One-pot synthesis of ene-lactams via N-debenzylation of keto-containing N-2,4-dimethoxylbenzylamides

Article abstract of DOI:10.1081/SCC-200039335

A general method of ene-lactam preparation is described. Ene-lactams can be prepared efficiently from keto-containing N-2,4-dimethoxylbenzylamides in good to excellent yields. This method is applicable for the preparation of substituted δ-, γ-, and ε-ene-lactams and bicyclic ene-lactams.

Full text of DOI:10.1081/SCC-200039335

This article was downloaded by: [University Of Pittsburgh]
On: 06 November 2014, At: 12:38
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
One‐Pot Synthesis
of Ene‐Lactams via
N‐Debenzylation
of Keto‐Containing
N‐2,4‐Dimethoxylbenzylamides
Wai Ming Kan a , Ching‐Lung Cheng b & Ching‐Yuh
Chern b
a Department of Pharmacology , National Cheng
Kung University , Tainan, Taiwan, R.O.C.
b Department of Applied Chemistry , National
Chiayi University , Chiayi, Taiwan, R.O.C.
Published online: 10 Jan 2011.
To cite this article: Wai Ming Kan , Ching‐Lung Cheng & Ching‐Yuh Chern (2004)
One‐Pot Synthesis of Ene‐Lactams via N‐Debenzylation of Keto‐Containing
N‐2,4‐Dimethoxylbenzylamides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:23, 4257-4264, DOI:
10.1081/SCC-200039335
To link to this article: http://dx.doi.org/10.1081/SCC-200039335
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our

platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4257–4264, 2004
One-Pot Synthesis of Ene-Lactams via
N-Debenzylation of Keto-Containing
N-2,4-Dimethoxylbenzylamides
Wai Ming Kan,1 Ching-Lung Cheng,2 and
Ching-Yuh Chern2,
*
1Department of Pharmacology, National Cheng Kung University,
Tainan, Taiwan, R.O.C.
2Department of Applied Chemistry, National Chiayi University,
Chiayi, Taiwan, R.O.C.
ABSTRACT
A general method of ene-lactam preparation is described. Ene-lactams
can be prepared efficiently from keto-containing N-2,4-dimethoxyl-
benzylamides in good to excellent yields. This method is applicable for
the preparation of substituted d-, g-, and 1-ene-lactams and bicyclic
ene-lactams.
Key Words: p-Toluenesulfonic acid; Ene-lactam.
*
Correspondence: Ching-Yuh Chern, Department of Applied Chemistry, National
Chiayi University, Chiayi, Taiwan, R.O.C.; Tel.: 05-2717952; Fax: 05-2717901;
E-mail: cychern@mail.ncyu.edu.tw.
4257
DOI: 10.1081/SCC-200039335
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4258
Kan, Cheng, and Chern
Ene-lactams are usefulintermediates for the preparationsofalkaloids, piper-
idinones, and many other biologically active heterocycles.[1,2] However, there
were only limited reports on the general preparation of this type of compound.
Many required high temperatures above 1808C or elevated pressure,[3–5] in
which more reaction conditions delicate starting materials may not survive.
Recently, there have been reports using the Michael addition of enamines to
acrylamides followed by cyclization for the preparation of ene-lactams.[6,7]
Others employed one-pot formation of ene-lactam involving RhH2(PPh3)4
catalyzed, DMSO/K2CO3/H2O and NH4OAc at 1808C in situ keto-amide
formation from keto-nitriles.[8,9] However, these methods are applicable to
g-ene-lactams only and suffer the use of high reaction temperature with
keto-amides producted in situ. Moreover, the synthesis of more difficult
lactams, such as 5-methyl-1, 3-dihydro-pyrrol-5-one, or 7-methyl-1,3,4,5-
tetrahydro-azepin-2-one is yet to be reported.
Previously, incorporation of electro-donating groups on the amidic
nitrogen was seldom employed unless it was a part of the synthetic
target.[10] The major objection is that an extra step is required for the
removal of the auxiliary group. Although N-benzyl groups are good candi-
dates,[11,12] N-debenzylation is usually difficult.[10] Thus, the uncertainty of
the outcome of N-debenzylation offsets the benefits of such an approach.
Recently, we reported an efficient, selective, and mild N-debenzylation
method[13] by which even acid-sensitive functional groups such as N-tert-
butoxy-, N-tert-BOC, and N-trityl- remain intact under the reported experi-
mental conditions. Moreover, no epimerization was detected for protected
amino acids. With a mild and efficient N-debenzylation method available,
the feasibility of the above approach is worthwhile examining.
In order to promote cyclization, the reaction was carried out first in
0.01 M solution with a catalytic amount (5% w/v) of p-TsOH in refluxing
toluene. When cyclization was completed as detected by thin-layer chromato-
graphy (TLC), the toluene was removed until the concentration of the starting
material reached 1 M to allow N-debenzylation. It was observed that d-ene-
lactam 2a and 1-ene-lactam 2c were synthesized in 80% and 71% yields,
while 2b was prepared in excellent yield (Table 1).
However, the attempted preparation of eight-member-ring ene-lactam 2d
failed; the synthesis of z-ene-lactam based on a similar mechanism is yet to
be reported. Cyclization of aliphatic ketone-amides lacking any substitutions
on the starting materials is particularly difficult. As illustrated by entry 6, it
took 24 h for the reaction to complete, although the desired product 2f can
be isolated in 81% yield. On the other hand, less than 20% of conversion of
2g and 2e was observed after 4 days and 1.5 days, respectively. Nevertheless,
it is the first report on the synthesis of 5-methyl-1,3-dihydro-pyrrol-5-one
and 7-methyl-1,3,4,5-tetrahydro-azepin-2-one. As expected, these methyl

One-Pot Synthesis of Ene-Lactams
Table 1. Examples of ene-lactams preparation.
4259
Entry
R
n
2 (%)
Time (h)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Ph
Ph
1
2
3
4
1
2
3
4
80
92
15
3.5
13
—
96
24
36
—
Ph
Ph
71
—
CH3
CH3
CH3
CH3
98a
81
g
h
95b
—
aRecovered starting material 80%.
bRecovered starting material 85%.
keto-amides react slower than the corresponding aryl ketones. Even with
the formation of g-ene-lactam 2f, it took 24 h for the reaction to complete,
compared to 3.5 h of its aryl ketone counterpart 2b. Moreover, the ring-size
limitation is even more obvious. It is known that substitution enhances the
reaction rate when aliphatic compounds undergo cyclization.[14] The phenyl
analog of 3 as the starting material reacted quickly, and the reaction was
completed within 4 h, with a yield of 4 in 91% yield (Scheme 1).
Bicyclic ene-lactams (Table 2) can be prepared similarly. Most of them
give their respective ene-lactams in excellent yields. Although 6a was
formed sluggishly, it is the first reported synthesis of ene-lactam 6a. Similarly,
6c was isolated in excellent yield. From these results, we may conclude that
this method is efficient and generally applicable to wide varieties of starting
materials.
Scheme 1.

4260
Kan, Cheng, and Chern
Table 2. Examples of bicyclic ene-lactams.
Entry
n
6 (%)
Time (h)
1
2
3
a
b
c
1
2
3
89a
92
120
12
95
96
aRecovered starting material 71%.
In this report, a novel and efficient method of one-pot ene-lactam
formation with simultaneous N-debenzylation of ketone-containing N-2,4-
dimethoxylbenzyl-amides is described. The method allows for the preparation
of ene-lactams that cannot be prepared with other methods. In our hands, the
reaction generally runs at 1108C, although similar results can be obtained at
808C, albeit with a longer reaction time. With the exception of z-ene-
lactams, all of the expected products were prepared. The versatility of this
method is illustrated by the preparation of ene-lactams 2e, 2g, and 6a that
were reported for the first time.
EXPERIMENTAL
Proton nuclear magnetic resonance (NMR) spectra were recorded at
200 MHz Varian Mercury-200 NMR spectrometer. Carbon NMR spectra
were recorded at 50 MHz Varian Mercury-200 NMR spectrometer. Proton
and carbon chemical shifts are reported on the delta scale as parts per
million (ppm) downfield from tetramethylsilane (TMS) as internal reference.
Mass spectra were measured with a VG Analytical Model 70-250s mass spec-
trometer. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 500
IR Spectrometer. All reagents were used as obtained commercially.
Representative Procedure
2,4-Dimethoxy-benzylamide 1 (0.29 mmol) was dissolved in 29 mL of
toluene. The reaction was carried out at first in 0.01 M solution with catalytic

One-Pot Synthesis of Ene-Lactams
4261
amount (5%) of pTsOH in refluxing toluene with a Dean–Stark trap. When
cyclization was completed as detected by TLC, the toluene was removed
until the concentration of the starting material reached 1 M. After 3.5 h
of reflux, the mixture was cooled to room temperature, and saturated
Na2CO3
was added to neturalize the acid. The aqueous phase was
(aq.)
extracted thrice with 10 mL of EtOAc. The combined organic phase was dried
and evaporated. Compound 2 was obtained after column chromatography
(EtOAc: Hexanes ¼ 1 : 10).
5-Phenyl-1,3-dihydro-1H-pyrrol-2-one (2a)[15]
1
IR n (CH2Cl2) cm21: 3200, 3100, 1678; H NMR (CDCl3, 200 MHz):
7.42–7.22(m, 5H), 5.32 (t, 1H, J ¼ 2.6 Hz), 3.18 (d, 2H, J ¼ 2.8 Hz); 13C
NMR (CDCl3, 50 MHz) d: 178.4, 147.4, 133.0, 129.1, 128.6, 128.5, 105.0,
39.4; EI-MS, m/e (relative intensity %):159 (Mþ, 14), 115 (32), 77 (100);
Anal. Calcd. for C10H9NO: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.64; H,
5.74; N, 8.82.
6-Phenyl-3,4-dihydro-1H-pyridin-2-one (2b)[15]
1
IR n (CH2Cl2)cm21: 3200, 3100, 1680; H NMR (CDCl3, 200 MHz):
7.43–7.34 (m, 5H), 5.45 (t, 1H, J ¼ 1.9 Hz), 2.61–2.44 (m, 4H); 13C NMR
(CDCl3, 50 MHz) d: 171.8, 137.0, 128.9, 128.8, 127.6, 124.8, 102.6, 30.3,
20.6; Anal. Calcd. for C11H11NO: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.42; H, 6.46; N, 8.10.
7-Phenyl-1,3,4,5-tetrahydro-azepin-2-one (2c)[15]
IRn(CH2Cl2) cm21: 3215, 3677, 3094, 2852, 1650, 1561, 1391, 1235, 1243;
1H NMR (d8-THF, 200 MHz): 7.45–7.34 (m, 5H), 6.67 (s, 1H, -NH), 5.95 (t, 1H,
J ¼ 6.6 Hz), 2.55(t, 2H, J ¼ 7.0 Hz), 2.41 (quin, 2H, J ¼ 7.0 Hz), 2.24
(quin, 2H, J ¼ 6.6 Hz); 13C NMR (d8-THF, 50MHz) d: 176.5, 137.7, 136.9,
133.2, 128.7, 125.7, 116.9, 34.5, 28.9, 25.5; EI-MS, m/e (relative intensity %):
187 (Mþ, 96), 159 (57), 115 (55), 104 (100), 77 (80); Anal. Calcd. for
C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 77.11; H, 7.10; N, 7.50.
5-Methyl-1,3-dihydro-pyrrol-5-one (2e)
1
IR n (CH2Cl2) cm21: 3108, 2950, 2910, 2850, 1670, 1380; H NMR
(CDCl3, 200 MHz): 5.45 (t, 1H, J ¼ 7.1 Hz), 3.09–3.03 (m, 2H), 2.14
(s, 3H); EI-MS, m/e (relative intensity %): 97 (Mþ,11), 82 (18), 69 (21), 55

4262
Kan, Cheng, and Chern
(100), 54 (16); Anal. Calcd. for C5H7NO: C, 61.84; H, 7.27; N, 14.42. Found:
C, 62.04; H, 7.24; N, 14.40.
6-Methyl-3,4-dihydro-1H-pyridin-2-one (2f)[8]
IR n (CH2Cl2) cm21: 3200, 2960, 2930, 2850, 1680, 1620, 1520, 1380,
1270, 1040, 810; 1H NMR (CDCl3, 200 MHz): 8.23 (bs, 1H, NH), 4.79 (t, 1H,
J ¼ 6.6 Hz), 2.47–2.38 (m, 2H), 2.33–2.18 (m, 2H), 1.81 (s, 3H); 13C NMR
(CDCl3, 50 MHz) d: 172.2, 133.0, 100.1, 30.1, 20.1, 18.8; Anal. Calcd. for
C6H9NO: C, 64.84; H, 8.16; N, 12.60. Found: C, 65.00; H, 7.17; N, 12.59.
7-Methyl-1,3,4,5-tetrahydro-azepin-2-one (2g)
1
IR n (CH2Cl2) cm21: 3210, 2934, 2908, 1695, 1350, 1210; H NMR
(CDCl3, 200 MHz): 5.44 (t, 1H, J ¼ 6.6 Hz), 2.48 (t, 2H, J ¼ 7.0 Hz), 2.13–
2.02 (m, 2H), 1.87 (s, 3H);13C NMR (CDCl3, 50 MHz) d: 174.5, 138.6,
119.4, 34.5, 30.7, 29.7, 23.1; EI-MS, m/e (relative intensity %): 125
(Mþ, 32), 101 (37), 97 (44), 83 (100), 68 (19); Anal. Calcd. for C7H11NO:
C, 67.17; H, 8.86; N, 11.19. Found: C, 67.34; H, 8.96; N, 11.20.
1,3,4,5,6,7-Hexahydro-indol-2-one (6a)
IR n (CH2Cl2) cm21: 3130, 1700, 1679, 828; 1H NMR (CDCl3,
200 MHz): 2.99 (bs, 2H, -CH2-), 2.28–1.25 (m, 8H); 13C NMR (CDCl3,
50 MHz) d: 171.6, 130.4, 118.5, 37.4, 33.1, 29.7, 28.4, 27.6; EI-MS, m/e
(relative intensity %): 137(Mþ, 100), 109 (60), 95 (54), 67 (73); HRMS m/z
Calcd. for C8H11NO: 137.0841; Found: 137.0846; Anal. Calcd. for C8H11NO:
C, 70.40; H, 8.08; N, 10.21. Found: C, 70.58; H, 8.12; N, 10.24.
3,4,5,6,7,8-Hexahydro-1H-quinolin-2-one (6b)[8]
IR n (KBr) cm21: 3220, 3177, 3094, 2932, 2862, 1669, 1489, 1441, 1391,
1202, 1134; 1H NMR (CDCl3, 200 MHz): 2.70 (t, 2H, J ¼ 7.2 Hz), 2.20–1.85
(m, 6H), 1.68–1.35 (m, 4H); 13C NMR (CDCl3, 50 MHz) d: 170.5, 131.7,
114.7, 38.5, 31.7, 29.0, 25.4, 24.8, 22.0; EI-MS, m/e (relative intensity %):
151 (Mþ, 100), 109 (3), 108 (13), 67 (10), 55 (20); Anal. Calcd. for
C9H13NO: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.58; H, 8.69; N, 9.28.
1,3,4,5,6,7,8,9-Octahydro-benzo[b]azepin-2-one (6c)[8]
IR n (CH2Cl2) cm21: 3130, 1680, 850; 1H NMR (CDCl3, 200 MHz): 2.41
(t, 2H, J ¼ 6.6 Hz), 2.28 (t, 2H, J ¼ 7.0 Hz), 2.24–1.90 (m, 6H), 1.66–1.52

One-Pot Synthesis of Ene-Lactams
4263
(m, 4H); 13C NMR (CDCl3, 50 MHz) d: 175.9, 130.3, 103.8, 50.5, 42.2, 34.1,
29.7, 28.1(2C), 25.1; EI-MS, m/e (relative intensity %): 165 (Mþ, 78), 137
(39), 109 (33), 81(29), 55 (100); HRMS m/z calcd. for C10H15NO:
165.1154; Found: 165.1157; Anal. Calcd. for C10H15NO: C, 72.69; H, 9.15;
N, 8.48. Found: C, 72.91; H, 9.20; N, 8.49.
ACKNOWLEDGMENT
This work was supported by the National Science Council, Taiwan,
R.O.C. grants NSC92-2113-M415-004.
REFERENCES
1. Ayer, W.A.; Habgood, T.E. Alkaloids 1968, 11, 459.
2. Witkop, B.; Gossinger, E. In The Alkaloids; Brossi, A., Ed.; Academic
Press: London, 1983; Vol. 21, 139.
3. Hasserodt, J.; Janda, K.D.; Lerner, R.A. A Class of 4-Aza-lithocholic
Acid-Derived Haptens for the Generation of Catalytic Antibodies with
Stereoid Synthase Capabilities. Bioorg. Med. Chem. 2000, 8, 995.
4. Kinder, F.R., Jr.; Wattanasin, S.; Versace, R.W.; Bair, K.W.;
Bontempo, J.; Green, M.A.; Marepalli, H.R.; Phillips, P.E.; Roche, D.;
Tran, L.D.; Waykole, L.; Xe, D.D. Total Syntheses of Bengamides B
and E. J. Org. Chem. 2001, 66, 2118.
5. Mader, M.; Helquist, P. Ti(OiPr)4 Mediated Lactamization. Tetrahedron
Lett. 1988, 29, 3049.
6. Singh, B. A Novel and Facile Two Step Synthesis of 5-aryl-2(1H)-pyri-
dones. Synth. Commun. 1985, 305.
´
¨
7. d’Angelo, A.; Cave, C.; Desmaele, D.; Gassama, A.; Thominiaux, C.;
Riche, C. Enantioselective Access to Five and Six-Membered Nitrogen-
Containing Heterocycles, Based on the Asymmetric Michael Addition
of Chiral Imines and Chiral Enamino Esters. Heterocycles 1998, 47, 725.
8. Murahashi, S.I.; Sasao, S.; Saito, E.; Naota, T. Ruthenium-Catalyzed
Hydration of Nitriles and Transformation of Delta-Keto Nitriles to
Ene-Lactams. J. Org. Chem. 1992, 57, 2521.
9. Citterio, A.; Carnevali, E.; Farine, A.; Meible, V.; Alini, S.; Cotarca, L.
Synthesis of 6-Hydroxy-3,4,5,6-Tetrahydro-2-Pyridones and 3,4-
Dihydro-2-Pyridones by H2O2/DMSO Hydration of d-Ketonitriles. Org.
Prep. Proc. Int. 1997, 29, 465.
10. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis;
John Wiley & Sons, Inc.: New York, 1991; 397.

4264
Kan, Cheng, and Chern
11. Shimshock, S.S.; Waltermire, R.E.; Deshong, P. A Total Synthesis of
(þ)-Tirandamycin B. J. Am. Chem. Soc. 1991, 113, 8791.
12. Webster, F.X.; Millar, J.G.; Silverstein, R.M. Cleavage of Hindered
a-Methylbenzylamides, Intermediates in the Resolution of Carboxylic
Acids. Tetrahedron Lett. 1986, 27, 4941.
13. Chern, C.-Y.; Huang, Y.-P.; Kan, W.M. Selective N-Debenzylation of
Amides with p-TsOH. Tetrahedron Lett. 2003, 44, 1039.
14. Bach, R.D.; Dmitrenko, O. The Effect of Substitutents on the Strain Ener-
gies of Small Ring Compounds. J. Org. Chem. 2002, 67, 2588.
15. Diller, D.; Bergmann, F. Studies on a b-Keto Sulfone. Halogenation and
Cyclization of g-Methylsulfonyl-g-benzoylbutyronitrile. J. Org. Chem.
1972, 37, 2147.
Received in Poland May 10, 2004