Synthesis of Acetylenic Amides with Propyllactam Moieties by in Situ DBU or DBN Ring-Opening Rearrangement in the Presence of Acetylenic Esters

Article abstract of DOI:10.1055/s-0036-1591852

DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) react with methyl esters of acetylenic acids and excess water (the reactant molar ratio 1:1, in aqueous MeCN, at 20-25 °C, for 48 h) to afford acetylenic amides with pyrro

Full text of DOI:10.1055/s-0036-1591852

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
en
O. A. Shemyakina et al.
Paper
Synthesis
Synthesis of Acetylenic Amides with Propyllactam Moieties by
In Situ DBU or DBN Ring-Opening Rearrangement in the Presence
of Acetylenic Esters
Olesya A. Shemyakina
R2
H2O (50 equiv), MeCN
O
Ol’ga G. Volostnykh
Anton V. Stepanov
Anastasiya G. Mal’kina
Igor’ A. Ushakov
N
R1
+
( )n
20–25 °C, 48 h
– MeOH
OMe
OH
N
R2
O
R2
O
O
O
R1
R1
Boris A. Trofimov*
or
N
H
N
N
H
N
OH
89–97%
OH
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch,
Russian Academy of Sciences, 1 Favorsky Str., 664033, Irkutsk,
Russian Federation
89–100%
R1 = Me, R2 = Me, Et, t-Bu; R1–R2 = (CH2)5
boris_trofimov@irioch.irk.ru
Received: 21.07.2017
Accepted after revision: 07.11.2017
Published online: 07.12.2017
alized oxazolopyrrolohexahydropyrimidines and oxazolo-
hexahydropyrimidoazepines. Notably, in the reaction of
DBN with methyl esters of acetylenic acids, the participa-
tion of trace water in the ring opening of the pyrimidine
moiety of the amidine was observed. This resulted in for-
mation of complex molecules containing pyrrolidone and
2(5H)-furanone structures linked with the 1,3-diamino-
propane chain.3f Thereby, the aim of the present work was to
study the reaction of DBN and DBU with available4 methyl
esters of acetylenic acids in the presence of water in order
to develop a general, efficient approach to the synthesis of
the above pharmaceutically attractive compounds. Indeed,
pyrrolidone and caprolactam are of high medicinal value.
These structures are frequently met in natural products5
(cotinine,5a mycobactin,5b cononusine,5c hygrocin,5d ervalu-
teine,5c pestalactams A–C,5e silvaticamide5f and the like), in
some common drugs (e.g., benazepril, pecilocin, pyrroli-
done-type nootropics as aniracetam, piracetam, pramirace-
tam, and others) and pharmacologically important com-
pounds exhibiting antitumor,6 anti-inflammatory,7 and
antimicrobial8 activities. Some lactam derivatives are effective
against Alzheimer’s disease9 and osteoporosis10 as well as
delivery carriers for therapeutic agents11 and transdermal
permeation enhancers12 (trademark Azone and analogues).
Our experiments revealed that the reaction of DBN and
DBU with methyl esters of acetylenic acids 1a–d (a molar
ratio amidines/1, 1:1, MeCN, 20–25 °C, 48 h) in the pres-
ence of excess water (1 mL, 50 equiv) proceeded chemo-
selectively (at the ester function only) and completed with
formation of acetylenic amides 2a–h tethered with pyrroli-
done or caprolactam moiety, with yields ranging from 89 to
100% (Table 1).
DOI: 10.1055/s-0036-1591852; Art ID: ss-2017-z0477-op
Abstract DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and DBU (1,8-diaza-
bicyclo[5.4.0]undec-7-ene) react with methyl esters of acetylenic acids
and excess water (the reactant molar ratio 1:1, in aqueous MeCN, at
20–25 °C, for 48 h) to afford acetylenic amides with pyrrolidone and
caprolactam moieties in 89–100% yields. The synthesis involves amines
formed in situ from the cyclic amidines, which further react with acety-
lenic esters.
Key words DBN (1,5-diazabicyclo[4.3.0]non-5-ene), DBU (1,8-diaza-
bicyclo[5.4.0]undec-7-ene), acetylenic acid esters, acetylenic amides,
lactam
Bicyclic amidines, DBN (1,5-diazabicyclo[4.3.0]non-5-
ene) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), which
are non-nucleophilic organic superbases, are widely used in
organic synthesis as catalysts.1 However, transformations of
these amidines as nucleophiles are less common although
this is currently attracting increasing attention.2 Among
them, there are rare reactions of DBN and DBU with acety-
lenic compounds, mostly alkynoates.3 DBU was shown to be
capable of annulating with dimethyl acetylenedicarboxyl-
ate, resulting in the formation of diazabenzoazulene.3a DBN
and DBU annulation with methyl perfluoro-2-alkynoates3b,c
and methyl propiolate3d led to diazaacenaphthalenes and
diazacycloheptanaphthalenes.3b–d p-Nitrophenyl carbon-
ates of 1-ethynylcyclohexanol and homopropargylic alco-
hol exclusively afforded the caprolactam and pyrrolidone
products, 2-propynyl and 3-butynyl N-[3-(2-oxo-1-pyrro-
lidinyl/azepanyl)propyl]carbamates, when 2 equivalents of
DBN and DBU were used.3e Recently, it was found3f that DBN
and DBU annulated with electron-deficient acetylenic alco-
hols bearing CN, C(O)Ph, or CO2Me electron-withdrawing
functions to give condensed tricyclic derivatives – function-
The progress of the reaction was monitored by 1H NMR
spectroscopy following the disappearance of the MeO-
group signal of starting acetylene 1 at δ = 3.77–3.74 ppm.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
O. A. Shemyakina et al.
Paper
Synthesis
Table 1 Synthesis of Acetylenic Amides 2a–h
R2
R2
O
O
O
H2O (50 equiv), MeCN
R1
N
R1
+
( )n
N
N
OH
( )n
OMe
H
20–25 °C, 48 h
– MeOH
OH
N
1a–d
2a–h
Amidine
Methyl ester of acetylenic acid 1
Product 2
Isolated yield (%)
96
Me
OH
O
Me
OH
O
O
Me
2a
Et
N
Me
N
H
N
OMe
N
1a
Me
O
O
Me
O
Et
89
97
N
N
OH
OMe
H
OH
1b
2b
t-Bu
2c
Me
O
O
Me
O
t-Bu
N
N
OH
H
OMe
OH
1c
O
O
O
97
100
93
N
H
N
OH
OMe
OH
1d
2d
Me
OH
O
O
Me
OH
O
Me
N
Me
N
N
H
OMe
N
1a
2e
Me
OH
O
O
Me
OH
O
Et
Et
N
N
H
OMe
1b
2f
Me
OH
O
O
Me
OH
O
t-Bu
t-Bu
N
N
89
H
OMe
1c
2g
O
O
O
98
N
N
OH
H
OMe
OH
1d
2h
The structures of amides 2a–h have been proven by 1H,
13C, 15N and 2D (NOESY, 1Н-13С HSQC, 1Н-13С and 1Н-15N
HMBC) NMR techniques, as well as IR spectra. In the 1Н
NMR spectra, the alkyl protons signals of lactam and alco-
hol moieties are present. In the 13С NMR spectra of com-
pounds 2a–h the carbonyl carbons resonate in the region of
159.1–161.4 and 164.5–167.4 ppm, the signals of the C≡C
carbons appear at 80.2–82.3 and 81.8–84.5 ppm. In the IR
spectra of the products 2a–h, the C≡C, C=O (lactam), and
C=O (amide) absorption bands are observed at 2213–2225,
1644–1689, and 1576–1593 cm–1, respectively.
Notably, in contrast to the expectations, the reaction
takes quite another direction as compared with the previ-
ous results.3f Indeed, the electron-deficient triple bond
avoids the nucleophilic attack from the site of amidine ni-
trogen. Apparently, in excess water this nitrogen undergoes
competitive protonation by a water molecule to give
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
O. A. Shemyakina et al.
Paper
Synthesis
ammonium hydroxide intermediate A (Scheme 1). In other
words, the amidines behave in this case as typical bases
rather than as nucleophiles. Furthermore, the covalent form
of intermediate A, intermediate B, is subjected to rearrange-
ment with the ring opening delivering 3-aminopropyl-
lactams C. Their reaction with the methyl ester of acetylenic
acid 1 leads to the final products, acetylenic amides 2 teth-
ered to lactam cycles by 1,3-diaminopropane linkers. Such a
rationalization is supported by reports13 that DBU in water
is protonated to form ammonium hydroxide (Scheme 1, in-
termediate A). Further support for the mechanism present-
ed in Scheme 1 is the report14 that DBN and DBU undergo
ring opening in water (85 °C, 12 h) to afford aminopropyl-
lactams in high yields (Scheme 1, intermediate C).
An additional support for the above mechanism is for-
mation of acetamide 4 when DBU is allowed to react with
methyl acetate under the same conditions (Scheme 3). This
reaction may have a general value for organic synthesis if it
is systematically developed.
O
Me
HN
H2O (50 equiv), MeCN
O
N
O
Me
+
N
20–25 °C, 48 h
– MeOH
OMe
N
4
Scheme 3 Reaction of DBU and methyl acetate
The excess water appeared to be crucial to determine
the reaction chemoselectivity. In fact, in the presence of
just 1.4 equivalents of water (relative to the reactant), acet-
ylenic amide 2e was not obtained. Instead, the DBU annula-
tion with methyl ester of acetylenic acid 1b took place to af-
ford [1,3]oxazolo[3′,2′:3,4]hexahydropyrimido[1,2-a]azepine3f
in 85% yield (Scheme 4).
H2O
N
N
N
( )n
HO
( )n
–OH
( )n
+
N
H
N
N
H
A
B
R2
O
R1
R2
O
H2N
OMe
OH
R1
1
O
N
N
OH
N
H
O
– MeOH
H2O (1.4 equiv), MeCN
20–25 °C, 48 h
Me
OH
O
N
C
N
N
( )n
O
2
+
Et
OMe
N
( )n
Et
Me
MeO
O
Scheme 1 Plausible mechanism
Scheme 4 The DBU annulation with methyl ester of acetylenic acid 1b
We have carried out the reaction of DBU with water
without acetylenic substrate under the same conditions (1
mL H2O, MeCN, 20–25 °C, 48 h) and observed by H NMR
In conclusion, a crucial effect of the excess water on the
reaction of DBN and DBU with methyl esters of acetylenic
acids has been established. Unlike the previously described
reactions3f carried out under anhydrous or water-limited
conditions that result in the synthesis of oxazolopyrrolo-
hexahydropyrimidines and oxazolohexahydropyrimidoaze-
pines, the excess water (50 equiv in MeCN, 20–25 °C) com-
pletely redirects the interaction to the formation of acety-
lenic amides having pyrrolidone and caprolactam moieties
in high yields (89–100%). The novel family of densely func-
tionalized acetylenes represents a rewarding field for re-
search towards the synthesis of drug precursors and build-
ing blocks for the design of pharmaceutically important
molecules.
1
spectroscopic analysis the formation of the expected amine
C in ca. 85% yield. Since the yields of acetylenic amides 2a–
h are higher (89–100%, Table 1) it may be suggested that the
presence of an acetylenic substrate facilitates the amida-
tion, probably through formation of the corresponding
zwitterion.3f When the reaction was conducted with meth-
yl propiolate (with DBU), instead of acetylenic alcohols 1a–
d, the expected acetylenic amide 2i is isolated in 84% yield
along with adduct 3 of intermediate C to the triple bond of
methyl propiolate (Scheme 2). Notably, such an addition
has not been detectable for acetylenic alcohols, which is a
specific feature of the latter.
H2O (50 equiv), MeCN
O
N
+
1Н and 13С NMR spectra were recorded with a Bruker DPX-400 spec-
trometer (400.1 and 100.6 MHz, respectively) in CDCl3 or CD3OD us-
ing hexamethyldisiloxane as internal reference at 20–25 °C. IR spectra
were measured with a Bruker Vertex-70 instrument in thin films or
KВr pellets. Microanalyses were performed with a Flash 2000 elemen-
tal analyzer. Melting points were determined with a Kofler micro hot-
stage.
20–25 °C, 48 h
– MeOH
OMe
N
NH
O
N
O
N
OMe
O
+
O
N
H
2i
3
The solvent was MeCN (spectroscopic grade) from Scientific Produc-
tion Company ‘Cryochrom’ (St. Petersburg, Russia). DBN, DBU, methyl
propiolate are commercial reagents (Merck). Methyl esters of acety-
Scheme 2 Reaction of DBU and methyl propiolate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
O. A. Shemyakina et al.
Paper
Synthesis
lenic acids 1a–d were prepared according to a published method.4
Commercially available starting materials were used without further
purification.
13С NMR (100.6 MHz, CDCl3): δ = 164.5 (C-2′), 159.3 (C=O), 82.5 (–C≡),
82.1 (≡C–), 73.4 (C–OH), 53.1 (C-5′), 42.5 (C-3), 38.1 [C(CH3)3], 38.0 (C-
1), 29.9 (C-3′), 25.2 [(CH3)3], 24.6 (CH3), 18.8 (C-2), 18.7 (C-4′).
Synthesized acetylenic amides 2a–h are hygroscopic.
Anal. Calcd for C16H26N2O3 (294.39): С, 65.28; Н, 8.90; N, 9.52. Found:
С, 65.04; Н, 8.52; N, 9.16.
4-Hydroxy-4-methyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-2-pent-
ynamide (2a); Typical Procedure
3-(1-Hydroxycyclohexyl)-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-2-
propynamide (2d)
To a stirred solution of DBN (124 mg, 1 mmol) in MeCN (4 mL), a solu-
tion of methyl 4-hydroxy-4-methyl-2-pentynoate (1a; 142 mg, 1
mmol) in MeCN (3 mL) and H2O (1 mL) was added dropwise over 10
min. The reaction mixture was stirred at 20–25 °C for 48 h. Solvent
was evaporated in vacuo and the residue was washed with a mixture
of hexane–acetone (1:1) to give the desired product 2a.
The residue was washed with a mixture of hexane–acetone (1:2) to
give the desired product 2d.
Yield: 282 mg (97%); snow-white solid; mp 138–144 °C.
IR (KBr): 3393, 3098, 3048, 2935, 2889, 2858, 2738, 2679, 2623, 2207
(–C≡C–), 1689, 1581 (C=O), 1448, 1335, 1282, 1259, 1218, 1167, 1132,
Yield: 242 mg (96%); snow-white solid; mp 131–135 °C.
1075, 994, 966, 894, 851, 781, 749, 711, 626, 522 cm–1
.
IR (KBr): 3405, 3248, 3105, 3054, 2974, 2929, 2884, 2773, 2219 (–C≡C–),
1Н NMR (400.1 MHz, CD3OD): δ = 3.72 (t, J = 7.2 Hz, 2 H, CH2-5′), 3.47
(t, J = 5.7 Hz, 2 H, CH2-3), 3.42 (t, J = 5.6 Hz, 2 H, CH2-1), 2.91 (t, J =
7.9 Hz, 2 H, CH2-3′), 2.18 (m, 2 H, CH2-4′), 2.06 (m, 2 H, CH2-2), 1.88
(m, 2 H, CH2), 1.70–1.49 (m, 7 H, CH2), 1.29 (m, 1 H, CH2).
13С NMR (100.6 MHz, CD3OD): δ = 165.8 (C-2′), 161.4 (C=O), 84.5 (–
C≡), 82.2 (≡C–), 68.8 (C-cHex), 54.7 (C-5′), 43.8 (C-3), 40.5 (C-cHex),
39.3 (C-1), 31.1 (C-3′), 26.3, 24.0 (C-cHex), 19.6 (C-2), 19.5 (C-4′).
1683, 1577 (C=O), 1460, 1340, 1211, 1173, 1142, 1067, 988, 946, 883,
849, 784, 734, 686, 559, 523, 464 cm–1
.
1Н NMR (400.1 MHz, CDCl3): δ = 3.64 (t, J = 7.1 Hz, 2 H, CH2-5′), 3.48
(t, J = 5.5 Hz, 2 H, CH2-3), 3.42 (t, J = 5.6 Hz, 2 H, CH2-1), 3.07 (t, J =
7.9 Hz, 2 H, CH2-3′), 2.16 (m, 2 H, CH2-4′), 2.05 (m, 2 H, CH2-2), 1.49 (s,
6 H, CH3).
13С NMR (100.6 MHz, CDCl3): δ = 164.5 (C-2′), 159.1 (C=O), 83.1 (–C≡),
80.2 (≡C–), 64.3 (C–OH), 53.2 (C-5′), 42.5 (C-3), 38.0 (C-1), 31.2 (CH3),
29.9 (C-3′), 18.8 (C-2), 18.7 (C-4′).
15N NMR (40.56 MHz, CD3OD): δ = –257.5 (N-1′), –280.4 (NH).
Anal. Calcd for C16H24N2O3 (292.37): C, 65.73; H, 8.27; N, 9.58. Found:
С, 65.78; Н, 8.46; N, 9.96.
Anal. Calcd for C13H20N2O3 (252.31): C, 61.88; H, 7.99; N; 11.10.
Found: С, 61.70; Н, 7.92; N, 10.91.
4-Hydroxy-4-methyl-N-[3-(2-oxo-1-azepanyl)propyl]-2-pentyn-
amide (2e)
4-Hydroxy-4-methyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-2-
hexynamide (2b)
The residue was washed with diethyl ether to give the desired prod-
uct 2e.
The residue was washed with a mixture of hexane–acetone (1:2) to
give the desired product 2b.
Yield: 280 mg (100%); snow-white solid; mp 94–98 °C.
IR (KBr): 3410, 3221, 3137, 3043, 2971, 2925, 2866, 2806, 2701, 2225
Yield: 236 mg (89%); snow-white solid; mp 104–108 °C.
(–C≡C–), 1648, 1582 (C=O), 1469, 1413, 1346, 1202, 1164, 1111, 987,
IR (KBr): 3360, 3292, 3105, 3051, 2971, 2934, 2882, 2781, 2628, 2213
949, 923, 891, 846, 787, 729, 608, 557, 529 cm–1
.
(–C≡C–), 1686, 1586 (C=O), 1461, 1399, 1337, 1286, 1190, 1134, 1061,
1Н NMR (400.1 MHz, CDCl3): δ = 3.50–3.44 (m, 6 H, CH2-1,3,7′), 2.85
(m, 2 H, CH2-3′), 2.02 (m, 2 H, CH2-2), 1.75, 1.67 (m, 6 H, CH2-4′,5′,6′),
1.50 (s, 6 H, CH3).
13С NMR (100.6 MHz, CDCl3): δ = 166.1 (C-2′), 159.3 (C=O), 82.7 (–C≡),
80.5 (≡C–), 64.7 (C–OH), 54.2 (C-7′), 48.6 (C-3), 38.1 (C-1), 32.1 (C-3′),
31.2 (CH3), 29.1 (C-5′), 27.0 (C-6′), 24.1 (C-4′), 19.7 (C-2).
1023, 965, 917, 886, 852, 783, 718, 689, 598, 524, 467 cm–1
.
1Н NMR (400.1 MHz, CDCl3): δ = 3.63 (t, J = 7.2 Hz, 2 H, CH2-5′), 3.48
(t, J = 5.7 Hz, 2 H, CH2-3), 3.40 (t, J = 5.8 Hz, 2 H, CH2-1), 3.08 (t, J =
8.0 Hz, 2 H, CH2-3′), 2.15 (m, 2 H, CH2-4′), 2.03 (m, 2 H, CH2-2), 1.68
(m, 2 H, CH3CH2), 1.45 (s, 3 H, CH3), 1.01 (t, J = 7.4 Hz, 3 H, CH3CH2).
13С NMR (100.6 MHz, CDCl3): δ = 164.5 (C-2′), 159.1 (C=O), 82.0 (–C≡),
81.5 (≡C–), 67.9 (C–OH), 53.1 (C-5′), 42.5 (C-3), 38.0 (C-1), 36.2
(CH3CH2), 29.9 (CH3), 28.9 (C-3′), 18.8 (C-2), 18.7 (C-4′), 8.9 (CH3CH2).
Anal. Calcd for C15H24N2O3 (280.36): C, 64.26; H, 8.63; N, 9.99. Found:
С, 64.58; Н, 8.61; N, 9.92.
Anal. Calcd for C13H20N2O3 (266.34): C, 63.13; H, 8.33; N, 10.52.
Found: С, 62.89; Н, 8.31; N, 10.12.
4-Hydroxy-4-methyl-N-[3-(2-oxo-1-azepanyl)propyl]-2-
hexynamide (2f)
The residue was washed with a mixture of hexane–acetone (2:1) to
give the desired product 2f.
4-Hydroxy-4,5,5-trimethyl-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-2-
hexynamide (2c)
Yield: 274 mg (93%); snow-white solid; mp 105–108 °C.
The residue was washed with a mixture of hexane–acetone (1:2) to
IR (KBr): 3379, 3261, 3107, 3039, 2974, 2929, 2882, 2785, 2733, 2680,
2636, 2217 (–C≡C–), 1644, 1583 (C=O), 1471, 1345, 1321, 1286, 1204,
1163, 1104, 1038, 972, 921, 855, 783, 724, 692, 639, 599, 563, 509
give the desired product 2c.
Yield: 284 mg (97%); snow-white solid; mp 138–143 °C.
IR (KBr): 3408, 3294, 3104, 3051, 2967, 2881, 2777, 2616, 2214 (–C≡C–),
cm–1
.
1681, 1576 (C=O), 1460, 1418, 1341, 1212, 1155, 1114, 1069, 1015,
1Н NMR (400.1 MHz, CDCl3): δ = 3.50–3.44 (m, 6 H, CH2-1,3,7′), 2.86
(m, 2 H, CH2-3′), 2.02 (m, 2 H, CH2-2), 1.75, 1.67 (m, 6 H, CH2-4′,5′,6′),
1.66 (m, 2 H, CH3CH2), 1.45 (s, 3 H, CH3), 1.01 (t, J = 7.4 Hz, 3 H,
CH3CH2).
970, 915, 856, 790, 734, 685, 590, 556, 462 cm–1
.
1Н NMR (400.1 MHz, CDCl3): δ = 3.62 (t, J = 7.1 Hz, 2 H, CH2-5′), 3.47
(t, J = 5.7 Hz, 2 H, CH2-3), 3.40 (t, J = 5.7 Hz, 2 H, CH2-1), 3.08 (t, J =
8.0 Hz, 2 H, CH2-3′), 2.15 (m, 2 H, CH2-4′), 2.03 (m, 2 H, CH2-2), 1.42 (s,
3 H, CH3), 1.03 (s, 9 H, CH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
O. A. Shemyakina et al.
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Synthesis
13С NMR (100.6 MHz, CDCl3): δ = 166.1 (C-2′), 159.3 (C=O), 81.8 (–C≡),
81.6 (≡C–), 68.3 (C–OH), 54.2 (C-7′), 48.6 (C-3), 38.0 (C-1), 36.3
(CH3CH2), 32.1 (C-3′), 29.1 (CH3), 29.0 (C-5′), 27.0 (C-6′), 24.1 (C-4′),
19.7 (C-2), 9.0 (CH3CH2).
1Н NMR (400.1 MHz, CDCl3): δ = 3.53 (m, 4 H, CH2-7′,3), 3.42 (m, 2 H,
CH2-1), 2.80 (m, 2 H, CH2-3′), 2.49 (s, 1 H, ≡CH), 2.03 (m, 2 H, CH2-2),
1.77–1.66 (m, 6 H, CH2-4′,5′,6′).
13С NMR (100.6 MHz, CDCl3): δ = 165.9 (C-2′), 157.8 (C=O), 81.8 (≡C–),
65.88 (≡CH), 54.1 (C-7′), 48.4 (C-3), 37.9 (C-1), 32.0 (C-3′), 28.8 (C-5′),
26.6 (C-6′), 23.8 (C-4′), 19.3 (C-2).
Anal. Calcd for C16H26N2O3 (294.39): С, 65.28; Н, 8.90; N, 9.52. Found:
С, 65.08; Н, 8.82; N, 9.20.
15N NMR (40.56 MHz, CDCl3): δ = –263.9 (N-1′), –261.4 (NH).
4-Hydroxy-4,5,5-trimethyl-N-[3-(2-oxo-1-azepanyl)propyl]-2-
hexynamide (2g)
Anal. Calcd for C12H18N2O2 (222.29): C, 64.84; H, 8.16; N, 12.60.
Found: С, 64.58; Н, 8.41; N, 12.65.
The residue was washed with a mixture of hexane–acetone (1:2) to
give the desired product 2g.
Methyl 3-((3-(2-Oxo-1-azepanyl)propyl)amino)acrylate (3)
Yield: 285 mg (89%); snow-white solid; mp 139–144 °C.
Light-yellow oil; E/Z ~ 80/20.
IR (KBr): 3408, 3236, 3055, 2974, 2929, 2864, 2794, 2757, 2705, 2214
IR (film): 3314, 3054, 2929, 2857, 1675, 1618, 1537, 1485, 1439,
1367, 1304, 1240, 1189, 1147, 1081, 1050, 983, 938, 546, 791, 718, 576
(–C≡C–), 1650, 1593 (C=O), 1474, 1454, 1384, 1337, 1234, 1206, 1161,
1108, 1008, 975, 915, 867, 801, 781, 730, 693, 606, 585, 558, 510 cm–1
.
cm–1
.
1Н NMR (400.1 MHz, CDCl3): δ = 3.50–3.44 (m, 6 H, CH2-1,3,7′), 2.86
(m, 2 H, CH2-3′), 2.02 (m, 2 H, CH2-2), 1.75, 1.67 (m, 6 H, CH2-4′,5′,6′),
1.43 (s, 3 H, CH3), 1.03 (s, 9 H, CH3).
13С NMR (100.6 MHz, CDCl3): δ = 166.1 (C-2′), 159.3 (C=O), 82.7 (–C≡),
81.5 (≡C–),73.6 (C–OH), 54.2 (C-7′), 48.6 (C-3), 38.2 [C(CH3)3], 38.0
(C-1), 32.0 (C-3′), 29.0 (C-5′), 27.0 (C-6′), 25.2 [(CH3)3], 24.6 (CH3), 24.1
(C-4′), 19.6 (C-2).
1Н NMR (400.1 MHz, CDCl3): δ (E-isomer) = 7.49 [m, 1 H, =CH(NH)],
5.73 (br s, 1 H, NH), 4.71 [d, J = 13.0 Hz, 1 H, =CH(CO2Me)], 3.60 (s, 3 H,
OMe), 3.41 (m, 2 H, CH2-3), 3.32 (m, 2 H, CH2-7′), 3.02 (m, 2 H, CH2-1),
2.51 (m, 2 H, CH2-3′), 1.77–1.60 (m, 8 H, CH2-2,4′,5′,6′); δ (Z-isomer) =
7.96 (br s, 1 H, NH), 6.62 [dd, J = 8.1 Hz, 1 H, =CH(NH)], 4.45 [d, J =
8.1 Hz, 1 H, =CH(CO2Me)], 3.60 (s, 3 H, OMe), 3.41 (m, 2 H, CH2-3),
3.32 (m, 2 H, CH2-7′), 3.16 (m, 2 H, CH2-1), 2.51 (m, 2 H, CH2-3′), 1.77–
1.60 (m, 8 H, CH2-2,4′,5′,6′).
13С NMR (100.6 MHz, CDCl3): δ (E-isomer) = 176.7 (C=O), 170.1 (OCO),
149.7 [=CH(NH)], 84.5 [=CH(CO2Me)], 50.4 (OMe), 49.7 (C-7′), 45.1 (C-
3), 40.0 (br, C-1), 37.1 (C-3′), 29.9 (C-5′), 28.5 (C-6′), 26.8 (br, C-2), 23.4
(C-4′); δ (Z-isomer) = 176.0 (C=O), 171.0 (OCO), 152.2 [=CH(NH)], 81.5
[=CH(CO2Me)], 50.1 (OMe), 49.6 (C-7′), 46.2 (C-1), 45.4 (C-3), 26.8 (C-
2), 37.1 (C-3′), 29.9 (C-5′), 28.7 (C-6′), 23.4 (C-4′).
Anal. Calcd for C18H30N2O3 (322.44): С, 67.05; Н, 9.38; N, 8.69. Found:
С, 66.81; Н, 9.40; N, 8.82.
3-(1-Hydroxycyclohexyl)-N-[3-(2-oxo-1-azepanyl)propyl]-2-pro-
pynamide (2h)
The residue was washed with acetone to give the desired product 2h.
Yield: 314 mg (98%); snow-white solid; mp 135–140 °C.
Anal. Calcd for C13H22N2O3 (254.33): C, 61.39; H, 8.72; N, 11.01.
Found: С, 61.41; Н, 8.52; N, 11.05.
IR (KBr): 3297, 3231, 3043, 2981, 2930, 2857, 2803, 2693, 2202 (–C≡C–),
1652, 1578 (C=O), 1465, 1450, 1339, 1266, 1204, 1174, 1166, 1082,
989, 970, 890, 845, 813, 784, 714, 682, 542 cm–1
.
N-[3-(2-Oxo-1-azepanyl)propyl]acetamide (4)
1Н NMR (400.1 MHz, CD3OD): δ = 3.62 (m, 2 H, CH2-7′), 3.57 (m, 2 H,
CH2-3), 3.37 (m, 2 H, CH2-1), 2.71 (m, 2 H, CH2-3′), 2.05 (m, 2 H, CH2-
2), 1.89 (m, 2 H, CH2), 1.79 (m, 2 H, CH2-5′), 1.76 (m, 2 H, CH2-4′), 1.72
(m, 2 H, CH2-6′), 1.65, 1.59, 1.56, 1.54 (m, 7 H, CH2), 1.27 (m, 1 H, CH2).
The residue was washed with diethyl ether to give the desired
product 4.
Yield: 180 mg (85%); light-yellow oil.
IR (film): 3390, 3253, 3096, 3035, 2929, 2863, 2810, 2698, 1644,
1574, 1442, 1397, 1325, 1205, 1157, 1108, 1009, 989, 916, 842, 748,
13С NMR (100.6 MHz, CD3OD): δ = 167.4 (C-2′), 161.3 (C=O), 84.5 (–C≡),
82.3 (≡C–), 68.8 (C-cHex), 55.3 (C-7′), 49.5 (C-3), 40.5 (C-cHex), 39.3
(C-1), 33.7 (C-3′), 29.9 (C-5′), 27.4 (C-6′), 26.3 (C-cHex), 24.9 (C-4′),
24.0 (C-cHex), 20.4 (C-2).
692, 647, 527, 506, 470 cm–1
.
1Н NMR (400.1 MHz, CDCl3): δ = 4.96 (br s, 1 H, NH), 3.44 (m, 6 H,
CH2-1,3,7′), 2.87 (m, 2 H, CH2-3′), 1.99 (m, 2 H, CH2-2), 1.96 (s, 3 H,
CH3), 1.76, 1.67 (m, 6 H, CH2-4′,5,6′).
13С NMR (100.6 MHz, CDCl3): δ = 177.9 (C-2′), 165.6 (C=O), 53.8 (C-7′),
48.3 (C-3), 37.8 (C-1), 31.8 (C-3′), 28.8 (C-5′), 26.7 (C-6′), 24.5 (CH3),
23.9 (C-4′), 19.4 (C-2).
15N NMR (40.56 MHz, CD3OD): δ = –259.7 (N-1′), –268.6 (NH).
Anal. Calcd for C18H28N2O3 (320.43): С, 67.47; Н, 8.81; N, 8.74. Found:
С, 67.13; Н, 8.78; N, 8.81.
N-(3-(2-Oxo-1-azepanyl)propyl)propiolamide (2i) and Methyl 3-
((3-(2-Oxo-1-azepanyl)propyl)amino)acrylate (3)
15N NMR (40.56 MHz, CDCl3): δ = –255.1 (N-1′), –266.8 (NH).
Anal. Calcd for C11H20N2O2 (212.15): С, 62.24; Н, 9.50; N, 13.20.
Found: С, 62.13; Н, 9.63; N, 13.29.
The residue was washed with diethyl ether to give 2i (186 mg, 84%),
solvent was removed from the diethyl ether fraction to obtain 3 (36
mg, 14%).
Acknowledgment
N-(3-(2-Oxo-1-azepanyl)propyl)propiolamide (2i)
Yellow oil.
The main results were obtained using the equipment of Baikal analyt-
ical center of collective using SB RAS.
IR (film): 3403, 3232, 3113, 3043, 2928, 2863, 2811, 2702, 2076,
1643, 1603, 1448, 1328, 1206, 1153, 1105, 987, 872, 791, 744, 693,
578, 506 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
O. A. Shemyakina et al.
Paper
Synthesis
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591852.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F