Synthesis of α,β-unsaturated caprolactams starting from heterocyclic imines

Article abstract of DOI:10.1002/jhet.381

(Chemical Equation Presented) New classes of α,β-unsaturated caprolactams containing variable heteroatoms in δ-position were synthesized from heterocyclic imines as a starting material. The synthetic route is based on an acid chloride addition followed by a ring-closing metathesis using a ruthenium catalyst.

Full text of DOI:10.1002/jhet.381

May 2010
Synthesis of a,b-Unsaturated Caprolactams Starting from
Heterocyclic Imines
697
Katharina Johannes, Martin Watzke, and Ju¨rgen Martens*
Institute of Pure and Applied Chemistry, University of Oldenburg, 26129 Oldenburg, Germany
*E-mail: juergen.martens@uni-oldenburg.de
Received August 17, 2009 Revised 9 December 2009; accepted 22 December 2009
DOI 10.1002/jhet.381
Published online 11 May 2010 in Wiley InterScience (www.interscience.wiley.com).
New classes of a,b-unsaturated caprolactams containing variable heteroatoms in d-position were syn-
thesized from heterocyclic imines as a starting material. The synthetic route is based on an acid chloride
addition followed by a ring-closing metathesis using a ruthenium catalyst.
J. Heterocyclic Chem., 47, 697 (2010).
INTRODUCTION
RESULTS AND DISCUSSION
a,b-Unsaturated lactams are categorized as interesting
structures because of their high bioactivity depending on
their functionalities as lactams and Michael acceptors.
Derivatives of a,b-unsaturated caprolactams, for exam-
ple, show central nervous system activity by causing
convulsions and loss of muscle control [1]. Furthermore,
anticancer activity was reported [2]. Saturated caprolac-
tam derivatives, for example, were effective as anti-
inflammatory agent [3] or growth-inhibiting activity on
plants [4].
We focused our attention on different heterocyclic
imines serving as a starting material in the intended syn-
thetic route. The monocyclic five-membered 2,5-dihy-
drothiazole 1a [7] and 2,5-dihydrooxazole 1b [8] were
synthesized by a modified Asinger protocol [9] starting
from the a-halogen aldehyde 2-chloro-2-methylpropanal.
In the first step of the synthesis, the heterocyclic
imines 2,5-dihydrothiazole 1a and 2,5-dihydrooxazole
1b were used as precursors in the addition of unsatu-
rated acid chloride. This type of reaction is based on
Leuchs’, Wulkow’s, and Gerland’s work [10], which
described the addition of different acid chlorides to 3H-
indole derivatives followed by addition of the nucleo-
philes, water, methanol, and ammonia. The insertion of
thiols was published by Schwarze et al. [11]. Thus, the
chosen acryloyl chloride and 2-methylacryloyl chloride
were added to the heterocyclic imines 1 (Scheme 1).
Without isolation of the a-chloro amides, allyl mercap-
tan or N-allylmethylamine was added in the presence of
triethylamine to obtain the acryl amides 2 in yields up
to 63% (Table 1).
In the recent past, we were able to report the first syn-
thesis of a,b-unsaturated d-oxacaprolactams. This new
substance class was synthesized by using heterocyclic
imines as precursors [5]. The reaction of imines with
unsaturated acid chlorides followed by treatment with
allyl alcohol led to acryl amides, which were used as a
starting material in ring-closing metathesis (RCM).
This synthetic route shows potential for further inves-
tigations (Fig. 1). Our aim to expand the application
range of this technology was realized by inserting differ-
ent heteroatoms in the lactam structure. In addition to
sulfur and nitrogen, the insertion of selenium was shown
in one example. Thus, the design of two new substance
classes was achieved in case of nitrogen and selenium
containing seven-membered lactam structures shown in
Figure 1. A few derivatives of a,b-unsaturated d-thia-
caprolactams were yet known, but synthesized in a pho-
tochemical reaction [6].
The introduction of selenium into acryl amides is a
demanding task because of the synthesis of allyl selenol.
Because of exotic reagents used in known synthesis [12]
of allyl selenol, we considered other procedures. The
reaction of alkyl halogenides and sodium hydrogen sele-
nide, formed in aqueous or ethanolic solution, leads to
aliphatic selenols [13]. To prepare aromatic selenols,
C
V
2010 HeteroCorporation

698
K. Johannes, M. Watzke, and J. Martens
Vol 47
Scheme 2. Preparation of selenium containing acryl amide 2g.
Reagents and conditions: (a) (i) Mg, Et2O, (ii) Se, reflux, 1 h; (b) (i)
H2C¼CHCOCl, Et2O, 0–5ꢀC, (ii) r.t., 3 h; (c) r.t., 18 h, 6%.
Figure 1. Retrosynthetical consideration of the target structure.
Scheme 1. Synthesis of acryl amides 2 starting from imines 1.
Reagents and conditions: (a) (CH3)2CO, NH3, NaSH or H2O, CH2Cl2,
0–5ꢀC, (ii) r.t., 18 h; (b) (i) H2C¼CRCOCl, CH2Cl2, 0–5ꢀC, (ii) r.t., 3
h; (c) (i) H2C¼CHCH2YH, Et3N, CH2Cl2, 0–5ꢀC, (ii) 2d–f: reflux, 5
h, 7–63%.
Scheme 3. Ring-closing metathesis to form lactams 3. Reagents and
conditions: (a) 5 mol% catalyst I, toluene, r.t. up to 70ꢀC, 2–6 h, 36–
90%.
elementary selenium reacts with aryl magnesium halo-
genides (Grignard reagent) by inserting between magne-
sium and aryl moiety [14]. The first called option was
not considered because water, respectively, ethanol in
excess would act as nucleophile rather than the selenol.
So, a selenium-Grignard reagent was formed and
directly added to an a-chloro amide synthesized simulta-
neously of imine 1a (Scheme 2). The acryl amide 2g
was obtained in small yield of only 6%.
catalyst I is comparable to a Grubbs catalyst of the sec-
ond generation (Fig. 2). The RCM was performed in tol-
uene, starting at room temperature and slowly increasing
the temperature up to 70ꢀC. The lactams 3 were
obtained in good yields up to 90% (Table 2). Accord-
ingly, the catalyst shows a high tolerance to several
functional groups.
Finally, the desired a,b-unsaturated caprolactams 3
were prepared from acryl amides 2 via RCM (Scheme
3). In the literature, only a few examples of RCM start-
ing from acryl amides are described [5,15].
The optimized reaction conditions tested in the syn-
thesis of a,b-unsaturated d-oxacaprolactams [5] were
transferred to the present reactions. The used ruthenium
CONCLUSION
In conclusion, we synthesized new a,b-unsaturated
caprolactams 3 containing sulfur, nitrogen, or selenium
in d-position. Starting from heterocyclic imines 1, an
addition of unsaturated acid chlorides followed by
Table 1
Acryl amides 2.
Imine
Acryl amide
X
Y
R
Yield (%)
1a
1b
1b
1a
1b
1b
2a
2b
2c
2d
2e
2f
S
O
O
S
O
O
S
S
S
H
H
Me
H
H
Me
44
15
18
63
14
7a
NMe
NMe
NMe
a The product was not obtained pure.
Figure 2. Used ruthenium catalyst I.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Synthesis of a,b-Unsaturated Caprolactams Starting from Heterocyclic Imines
699
Table 2
g (0.6 mmol, 44%); colorless solid; mp 33ꢀC; Rf ¼ 0.53 (n-
hexane–EtOAc, 7:3); IR: 3078, 2982, 2960, 2933, 1650, 1631,
a,b-Unsaturated caprolactams 3.
1
1607, 1464, 1404, 1376, 1346, 957, 918 cmꢂ1; H NMR (500
MHz, CDCl3): d ¼ 1.51 [s, 3 H, SC(CH3)2CH], 1.60 [s, 3 H,
SC(CH3)2CH], 1.88 [s, 3 H, SC(CH3)2N], 1.96 [s, 3 H,
SC(CH3)2N], 3.24 (dd, 2J ¼ 13.4 Hz, 3J ¼ 7.5 Hz, 1 H,
SCH2CHCH2), 3.32 (dd, 2J ¼ 13.4 Hz, 3J ¼ 6.8 Hz, 1 H,
SCH2CHCH2), 5.08 (br s, 1 H, NCH), 5.16–5.19 (m, 2 H,
Acryl amide
Lactam
X
Y
R
Yield (%)
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
S
O
O
S
S
S
H
H
74
45
88
90
74
50
36
S
Me
H
NMe
NMe
NMe
Se
3
SCH2CHCH2), 5.69 (d, J ¼ 10.4 Hz, 1 H, COCHCH2), 5.80–
O
O
S
H
5.89 (m, 1 H, SCH2CHCH2), 6.32 (d, 3J ¼ 16.6 Hz, 1 H,
COCHCH2), 6.55 (dd, 3J ¼ 10.4 Hz, 3J ¼ 16.6 Hz, 1 H,
Me
H
2g
3g
COCHCH2); 13C NMR (125 MHz, CDCl3):
d
¼
25.2
[SC(CH3)2CH], 31.7 [SC(CH3)2N], 35.9 (SCH2CHCH2), 53.7
[SC(CH3)2CH], 72.3 [SC(CH3)2N], 78.0 (NCH), 117.9
(SCH2CHCH2), 127.9 (COCHCH2), 130.6 (COCHCH2), 133.8
(SCH2CHCH2), 165.0 (CO); MS (CI, isobutane): m/z (%):
272.1 (28) [M þ H]þ, 198.1 (100) [MH ꢂ CH3SH]þ; HRMS
(CI, isobutane): m/z calcd for [C13H22NOS2]þ: 272.1143;
found: 272.1143.
substituting the chloride with unsaturated nucleophiles
and subsequent RCM led to lactams 3 offering opportu-
nities for further functionalizations.
EXPERIMENTAL
(RS)-1-(4-Allylsulfanyl-2,2,5,5-tetramethyloxazolidin-3-yl)-
propenone (2b).. Following GP A, 2,5-dihydrooxazole 1b
(0.64 g, 5.0 mmol), acryloyl chloride (0.50 g, 5.5 mmol), allyl
mercaptan (70%) (1.06 g, 10.0 mmol), and triethylamine (0.89
g, 8.75 mmol) were used. The product was purified by column
chromatography (silica gel; n-hexane–EtOAc, 7:3); yield: 0.19
g (0.7 mmol, 15%); yellow oil; Rf ¼ 0.58 (n-hexane–EtOAc,
Synthetic procedures were performed on a vacuum line
using standard Schlenk techniques under argon. All reagents
and solvents were commercial grade and purified before use
when necessary. The ruthenium catalyst I, catME-
R
V
Tium IMesPCy [CAS 254972-49-1], is available at Strem
Chemicals. Preparative column chromatography was carried
out using Grace SiO2 (0.040–0.063 mm, type KG 60). TLC
was performed on Merck SiO2 F254 plates on aluminum
sheets. 1H and 13C NMR spectra were recorded with Bruker
AMX R 500 and AM 300 spectrometers. NMR chemical shifts
are reported in ppm using TMS as an internal standard.
Assignments of the signals in the 13C NMR spectrum were
supported by measurements applying COSY and J modulated
techniques. CI-MS and HRMS spectra were recorded on a Fin-
nigan MAT 212 spectrometer. IR spectra were recorded on a
Bruker Tensor 27 spectrometer equipped with a GoldenGate
diamond-ATR unit.
General procedure for the preparation of acryl amides 2
(GP A).. Under argon atmosphere, the respective imine 1 (1
equiv) dissolved in anhydrous dichloromethane (10 mL) was
cooled down to 0–5ꢀC before acid chloride (1.1 equiv) in an-
hydrous dichloromethane (15 mL) was added dropwise. After
stirring for 3 h at room temperature, a mixture of allyl mercap-
tan or N-allylmethylamine (2 equiv) and anhydrous triethyl-
amine (1.75 equiv) in anhydrous dichloromethane (10 mL)
was added dropwise at 0–5 C. If N-allylmethylamine was
used, the reaction mixture was refluxed for 5 h. After stirring
overnight at room temperature, the solution was poured into
ice-water (20 mL). The phases were separated and the aqueous
phase was extracted with dichloromethane (3 ꢁ 20 mL). The
combined organic phases were washed with saturated aqueous
sodium hydrogen carbonate (20 mL), water (2 ꢁ 20 mL) and
dried over magnesium sulfate. The solvent was removed under
reduced pressure and the product was purified as described
later.
1
7:3); IR: 2980, 2937, 1655, 1614, 1411, 1356 cmꢂ1; H NMR
(500 MHz, CDCl3): d ¼ 1.38 [s, 3 H, OC(CH3)2CH], 1.50 [s,
3 H, OC(CH3)2CH], 1.60 [s, 3 H, OC(CH3)2N], 1.70 [s, 3 H,
OC(CH3)2N], 3.15–3.27 (m, 2 H, SCH2CHCH2), 4.70 (br s, 1
H, NCH), 5.09–5.22 (m, 2 H, SCH2CHCH2), 5.72 (dd, 2J ¼
1.8 Hz, 3J ¼ 10.3 Hz, 1 H, COCHCH2), 5.82–5.91 (m, 1 H,
SCH2CHCH2), 6.39 (dd, 2J ¼ 1.8 Hz, 3J ¼ 16.6 Hz, 1 H,
COCHCH2), 6.56 (dd, 3J ¼ 10.3 Hz, 3J ¼ 16.6 Hz, 1 H,
COCHCH2); 13C NMR (125 MHz, CDCl3):
d
¼
25.2
[OC(CH3)2CH], 27.6 [OC(CH3)2N], 27.8 [OC(CH3)2N], 28.7
[OC(CH3)2CH], 35.6 (SCH2CHCH2), 69.7 (NCH), 82.0
[OC(CH3)2CH], 95.3 [OC(CH3)2N], 118.0 (SCH2CHCH2),
128.0 (COCHCH2), 129.5 (COCHCH2), 133.1 (SCH2CHCH2),
163.3 (CO); MS (CI, isobutane): m/z (%): 256.1 (100) [M þ
H]þ, 182.2 (55) [M ꢂ SCH2CHCH2]þ; HRMS (CI, isobutane):
m/z calcd for [C13H22NO2S]þ: 256.1371; found: 256.1369.
(RS)-1-(4-Allylsulfanyl-2,2,5,5-tetramethyloxazolidin-3-yl)-
2-methylpropenone (2c).. Following GP A, 2,5-dihydrooxa-
zole 1b (0.32 g, 2.5 mmol), 2-methylacryloyl chloride (0.29 g,
2.75 mmol), allyl mercaptan (70%) (0.53 g, 5.0 mmol), and
triethylamine (0.45 g, 4.4 mmol) were used. The product was
purified by column chromatography (silica gel; n-hexane–
EtOAc, 7:3); yield: 0.12 g (0.4 mmol, 18%); light yellow
solid; mp 54–56 C; Rf ¼ 0.60 (n-hexane–EtOAc, 7:3); IR:
2979, 2936, 1652, 1630, 1410, 1391, 1368 cmꢂ1 1H NMR
;
(500 MHz, CDCl3): d ¼ 1.39 [s, 3 H, OC(CH3)2CH], 1.45 [s,
3 H, OC(CH3)2CH], 1.60 [s, 3 H, OC(CH3)2N], 1.65 [s, 3 H,
2
OC(CH3)2N], 2.04–2.05 [m, 3 H, COC(CH3)CH2], 3.15 (dd, J
¼ 13.5 Hz, 3J ¼ 7.5 Hz, 1 H, SCH2CHCH2), 3.20 (dd, 2J ¼
13.5 Hz, 3J ¼ 7.1 Hz, 1 H, SCH2CHCH2), 4.96 (br s, 1 H,
NCH), 5.05–5.11 (m, 2 H, SCH2CHCH2), 5.14–5.15 [m, 1 H,
COC(CH3)CH2], 5.24–5.25 [m, 1 H, COC(CH3)CH2], 5.72–
5.80 (m, 1 H, SCH2CHCH2); 13C NMR (125 MHz, CDCl3): d
(RS)-1-(4-Allylsulfanyl-2,2,5,5-tetramethylthiazolidin-3-yl)-
propenone (2a).. Following GP A, 2,5-dihydrothiazole 1a
(0.20 g, 1.4 mmol), acryloyl chloride (0.14 g, 1.5 mmol), allyl
mercaptan (70%) (0.30 g, 2.8 mmol), and triethylamine (0.25
g, 2.4 mmol) were used. The product was purified by column
chromatography (silica gel; n-hexane–EtOAc, 7:3); yield: 0.17
¼
20.3 [COC(CH3)CH2], 25.5 [OC(CH3)2CH], 27.6
[OC(CH3)2N], 28.0 [OC(CH3)2N], 28.6 [OC(CH3)2CH], 36.3
Journal of Heterocyclic Chemistry
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700
K. Johannes, M. Watzke, and J. Martens
Vol 47
(SCH2CHCH2), 72.0 (NCH), 81.5 [OC(CH3)2CH], 94.8
[OC(CH3)2N], 115.4 (COC(CH3)CH2), 117.4 (SCH2CHCH2),
133.7 (SCH2CHCH2), 142.2 (COC(CH3)CH2), 170.5 (CO);
MS (CI, isobutane): m/z (%): 270.1 (100) [M þ H]þ, 196.1
(72) [M ꢂ SCH2CHCH2]þ; HRMS (CI, isobutane): m/z calcd
for [C14H24NO2S]þ: 270.1528; found: 270.1529.
(RS)-1-[4-(Allylmethylamino)-2,2,5,5-tetramethyloxazolidin-
3-yl]-2-methylpropenone (2f).. Following GP A, 2,5-dihy-
drooxazole 1b (0.32 g, 2.5 mmol), 2-methylacryloyl chloride
(0.29 g, 2.75 mmol), N-allylmethylamine (0.36 g, 5.0 mmol),
and triethylamine (0.45 g, 4.4 mmol) were used. The product
was purified by column chromatography (silica gel; n-hexane–
EtOAc, 1:1); yield: 0.05 g (0.2 mmol, 7%); yellow oil; Rf ¼
0.83 (n-hexane–EtOAc, 1:1). The product was not obtained
pure, but its structure was verified by MS, HRMS and further
reaction to analytically pure (RS)-1,4,7,7,9,9-hexamethyl-9,9a-
dihydro-2H-oxazolo[4,3-b][1,3]diazepin-5-one 3f; MS (CI, iso-
butane): m/z (%): 267.4 (12) [M þ H]þ, 196.3 (60) [M ꢂ
N(CH3)CH2CHCH2]þ, 142.1 (100) [C7H14N2O]þ; HRMS (CI,
isobutane): m/z calcd for [C15H27N2O2]þ: 267.2073; found:
267.2068.
(RS)-1-[4-(Allylmethylamino)-2,2,5,5-tetramethylthiazolidin-
3-yl]-propenone (2d).. Following GP A, 2,5-dihydrothiazole
1a (0.20 g, 1.4 mmol), acryloyl chloride (0.14 g, 1.5 mmol),
N-allylmethylamine (0.20 g, 2.8 mmol), and triethylamine
(0.25 g, 2.4 mmol) were used. The product was purified by
column chromatography (silica gel; n-hexane–EtOAc, 7:3);
yield: 0.24 g (0.9 mmol, 63%); colorless oil; Rf ¼ 0.67 (n-hex-
ane–EtOAc, 7:3); IR: 3077, 2982, 2932, 1652, 1612, 1468,
1
1406, 1338, 972, 918 cmꢂ1; H NMR (500 MHz, CDCl3): d ¼
1.38 [s, 3 H, SC(CH3)2CH], 1.54 [s, 3 H, SC(CH3)2CH], 1.93
[s, 3 H, SC(CH3)2N], 1.94 [s, 3 H, SC(CH3)2N], 2.57 (s, 3 H,
NCH3), 3.42 (dd, 2J ¼ 14.8 Hz, 3J ¼ 6.0 Hz, 1 H,
NCH2CHCH2), 3.73 (d, 2J ¼ 14.8 Hz, 1 H, NCH2CHCH2),
(RS)-1-(4-Allylselanyl-2,2,5,5-tetramethylthiazolidin-3-yl)-
propenone (2g).. Under argon atmosphere, 2,5-dihydrothiazole
1a (0.30 g, 2.1 mmol) was dissolved in anhydrous diethyl ether
(5 mL) and cooled to 0–5ꢀC before acryloyl chloride (0.19 g,
2.1 mmol) dissolved in anhydrous diethyl ether (1 mL) was
added dropwise. The solution was stirred for 3 h at room tem-
perature. Simultaneously, in another flask magnesium turnings
(0.08 g, 3.1 mmol) were covered with anhydrous diethyl ether
(5 mL) under argon atmosphere. Under continuous boiling,
allyl bromide (0.38 g, 3.1 mmol) was added dropwise. After
finishing addition, selenium (0.25 g, 3.1 mmol) was added and
the reaction mixture was refluxed for 1 h. At room temperature,
the first prepared solution of a-chloro amide was added to sele-
nium-Grignard reagent dropwise. After stirring overnight, water
(10 mL) was added and the phases were separated. The aque-
ous phase was extracted with dichloromethane (2 ꢁ 10 mL).
The combined organic phases were dried over magnesium sul-
fate. The solvent was removed under reduced pressure and the
product was purified by column chromatography (silica gel; n-
hexane–EtOAc, 7:3); yield: 43 mg (0.14 mmol, 6%); light yel-
low oil; Rf ¼ 0.53 (n-hexane–EtOAc, 7:3); the product was not
obtained pure, but its structure was verified by further reaction
to analytically pure (RS)-7,7,9,9-tetramethyl-9,9a-dihydro-2H-
2
3
4.68 (br s, 1 H, NCH), 5.06 (dd, J ¼ 1.5 Hz, J ¼ 10.0 Hz, 1
2
3
H, NCH2CHCH2), 5.13 (dd, J ¼ 1.5 Hz, J ¼ 17.1 Hz, 1 H,
NCH2CHCH2), 5.62 (dd, 2J ¼ 1.6 Hz, 3J ¼ 10.4 Hz, 1 H,
COCHCH2), 5.64–5.71 (m, 1 H, NCH2CHCH2), 6.32 (dd, 2J
¼ 1.6 Hz, 3J ¼ 16.3 Hz, 1 H, COCHCH2), 6.50 (dd, 3J ¼
10.4 Hz, 3J ¼ 16.3 Hz, 1 H, COCHCH2); 13C NMR (125
MHz, CDCl3): d ¼ 24.6 [SC(CH3)2CH], 33.8 [SC(CH3)2CH],
28.9 [SC(CH3)2N], 32.1 [SC(CH3)2N], 37.2 (NCH3), 53.1
[SC(CH3)2CH], 55.5 (NCH2CHCH2), 71.7 [SC(CH3)2N], 91.0
(NCH), 116.3 (NCH2CHCH2), 126.9 (COCHCH2), 131.3
(COCHCH2), 136.3 (NCH2CHCH2), 166.2 (CO); MS (CI, iso-
butane): m/z (%): 269.2 (100) [M þ H]þ, 198.1 (50) [MH ꢂ
C4H9N]þ; HRMS (CI, isobutane): m/z calcd for
[C14H25N2OS]þ: 269.1688; found: 269.1688.
(RS)-1-[4-(Allylmethylamino)-2,2,5,5-tetramethyloxazolidin-
3-yl]-propenone (2e).. Following GP A, 2,5-dihydrooxazole
1b (0.32 g, 2.5 mmol), acryloyl chloride (0.25 g, 2.75 mmol),
N-allylmethylamine (0.36 g, 5.0 mmol), and triethylamine
(0.45 g, 4.4 mmol) were used. The product was purified by
column chromatography (silica gel; n-hexane–EtOAc, 1:1);
yield: 0.09 g (0.4 mmol, 14%); light yellow oil; Rf ¼ 0.83 (n-
hexane–EtOAc, 1:1); IR: 2980, 2941, 1651, 1613, 1414, 1353
1
thiazolo[4,3-b][1,3]selenazepin-5-one 3g; H NMR (500 MHz,
CDCl3): d ¼ 1.53 [s, 3 H, SC(CH3)2CH], 1.65 [s, 3 H,
SC(CH3)2CH], 1.87 [s, 3 H, SC(CH3)2N], 1.99 [s, 3 H,
SC(CH3)2N], 3.32–3.43 (m, 2 H, SeCH2CHCH2), 5.09–5.12
cmꢂ1
;
1H NMR (500 MHz, CDCl3): d ¼ 1.33 [s, 3 H,
2
OC(CH3)2CH], 1.34 [s, 3 H, OC(CH3)2CH], 1.67 [s, 3 H,
OC(CH3)2N], 1.72 [s, 3 H, OC(CH3)2N], 2.44 (s, 3 H, NCH3),
3.31 (dd, 2J ¼ 14.6 Hz, 3J ¼ 6.0 Hz, 1 H, NCH2CHCH2),
3.43 (dd, 2J ¼ 14.6 Hz, 3J ¼ 5.8 Hz, 1 H, NCH2CHCH2),
(m, 2 H, SeCH2CHCH2), 5.30 (s, 1 H, NCH), 5.70 (dd, J ¼
3
3
1.6 Hz, J ¼ 10.4 Hz, 1 H, COCHCH2), 5.96 (dddd, J ¼ 7.8
Hz, 3J ¼ 7.8 Hz, 3J ¼ 9.6 Hz, 3J ¼ 17.3 Hz, 1 H,
SeCH2CHCH2), 6.33 (dd, 2J ¼ 1.6 Hz, 3J ¼ 16.6 Hz, 1 H,
COCHCH2), 6.57 (dd, 3J ¼ 10.4 Hz, 3J ¼ 16.6 Hz, 1 H,
COCHCH2); MS (CI, isobutane): m/z (%): 320.1 (18) [M þ
H]þ, 198.1 (100) [MH ꢂ C3H6Se]þ; HRMS (CI, isobutane): m/
z calcd for [C13H22NOSSe]þ: 320.0587; found: 320.0587.
General procedure for the preparation of lactams 3 (GP
B).. Acryl amide 2 (1 equiv) and the ruthenium catalyst I
(0.05 equiv) were dissolved in toluene (8 mL) and heated to
30ꢀC. Following the solution was slowly heated to at most
70ꢀC over a period of 2-6 h (heating rate: about 10ꢀC /h) until
the reaction was complete as continuously controlled by TLC.
The solvent was removed under reduced pressure and the
product was purified as described later.
2
3
4.50 (s, 1 H, NCH), 5.08 (dd, J ¼ 1.0 Hz, J ¼ 10.2 Hz, 1 H,
NCH2CHCH2), 5.15 (dd, 2J ¼ 1.0 Hz, 3J ¼ 17.1 Hz, 1 H,
NCH2CHCH2), 5.65 (dd, 2J ¼ 1.7 Hz, 3J ¼ 10.2 Hz, 1 H,
COCHCH2), 5.67–5.73 (m, 1 H, NCH2CHCH2), 6.38 (dd, 2J
¼ 1.7 Hz, 3J ¼ 16.7 Hz, 1 H, COCHCH2), 6.53 (dd, 3J ¼
10.2 Hz, 3J ¼ 16.7 Hz, 1 H, COCHCH2); 13C NMR (125
MHz, CDCl3): d ¼ 24.3 [OC(CH3)2CH], 27.2 [OC(CH3)2N],
28.1 [OC(CH3)2N], 30.0 [OC(CH3)2CH], 36.8 (NCH3), 56.0
(NCH2CHCH2), 82.5 [OC(CH3)2CH], 83.9 (NCH), 94.5
[OC(CH3)2N], 116.6 (NCH2CHCH2), 127.3 (COCHCH2),
130.2 (COCHCH2), 136.2 (NCH2CHCH2), 164.6 (CO); MS
(CI, isobutane): m/z (%): 253.2 (20) [M þ H]þ, 182.1 (52) [M
ꢂ N(CH3)CH2CHCH2]þ, 142.1 (100) [C7H14N2O]þ; HRMS
(CI, isobutane): m/z calcd for [C14H25N2O2]þ: 253.1916;
found: 253.1916.
(RS)-7,7,9,9-Tetramethyl-9,9a-dihydro-2H-thiazolo[4,3-b]
[1,3]thiazepin-5-one (3a).. Following GP B, the acryl amide
2a (41 mg, 0.15 mmol) and ruthenium catalyst I (7.2 mg, 8
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Synthesis of a,b-Unsaturated Caprolactams Starting from Heterocyclic Imines
701
lmol) were used. The product was purified by column chroma-
tography (silica gel; n-hexane–EtOAc, 1:1); yield: 27 mg (0.11
mmol, 74%); colorless solid; mp 120ꢀC; Rf ¼ 0.47 (n-hexane–
EtOAc, 1:1); IR: 2964, 2932, 1643, 1609, 1467, 1437, 1375,
lmol) were used. The product was purified by column chroma-
tography (silica gel; n-hexane–EtOAc, 1:1); yield: 32 mg (0.13
mmol, 90%); colorless solid; mp 67ꢀC; Rf ¼ 0.40 (n-hexane–
EtOAc, 1:1); IR: 2986, 2953, 2859, 1655, 1604, 1469, 1440,
1
1338, 808 cmꢂ1; H NMR (500 MHz, CDCl3): d ¼ 1.46 [s, 3
1416, 1398, 1365, 1344, 815 cmꢂ1 1H NMR (500 MHz,
;
H, SC(CH3)2CH], 1.67 [s, 3 H, SC(CH3)2CH], 1.95 [s, 3 H,
CDCl3): d ¼ 1.31 [s, 3 H, SC(CH3)2CH], 1.57 [s, 3 H,
SC(CH3)2CH], 1.89 [s, 3 H, SC(CH3)2N], 1.94 [s, 3 H,
SC(CH3)2N], 2.54 (s, 3 H, NCH3), 3.19–3.23 (m, 1 H, CH2),
3.85 (ddd, 2J ¼ 20.7 Hz, 3J ¼ 2.8 Hz, 4J ¼ 2.6 Hz, 1 H,
2
SC(CH3)2N], 2.09 [s, 3 H, SC(CH3)2N], 3.14 (ddd, J ¼ 13.3
Hz, 3J ¼ 7.4 Hz, 4J ¼ 1.8 Hz, 1 H, CH2), 3.40 (ddd, 2J ¼
3
4
13.3 Hz, J ¼ 6.4 Hz, J ¼ 0.9 Hz, 1 H, CH2), 5.10 (s, 1 H,
NCH), 6.04–6.12 (m, 2 H, COCHCH); 13C NMR (125 MHz,
CDCl3): d ¼ 25.0 [SC(CH3)2CH], 30.2 [SC(CH3)2CH], 25.6
(CH2), 32.6 [SC(CH3)2N], 32.9 [SC(CH3)2N], 51.7
[SC(CH3)2CH], 73.4 [SC(CH3)2N], 78.1 (NCH), 126.9
(COCHCH), 129.7 (COCHCH), 166.3 (CO); MS (CI, isobu-
tane): m/z (%): 244.1 (100) [M þ H]þ; HRMS (CI, isobutane):
m/z calcd for [C11H18NOS2]þ: 244.0830; found: 244.0832.
(RS)-7,7,9,9-Tetramethyl-9,9a-dihydro-2H-oxazolo[4,3-b]
[1,3]thiazepin-5-one (3b).. Following GP B, the acryl amide
2b (40 mg, 0.16 mmol) and ruthenium catalyst I (7.4 mg, 8
lmol) were used. The product was purified by column chroma-
tography (silica gel; n-hexane–EtOAc, 7:3); yield: 16 mg (0.07
mmol, 45%); colorless solid; mp 79–80ꢀC; Rf ¼ 0.23 (n-hex-
ane–EtOAc, 7:3); IR: 2984, 2935, 1656, 1605, 1393, 1370,
3
4
CH2), 4.72 (s, 1 H, NCH), 5.91 (ddd, J ¼ 12.9 Hz, J ¼ 2.6
4
3
3
Hz, J ¼ 1.7 Hz, 1 H, COCHCH), 6.02 (ddd, J ¼ 2.8 Hz, J
¼ 2.9 Hz, 3J ¼ 12.9 Hz, 1 H, COCHCH); 13C NMR (125
MHz, CDCl3): d ¼ 25.3 [SC(CH3)2CH], 34.7 [SC(CH3)2CH],
38.0 [SC(CH3)2N], 31.6 [SC(CH3)2N], 36.5 (NCH3), 50.0
[SC(CH3)2CH], 59.2 (CH2), 70.8 [SC(CH3)2N], 88.8 (NCH),
128.0 (COCHCH), 140.4 (COCHCH), 165.6 (CO); MS (CI,
isobutane): m/z (%): 241.2 (100) [M þ H]þ; HRMS (CI, iso-
butane): m/z calcd for [C12H21N2OS]þ: 241.1375; found:
241.1376.
(RS)-1,7,7,9,9-Pentamethyl-9,9a-dihydro-2H-oxazolo[4,3-b]
[1,3]diazepin-5-one (3e).. Following GP B, the acryl amide 2e
(37 mg, 0.15 mmol) and ruthenium catalyst I (6.9 mg, 7 lmol)
were used. The product was purified by column chromatogra-
phy (silica gel; n-hexane–EtOAc, 7:3); yield: 24 mg (0.11
mmol, 74%); colorless solid; mp 83–86ꢀC, Rf ¼ 0.09 (n-hex-
ane–EtOAc, 7:3); IR: 2956, 2936, 2871, 1651, 1604, 1428,
1195 cmꢂ1
;
1H NMR (500 MHz, CDCl3): d ¼ 1.42 [s, 3 H,
OC(CH3)2CH], 1.45 [s, 3 H, OC(CH3)2CH], 1.73 [s, 3 H,
OC(CH3)2N], 1.79 [s, 3 H, OC(CH3)2N], 3.16 (dd, 2J ¼ 13.9
Hz, 3J ¼ 7.6 Hz, 1 H, CH2), 3.35 (ddd, 2J ¼ 13.9 Hz, 3J ¼
1405, 1369, 1198 cmꢂ1
;
1H NMR (500 MHz, CDCl3): d ¼
4
6.8 Hz, J ¼ 1.0 Hz, 1 H, CH2), 4.88 (s, 1 H, NCH), 6.08 (dd,
1.31 [s, 3 H, OC(CH3)2CH], 1.38 [s, 3 H, OC(CH3)2CH], 1.67
[s, 3 H, OC(CH3)2N], 1.69 [s, 3 H, OC(CH3)2N], 2.37 (s, 3 H,
3J ¼ 10.9 Hz, J ¼ 1.0 Hz, 1 H, COCHCH), 6.20 (ddd, J ¼
6.8 Hz, 3J ¼ 7.6 Hz, 3J ¼ 10.9 Hz, 1 H, COCHCH); 13C
NMR (125 MHz, CDCl3): d ¼ 25.2 [OC(CH3)2CH], 26.2
(CH2), 28.0 [OC(CH3)2N], 28.4 [OC(CH3)2N], 29.4
[OC(CH3)2CH], 69.7 (NCH), 80.6 [OC(CH3)2CH], 95.9
[OC(CH3)2N], 129.2 (COCHCH), 129.6 (COCHCH), 164.5
(CO); MS (ESI): m/z (%): 250.0 (100) [M þ Na]þ; HRMS
(CI, isobutane): m/z calcd for [C11H18NO2S]þ: 228.1058;
found: 228.1058.
4
3
2
3
4
NCH3), 3.25 (ddd, J ¼ 20.4 Hz, J ¼ 3.3 Hz, J ¼ 1.6 Hz, 1
2
3
4
H, CH2), 3.83 (ddd, J ¼ 20.4 Hz, J ¼ 2.6 Hz, J ¼ 2.6 Hz,
3
4
1 H, CH2), 4.53 (s, 1 H, NCH), 5.92 (ddd, J ¼ 13.1 Hz, J ¼
4
3
1.6 Hz, J ¼ 2.6 Hz, 1 H, COCHCH), 6.05 (ddd, J ¼ 2.6 Hz,
3
3J ¼ 3.3 Hz, J ¼ 13.1 Hz, 1 H, COCHCH); 13C NMR (125
MHz, CDCl3): d ¼ 24.2 [OC(CH3)2CH], 26.6 [OC(CH3)2N],
27.7 [OC(CH3)2N], 30.9 [OC(CH3)2CH], 36.5 (NCH3), 58.8
(CH2), 80.6 [OC(CH3)2CH], 82.2 (NCH), 93.9 [OC(CH3)2N],
127.5 (COCHCH), 140.3 (COCHCH), 164.4 (CO); MS (CI,
isobutane): m/z (%): 225.2 (100) [M þ H]þ; HRMS (CI, iso-
butane): m/z calcd for [C12H21N2O2]þ: 225.1603; found:
225.1602.
(RS)-4,7,7,9,9-Pentamethyl-9,9a-dihydro-2H-oxazolo[4,3-b]
[1,3]thiazepin-5-one (3c).. Following GP B, the acryl amide
2c (40 mg, 0.15 mmol) and ruthenium catalyst I (7.0 mg, 7
lmol) were used. The product was purified by column chroma-
tography (silica gel; n-hexane–EtOAc, 7:3); yield: 31 mg (0.13
mmol, 88%); light yellow solid; mp 75–78ꢀC; Rf ¼ 0.51 (n-
hexane–EtOAc, 7:3); IR: 2991, 2929, 1650, 1627, 1402, 1374,
(RS)-1,4,7,7,9,9-Hexamethyl-9,9a-dihydro-2H-oxazolo[4,3-
b][1,3]diazepin-5-one (3f).. Following GP B, the acryl amide
2f (47 mg, 0.18 mmol) and ruthenium catalyst I (8.4 mg, 9
lmol) were used. The product was purified by column chroma-
tography (silica gel; n-hexane–EtOAc, 7:3); yield: 21 mg (0.09
mmol, 50%); colorless solid; mp 39–43ꢀC; Rf ¼ 0.26 (n-hex-
ane–EtOAc, 7:3); IR: 2987, 2936, 1649, 1592, 1423, 1367,
1203 cmꢂ1
;
1H NMR (500 MHz, CDCl3): d ¼ 1.40 [s, 3 H,
OC(CH3)2CH], 1.43 [s, 3 H, OC(CH3)2CH], 1.73 [s, 3 H,
OC(CH3)2N], 1.80 [s, 3 H, OC(CH3)2N], 1.96 [dd, 4J ¼ 1.6
5
2
Hz, J ¼ 1.0 Hz, 3 H, COC(CH3)CH], 2.97 (dd, J ¼ 13.2 Hz,
3J ¼ 8.4 Hz, 1 H, CH2), 3.28 (ddd, 2J ¼ 13.2 Hz, 3J ¼ 7.7
1198 cmꢂ1
;
1H NMR (500 MHz, CDCl3): d ¼ 1.34 [s, 3 H,
5
3
Hz, J ¼ 1.0 Hz, 1 H, CH2), 4.81 (s, 1 H, NCH), 5.83 [ddq, J
OC(CH3)2CH], 1.37 [s, 3 H, OC(CH3)2CH], 1.68 [s, 3 H,
OC(CH3)2N], 1.71 [s, 3 H, OC(CH3)2N], 1.97–1.98 [m, 3 H,
3
4
¼ 7.7 Hz, J ¼ 8.4 Hz, J ¼ 1.6 Hz, 1 H, COC(CH3)CH]; 13C
NMR (125 MHz, CDCl3): d ¼ 18.1 [COC(CH3)CH], 24.8
[OC(CH3)2CH], 25.3 (CH2), 28.2 [OC(CH3)2N], 28.4
[OC(CH3)2N], 29.3 [OC(CH3)2CH], 69.5 (NCH), 80.5
[OC(CH3)2CH], 95.7 [OC(CH3)2N], 122.3 [COC(CH3)CH],
137.9 [COC(CH3)CH], 167.2 (CO); MS (CI, isobutane): m/
z(%): 242.2 (100) [M þ H]þ; HRMS (CI, isobutane): m/z
calcd for [C12H20NO2S]þ: 242.1215; found: 242.1213.
2
COC(CH3)CH], 2.31 (s, 3 H, NCH3), 3.29 (dd, J ¼ 18.9 Hz,
3J ¼ 2.2 Hz, 1 H, CH2), 3.63 (d, 2J ¼ 18.9 Hz, 1 H, CH2),
4.24 (s, 1 H, NCH), 6.00–6.02 [m, 1 H, COC(CH3)CH]; 13C
NMR (125 MHz, CDCl3): d ¼ 21.7 [COC(CH3)CH], 24.3
[OC(CH3)2CH], 27.0 [OC(CH3)2N], 28.0 [OC(CH3)2N], 30.5
[OC(CH3)2N], 37.7 (NCH3), 56.7 (CH2), 81.0 [OC(CH3)2CH],
82.1 (NCH), 94.5 [OC(CH3)2N], 133.6 [COC(CH3)CH], 133.7
[COC(CH3)CH], 166.2 (CO); MS (CI, isobutane): m/z (%):
239.2 (100) [M þ H]þ; HRMS (CI, isobutane): m/z calcd for
[C13H23N2O2]þ: 239.1760; found: 239.1760.
(RS)-1,7,7,9,9-Pentamethyl-9,9a-dihydro-2H-thiazolo[4,3-b]
[1,3]diazepin-5-one (3d).. Following GP B, the acryl amide
2d (36 mg, 0.15 mmol) and ruthenium catalyst I (7.0 mg, 7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

702
K. Johannes, M. Watzke, and J. Martens
Vol 47
[2] Catsoulacos, P.; Camoutsis, C.; Papageorgiou, A.; Margariti,
E.; Psaraki, K.; Demopoulos, N. J Pharm Sci 1993, 82, 204.
[3] Ponec, M.; Haverkort, M.; Soei, Y. L.; Kempenaar, J.;
Brussee, J.; Bodde, H. J Pharm Sci 1989, 78, 738.
[4] Hasegawa, K.; Knegt, E.; Bruinsma, J. Phytochemistry
1983, 22, 2611.
(RS)-7,7,9,9-Tetramethyl-9,9a-dihydro-2H-thiazolo[4,3-
b][1,3]selenazepin-5-one (3g).. Following GP B, the acryl am-
ide 2g (15 mg, 0.05 mmol) and ruthenium catalyst I (2.4 mg,
3 lmol) were used. The product was purified by column chro-
matography (silica gel; n-hexane–EtOAc, 1:1); yield: 5 mg
(0.02 mmol, 36%); colorless solid; Rf ¼ 0.50 (n-hexane–
EtOAc, 1:1); IR: 2964, 2925, 2855, 1655, 1612, 1465, 1377,
[5] Watzke, M.; Schulz, K.; Johannes, K.; Ullrich, P.; Martens,
J. Eur J Org Chem 2008, 3859.
795 cmꢂ1
;
1H NMR (500 MHz, CDCl3): d ¼ 1.50 [s, 3 H,
[6] Sakamato, M.; Watanabe, S.; Fujita, T.; Yanase, T. J Org
Chem 1990, 55, 2986.
SC(CH3)2CH], 1.69 [s, 3 H, SC(CH3)2CH], 2.01 [s, 3 H,
2
SC(CH3)2N], 2.10 [s, 3 H, SC(CH3)2N], 3.12 (ddd, J ¼ 11.8
¨
[7] Kopper, S.; Lindner, K.; Martens, J. Tetrahedron 1992, 48,
10277.
[8] Weber, M.; Jakob, J.; Martens, J. Liebigs Ann Chem 1992, 1.
[9] (a) Martens, J.; Offermanns, H.; Scherberich, P. Angew
3
4
2
Hz, J ¼ 7.6 Hz, J ¼ 1.9 Hz, 1 H, CH2), 3.47 (dd, J ¼ 11.8
Hz, 3J ¼ 7.1 Hz, 1 H, CH2), 5.31 (s, 1 H, NCH), 5.99–6.07
(m, 2 H, COCHCH); 13C NMR (125 MHz, CDCl3): d ¼ 26.4
[SC(CH3)2CH], 39.9 [SC(CH3)2CH], 29.7 (CH2), 32.2
[SC(CH3)2N], 33.2 [SC(CH3)2N], 52.5 [SC(CH3)2CH], 73.7
[SC(CH3)2N], 75.0 (NCH), 127.1 (COCHCH), 128.0
(COCHCH), 166.1 (CO); MS (CI, isobutane): m/z (%): 292.0
(100) [M þ H]þ; HRMS (CI, isobutane): m/z calcd for
[C11H18NOSSe]þ: 292.0274; found: 292.0276.
Chem 1981, 93, 680; (b) Martens, J.; Offermanns, H.; Scherberich, P.
Angew Chem Int Ed Engl 1981, 20, 668.
[10] Leuchs, H.; Wulkow, G.; Gerland, H. Chem Ber 1932, 62,
1586.
[11] Schwarze, W.; Drauz, K.; Martens, J. Chem-Ztg 1987, 111,
149.
[12] Riague, E. H.; Guillemin, J.-C. Organometallics 2002, 21,
68.
Acknowledgment. The authors are indebted to Ludmila Her-
mann for the preparative assistance. The ruthenium catalyst I was
generously supplied by Evonik Degussa GmbH and the silica gel
by Grace GmbH & Co. KG. K. J. gratefully acknowledges the
Heinz Neumu¨ller-Stiftung for a doctoral fellowship.
[13] Klayman, D. L.; Griffin, T. S. J Am Chem Soc 1973, 95,
197.
[14] Taboury, F. Ann Chim Phys 1908, 15, 5.
[15]
(a) Rodriguez, S.; Castillo, E.; Carda, M.; Marco, J. A.
Tetrahedron 2002, 58, 1185; (b) Chen, Y.; Zhang, H.; Nan, F. J
Comb Chem 2004, 6, 684; (c) Deiters, A.; Pettersson, M.; Martin, S.
F. J Org Chem 2006, 71, 6547; (d) Liu, G.; Tai, W.-Y.; Li, Y.-L.;
Nan, F.-J. Tetrahedron Lett 2006, 47, 3295; (e) Fiorelli, C.; Savoia,
D. J Org Chem 2007, 72, 6022; (f) Schulz, K.; Watzke, M.; Johannes,
K.; Ullrich, P.; Martens, J. Synthesis 2009, 665.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet