA), 3.58 (1H,
dd, 2J¼17.9, 3J¼1.8 Hz, 7-HB), 2.13 (3H, dd, 5J¼2.1, 5J¼1.2 Hz, 5-CH3),
1.96 (1H, dddq, 3J¼6.9, 3J¼4.9, 3J¼4.3, 3J¼1.8 Hz, 8-H), 1.24 (3H, d,
5J¼1.3 Hz, 4-CH3), 0.92 (3H, d, 3J¼6.9 Hz, 8-CH3); 1H NMR of the
References and notes
1. For reviews on pyridopyrimidines, see: (a) Irwin, W. J.; Wibberley, D. G. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton, A. J., Eds.; Aca-
demic: New York, NY, 1969; Vol. 10, pp 149e198; (b) Delia, T. J. In The Chemistry
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Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Elsevier: Amsterdam,
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Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Ramsden, C. A., Scriven,
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Netherlands, 2008; Vol. 10, pp 759e844.
minor isomer (300.13 MHz, DMSO-d6) d: 8.54 (1H, br s, N(3)H),
7.34e7.44 (5H, m, Ph, overlap with signals of analogous protons of
the major isomer), 7.21 (1H, br d, 3J¼1.5 Hz, N(1)H), 3.70 (1H, dd,
2J¼16.8, 3J¼5.1 Hz, 7-HA), 3.67 (1H, ddq, 3J¼8.7, 3J¼1.5, 5J¼1.3 Hz,
8a-H), 3.37 (1H, dd, 2J¼16.8, 3J¼8.8 Hz, 7-HB), 1.86 (1H, dddq,
3J¼8.8, 3J¼8.7, 3J¼6.6, 3J¼5.1 Hz, 8-Ha), 1.25 (3H, d, 5J¼1.3 Hz, 4-
CH3), 0.91 (3H, d, 3J¼6.6 Hz, 8-CH3); 13C NMR of the major isomer
(75.48 MHz, DMSO-d6) d: 164.7 (C-5), 153.4 (C-2), 141.8 (C), 136.3
(C-4), 128.7 (CH), 128.2 (2CH), 127.5 (2CH), 102.9 (C-4a), 56.1 (C-7),
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55.2 (C-8a), 37.1 (C-8), 18.1 (4-CH3), 15.7 (8-CH3); 13C NMR of the
minor isomer (75.48 MHz, DMSO-d6) d: 163.5 (C-5), 152.9 (C-2),
3. (a) Rosowsky, A.; Forsch, R. A.; Bader, H.; Freisheim, J. H. J. Med. Chem. 1991, 34,
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142.3 (C), 135.7 (C-4), 128.4 (CH), 128.1 (2CH), 99.3 (C-4a), 55.5 (C-
7), 53.0 (C-8a), 33.1 (C-8), 12.4 (8-CH3). Signals of other carbons
were not detectable; IR (Nujol) n
, cmꢀ1: 3229 (br s), 3112 (br s) (NH),
1697 (vs) (amide-I), 1667 (m), 1627 (m) (C]C), 1589 (w) (CCarom),
1561 (m) (C]N), 779 (s), 705 (s) (CHarom). Anal. Calcd for
C
15H17N3O$0.1H2O: C, 70.07; H, 6.74; N, 16.34. Found: C, 70.04; H,
6. Sanfilippo, P. J.; Urbanski, M.; Williams, L.; Press, J. B.; Katz, L. B.; Shriver, D. A.;
Fernandez, J. A.; Shatynski, D.; Offord, S. J. Eur. J. Med. Chem. 1992, 27, 655e661.
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6.73; N, 16.60.
4.6.8. Ethyl 7-methyl-2-oxo-5-phenyl-1,2,3,7,8,8a-hexahydropyrido
[4,3-d]pyrimidin-4-carboxylate (10h). A solution of pyrimidine 9m
8. Mo, W.; Liao, G.; Wang, T.; He, H. J. Fluorine Chem. 2008, 129, 519e523.

5414
A.A. Fesenko, A.D. Shutalev / Tetrahedron 70 (2014) 5398e5414
ꢀ
9. For reviews on Staudinger/aza-Wittig reaction, see: (a) Hajos, G.; Nagy, I. Curr.
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(30 min after destillation) showed the presence of three main components in
a ratio of 86:4:10, namely azidoaldehyde 2a, acroleine 1a, and a non-carbonyl
compound, which was identified as 1,3-diazidopropan-1-ol (13).27 Therefore,
spontaneous decomposition of azidoaldehyde 2a in CDCl3 solution includes
slow HN3 elimination followed by addition of HN3 to the carbonyl group of
azidoaldehyde 2a to give compound 12. Addition of hydrazoic acid to aldehydes
€
H.; Richardt, G.; Stolben, S. Iminophosphoranes: Versatile Tools in Heterocyclic
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to provide a
-azido alcohols has been recently reported.28
20. Excesses of ureas 4a,b were used to prevent formation of N,N0-disubstituted
side products (see Ref. 10i).
21. Previously29 we proposed a convenient criterion for the determination of the
substituent orientation at C-4 and C-6 in hexahydropyrimidine-2-
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JN(1)H,6-H and JN(3)H,4-H
.
22. Other possible tautomeric forms of these compounds have not been taken into
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tomers 10 and 12.
€
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18. Caution! Although we never experienced any accidents with azides 2 on scales
described within this article, we recommend great caution. These compounds
may be explosive and must be manipulated behind splash shields.
19. After 2 h of storage at ꢀ18 ꢁC under argon, the distilled 2a turned into dark
brown liquid (strong gas evolution). 1H and 13C NMR spectra of 2a in CDCl3
27. 1H NMR spectrum of 13 (300.13 MHz, CDCl3)
d
: 5.05 (1H, t, 3J¼5.7 Hz, CHN3), 3.
36e3.49 (2H, m, CH2N3), 1.82e1.88 (2H, m, CH2). 13C NMR spectrum of 13 (75.
48 MHz, CDCl3) d: 83.3 (CHN3), 46.7 (CH2N3), 35.1 (CH2).
€
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