Efficient synthesis of 2-(2-aminophenyl)-2,3-dihydropyridin-4(1H)-ones based on a cyclization/ring cleavage procedure

Article abstract of DOI:10.1002/hlca.201100130

(Benzyloxycarbonyl)-protected 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1] non-7-enes were prepared by one-pot cyclizations of 1,3-bis(silyl enol ethers) with quinazolines. Subsequent hydrogenation resulted in one-pot deprotection and rearrangement to give

Full text of DOI:10.1002/hlca.201100130

Helvetica Chimica Acta – Vol. 94 (2011)
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Efficient Synthesis of 2-(2-Aminophenyl)-2,3-dihydropyridin-4(1H)-ones
Based on a Cyclization/Ring Cleavage Procedure
by Vahuni Karapetyana)b), Satenik Mkrtchyana)b), Gnuni Karapetyana), Alexander Villingera),
Ashot Saghiyanb)c), Tariel V. Ghochikyanb), and Peter Langer*a)d)
a) Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Strasse 3a, D-18059 Rostock
b) Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
c) CJSC Scientific Research Institute of Biotechnology, Gyurjyan Str. 14, 0056, Yerevan, Armenia
d) Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt, Rostock, Albert-Einstein-Str. 29a,
D-18059 Rostock
(Benzyloxycarbonyl)-protected 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes were pre-
pared by one-pot cyclizations of 1,3-bis(silyl enol ethers) with quinazolines. Subsequent hydrogenation
resulted in one-pot deprotection and rearrangement to give 2-(2-aminophenyl)-2,3-dihydropyridin-
4(1H)-ones.
Functionalized pyridin-4-ones, 2,3-dihydropyridin-4-ones, and tetrahydropyridin-4-
ones (piperidin-4-ones) are of great importance in medicinal chemistry [1]. Christoffers
and co-workers recently developed the first approach to 3-arylpiperidin-4-ones [1]. 2-
Aryl-2,3-dihydropyridin-4(1H)-ones (which can be regarded as partly unsaturated
piperidin-4-ones or as 2,3-dihydropyridin-4(1H)-ones) have only scarcely been
reported so far. Barluenga et al. prepared simple derivatives by cyclization of acrylates
with enamines or hydrazones [2]. Iminium salts have been widely used for the synthesis
and synthetic transformations of N-heterocycles [3]. In recent years, we have studied
the application of iminium salts as building blocks in cyclocondensation reactions with
bis(silyl enol ethers). These reactions provide a convenient approach to various N-
heterocycles (for a review, see [4]). Recently, we have reported the synthesis of 2,9-
bis(methoxycarbonyl)-3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes, densely
functionalized bridged quinazoline derivatives [5], by MeOCOCl-mediated cyclization
of 1,3-bis[(trimethylsilyl)oxy]buta-1,3-dienes [6] with quinazolines. However, our
attempts to deprotect the N-atoms by cleavage of the MeOCO group and to isolate the
corresponding bicyclic aminals failed, and complex mixtures were obtained [5b]. A
possible explanation for that is that electron-rich bicyclic aminals are not stable under
reaction conditions and undergo further rearrangements. Recently, we studied the
synthesis of 7,8-benzo-9-azabicyclo[3.3.1]nonan-3-ones by cyclocondensation of 1,3-
bis[(trimethylsilyl)oxy]buta-1,3-dienes with isoquinolines [7]. The deprotected prod-
ucts were successfully prepared by employment of the N-(benzyloxycarbonyl)
protecting group which could be cleaved by hydrogenation under mild conditions.
Here, we report new (benzyloxycarbonyl)-protected 3,4-benzo-7-hydroxy-2,9-diazabi-
cyclo[3.3.1]non-7-enes by BnOCOCl-mediated cyclization of 1,3-bis[(trimethylsilyl)-
oxy]buta-1,3-dienes with quinazolines. The hydrogenation resulted in deprotection and
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢀrich

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Helvetica Chimica Acta – Vol. 94 (2011)
subsequent cleavage of a CꢀN bond to provide functionalized 2-(2-aminophenyl)-2,3-
dihydropyridin-4(1H)-ones. The highly functionalized products reported here have, to
the best of our knowledge, not been previously prepared. They are of pharmacological
relevance and can be expected not to be readily available by other methods.
Results and Discussion. – 1,3-Bis[(trimethylsilyl)oxy]buta-1,3-dienes 2b – 2f were
prepared from the corresponding b-keto esters in two steps [8][9]. Diene 2a is available
from acetylacetone in one step [10]. The cyclization of quinazolines 1a – 1c [11] with
1,3-bis[(trimethylsilyl)oxy]buta-1,3-dienes 2a – 2f, in the presence of benzyl chlorofor-
mate (4.0 equiv.), afforded the novel (benzyloxycarbonyl) (BnOCO)-protected 3,4-
benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes 3a – 3j (Scheme and Table). The
use of only 3.0 (rather than 4.0) equiv. of BnOCOCl resulted in a decrease of the yield.
Optimal yields were obtained when the reaction was carried out at room temperature,
and direct chromatographic purification was performed without aqueous workup. The
formation of the products can be explained by the formation of an iminium salt A by
reaction of 1a with BnOCOCl and subsequent regioselective attack of the terminal C-
atom of the 1,3-bis[(trimethylsilyl)oxy]buta-1,3-diene 2a onto C(4) of the quinazoline
(! intermediate A). The reaction of the second N-atom with BnOCOCl again
afforded an iminium ion (intermediate B), which is attacked by the central C-atom of
the 1,3-dicarbonyl unit to provide product 3a.
Schemea)
i) 1a – 1c (1.0 equiv.), 2a – 2f (1.4 equiv.), BnOCOCl (4.0 equiv.), CH2Cl2, 08, 2 h, then 208, 12 h. ii) Pd/C
(10 mol-%), H2, MeOH, 208, 12 h.
a) For R1 – R4 and yields of 3 and 4, see the Table.
The hydrogenation of 3a – 3j afforded the 2-(2-aminophenyl)-2,3-dihydropyridin-
4(1H)-ones 4a – 4j (Scheme and Table). The formation of products 4a – 4j can be

Helvetica Chimica Acta – Vol. 94 (2011)
Table. Products and Yields
2047
1
2
3, 4
R1
R2
R3
Yield [%]a)
3
4
a
a
a
a
a
a
b
b
c
a
b
c
d
e
f
b
c
b
c
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
Me
Me
Me
40
60
51
57
53
49
43
42
53
52
44
90
93
83
80
81
66
60
65
68
MeO
EtO
iPrO
iBuO
MeO(CH2)2O
MeO
EtO
ꢀ(CH2)3ꢀ
MeO
EtO
c
j
ꢀ(CH2)3ꢀ
a) Yields of isolated products.
explained by hydrogenolysis of the BnOCO groups to provide bicyclic aminal C and
subsequent cleavage of a CꢀN bond (retro-Michael reaction).
1
All structures were established by spectroscopic methods. The H- and 13C-NMR
spectra of 3 show a splitting of several signals, due to dynamic processes of the
carbamate moiety possessing a significant double-bond character. The structures of 3e
and 4f were additionally confirmed by X-ray crystal-structure analyses (Figs. 1 and
2)1).
In conclusion, we have reported the synthesis of BnOCO-protected 3,4-benzo-7-
hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes by cyclization of 1,3-bis[(trimethylsilyl)oxy]-
buta-1,3-dienes with quinazolines in the presence of BnOCOCl. Their hydrogenation
resulted in the formation of functionalized 2-(2-aminophenyl)-2,3-dihydropyridin-
4(1H)-ones by deprotection and subsequent ring cleavage. The products are of
pharmacological relevance and not readily available by other methods.
Experimental Part
General. All solvents were dried by standard methods. CH2Cl2 (anh., 99.8%) was purchased from
ACROS and used without further purification. All reactions were carried out under an inert atmosphere.
Anal. TLC: 0.20-mm 60 A silica-gel plates. Column chromatography (CC): 60 A silica gel (60 – 200 mesh;
Merck). M.p.: Microheating table HMK 67/1825 Kuestner (Bꢀchi apparatus); uncorrected. IR Spectra:
Nicolet 380 FT-IR spectrometer; in cmꢀ1. 1H- and 13C-NMR spectra: Bruker Avance 300 III and Avance
250 II in CDCl3 (if not stated otherwise) at 250, 300, and 500 MHz, resp.; chemical shifts in d [ppm] using
the solvent internal standard (CDCl3, d 7.26 and d 77.0, resp.), J in Hz. MS: Finnigan MAT 95-XP
instrument; in m/z (rel.).
General Procedure for the Reaction of 1,3-Bis(silyl enol ethers) with Quinazolines. To a soln. of the
quinazoline (4.0 mmol) in CH2Cl2 (40 ml), 1,3-bis(silyl enol ether) (5.6 mmol) and BnOCOCl
(16.0 mmol) were subsequently added at 08. The soln. was stirred for 2 h at 08 and for 12 h at 208. The
1
)
CCDC-825761 (4f) and CCDC-825760 (3e) contain all crystallographic details of this publication
which are available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered
from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB21EZ; Fax: (þ44)1223-336-033; or deposit@ccdc.cam.ac.uk.

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Helvetica Chimica Acta – Vol. 94 (2011)
Fig. 1. ORTEP Plot of 3e. The thermal ellipsoids of 50% probability are shown for the non-H-atoms.
Fig. 2. ORTEP Plot of 4f. The thermal ellipsoids of 50% probability are shown for the non-H-atoms.
solvent was removed in vacuo, and the residue was purified by CC (silica gel; AcOEt/ heptane, gradient
0 ! 33% AcOEt). Product 3a was directly transformed into 4a.
1,11-Dibenzyl 3-Methyl 5,6-Dihydro-4-hydroxy-2,6-epimino-1-benzazocine-1,3,11(2H)-tricarboxy-
late (3b). Starting from quinazoline (1a; 0.260 g, 2.0 mmol), 1-methoxy-1,3-bis-[(trimethylsilyl)oxy]-
buta-1,3-diene (2b; 0.782 g, 3.0 mmol), and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3b (0.617 g,
60%) was obtained. Yellow, highly viscous oil. IR (ATR): 3064w, 3032w, 2952w, 1703s, 1652m, 1490w,
1445m, 1382m, 1258s, 1224s, 1132m, 1102m, 1064m, 1022m, 1000m, 909m, 763m, 728s, 695s, 648w.

Helvetica Chimica Acta – Vol. 94 (2011)
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2
2
1H-NMR (250 MHz): 2.33 (d, J ¼ 17.7, 1 H, NCHCH2); 2.88 (br. d, J ¼ 17.7, 1 H, NCHCH2); 3.38 (s,
MeO); 4.99 – 5.38 (m, 2 CH2O, NCHCH2); 6.97 – 7.03 (m, 2 arom. H); 7.14 – 7.39 (m, 11 arom H, NCHN);
7.76 (d, 3J ¼ 8.3, 1 arom. H); 12.21 (s, OH). 13C-NMR (62.9 MHz): 38.1 (NCHCH2); 48.5 (br.), 49.1 (br.)
(NCHCH2, rotamers); 51.5 (MeO); 58.8 (br., NCHN); 67.6, 67.8 (CH2O); 97.8 (NCHCCO); 124.2, 126.3,
127.6, 127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 128.6, 128.7, 128.7 (arom. CH); 129.2 (NCHN); 133.2, 134.4
(br.), 135.8, 136.1 (arom. C); 152.8, 153.1 (br.) (NCOO); 170.5 (C); 173.3 (br., C). EI-MS: 514 (Mþ, 5),
379 (65), 335 (11), 303 (12), 91 (100), 65 (9). HR-EI-MS: 514.17395 (Mþ, C29H26N2O7þ ; calc. 514.17345).
1,11-Dibenzyl 3-Ethyl 5,6-Dihydro-4-hydroxy-2,6-epimino-1-benzazocine-1,3,11(2H)-tricarboxylate
(3c). Starting from 1a (0.260 g, 2.0 mmol), 1-ethoxy-1,3-bis[(trimethylsilyl)oxy]buta-1,3-diene (2c;
0.823 g, 3.0 mmol), and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3c (0.539 g, 51%) was
obtained. Light yellow viscous oil. IR (neat): 3033m, 2981w, 1709s, 1653s, 1620s, 1491m, 1429s, 1386s,
1327s, 1295s, 1261s, 1228s, 1181m, 1135s, 1065m, 1024m, 1004m, 948w, 827w, 738m. 1H-NMR (300 MHz):
1.06 (t, 3J ¼ 7.1, OCH2Me); 2.41 (d, 3J ¼ 17.6, 1 H, NCHCH2); 2.93 (d, 3J ¼ 16.1, 1 H, NCHCH2); 4.04 (q,
3J ¼ 7.1, OCH2Me); 5.00 – 5.54 (br. m, 2 CH2O, NCHCH2); 7.05 – 7.13 (m, 2 arom. H); 7.27 – 7.51 (br. m, 11
arom. H, NCHN); 7.82 (d, 3J ¼ 8.2, 1 arom. H); 12.38 (s, OH). 13C-NMR (75.5 MHz): 14.0 (OCH2Me);
38.2 (br., NCHCH2); 48.7 (br., NCHCH2); 58.9 (br., NCHN); 60.9 (OCH2Me); 67.7(br., CCH2O); 98.2
(NCHCCO); 124.3, 124.5, 126.3, 126.9, 127.7, 128.0, 128.1, 128.3, 128.4, 128.5 (CH of Ar); 134.6, 136.0,
136.1, 152.8, 153.2 (arom. C); 170.2 (C); 173.3 (br., C). EI-MS: 528 (Mþ, 11), 456 (2), 393 (88), 349 (25),
303 (30), 258 (11), 212 (10), 91 (100), 65 (14). HR-EI-MS: 528.18879 (Mþ, C30H28N2O7þ ; calc. 528.18910).
1,11-Dibenzyl 3-(1-Methylethyl) 5,6-Dihydro-4-hydroxy-2,6-epimino-1-benzazocine-1,3,11(2H)-tri-
carboxylate (3d). Starting from 1a (0.260 g, 2.0 mmol), 1-(1-methylethoxy)-1,3-bis[(trimethylsilyl)oxy]-
buta-1,3-diene (2d; 0.866 g, 3.0 mmol), and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3d (0.619 g,
57%) was obtained. Yellow, highly viscous oil. IR (ATR): 3064w, 3032w, 2939w, 1704m, 1643m, 1552w,
1490w, 1402m, 1323m, 1257s, 1224s, 1133m, 1100m, 1022m, 998m, 946w, 764w, 733s, 695s, 662w. 1H-NMR
(250 MHz): 1.00, 1.03 (d, 3J ¼ 6.3, OCHMe2); 2.31 (d, 2J ¼ 17.8, 1 H, NCHCH2); 2.90 (br. d, 2J ¼ 16.9, 1 H,
NCHCH2); 4.95 (m, OCHMe2); 5.00 – 5.38 (br. m, 2 CH2O, NCHCH2); 6.97 – 7.03 (m, 2 arom. H); 7.15 –
3
7.44 (m, 11 arom. H, NCHN); 7.71 (d, J ¼ 8.4, 1 arom. H); 12.38 (s, OH). 13C-NMR (62.9 MHz): 21.5,
21.6 (OCHMe2); 38.2 (NCHCH2); 48.8 (br., NCHCH2); 58.9 (br., NCHN); 67.6, 67.8 (OCH2); 68.7
(OCHMe2); 98.4 (NCHCCO); 124.3, 124.5, 126.3 (arom. CH); 126.9 (arom. C); 127.6, 127.9, 128.0, 128.2,
128.4 (arom. CH); 128.5 (NCHN); 134.6, 136.0 (arom. C); 152.6, 153.3 (br., NCOO); 169.8 (C); 172.3
(br., C). EI-MS: 542 (Mþ, 7), 456 (1), 407 (81), 365 (18), 303 (14), 91 (100), 65 (10). HR-EI-MS:
542.20453 (Mþ, C31H30N2Oþ7 ; calc. 542.20475).
1,11-Dibenzyl 3-(2-Methylpropyl) 5,6-Dihydro-4-hydroxy-2,6-epimino-1-benzazocine-1,3,11(2H)-
tricarboxylate (3e). Starting from quinazoline 1a (0.260 g, 2.0 mmol), 1-(2-methylpropyl)-1,3-bis-
[(trimethylsilyl)oxy]buta-1,3-diene (2e; 0.908 g, 3.0 mmol), and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2
(20 ml), 3e (0.589 g, 53%) was obtained. Colorless solid. M.p. 104 – 1058. IR (ATR): 3071w, 2873w,
1711m, 1688s, 1650m, 1612m, 1454w, 1440m, 1415m, 1379 m, 1262s, 1220s (br.), 1168m, 1131s, 1062m,
1
3
1010s, 974m, 851s, 824m, 761m, 734s, 710m, 693s, 670m, 624m. H-NMR (250 MHz): 0.80 (d, J ¼ 6.7,
CH2CHMe2); 1.76 (CH2CHMe2); 2.41 (d, 2J ¼ 17.5, 1 H, NCHCH2); 2.99 (br. d, 2J ¼ 16.2, 1 H, NCHCH2);
3.67 – 3.74 (m, 1 H, CH2CHMe2); 3.92 – 3.99 (m, 1 H, CH2CHMe2); 5.18 – 5.45 (br. m, 2 CH2O,
3
NCHCH2); 7.08 – 7.11 (m, 2 arom. H); 7.20 – 7.53 (br. m, 11 arom. H, NCHN); 7.73 (d, J ¼ 8.2, 1 arom.
H); 12.43 (s, OH). 13C-NMR (62.9 MHz): 18.6, 18.7 (CH2CHMe2); 27.4 (CH2CHMe2); 38.1 (NCHCH2);
48.7 (br.) (NCHCH2); 58.9 (br., NCHN); 67.7, 67.9 (CH2O); 70.9 (CH2CHMe2); 98.1 (NCHCCO); 124.4,
124.8, 126.3, 126.9 (arom. CH); 127.0 (arom. C); 127.6, 128.1, 128.4, 128.5 (arom. CH); 134.6 (NCHN);
136.0 (arom. C); 152.7, 153.4 (br., NCOO); 170.3 (C); 173.4 (br., C). EI-MS: 556 (Mþ, 8), 421 (68), 377
(13), 347 (14), 321 (22), 303 (38), 241 (14), 213 (21), 108 (26), 91 (100), 79 (23). HR-EI-MS: 556.21991
(Mþ, C32H32N2Oþ7 ; calc. 556.22040).
1,11-Dibenzyl 3-(2-Methoxyethyl) 5,6-Dihydro-4-hydroxy-2,6-epimino-1-benzazocine-1,3,11(2H)-
tricarboxylate (3f). Starting from 1a (0.260 g, 2.0 mmol), 1-(2-methoxyethoxy)-1,3-bis[(trimethylsilyl)-
oxy]buta-1,3-diene (2f; 0.914 g, 3.0 mmol), and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3f
(0.551 g, 49%) was obtained. Yellow, highly viscous oil. IR (ATR): 3063w, 3032w, 2949w, 1703s, 1651m,
1499w, 1416m, 1384m, 1323m, 1255s, 1222m, 1178w, 1130m, 1063m, 1022m, 1001m, 912w, 762m, 735s,
695s, 615w. 1H-NMR (250 MHz): 2.41 (d, 2J ¼ 17.5, 1 H, NCHCH2); 2.98 (br. d, 2J ¼ 16.5, 1 H, NCHCH2);

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Helvetica Chimica Acta – Vol. 94 (2011)
3.24 (s, CH2OMe); 3.35 (m, CH2OMe); 4.19 (m, OCH2CH2O); 5.11 – 5.45 (br. m, 2 CH2O, NCHCH2);
7.05 – 7.09 (m, 2 arom. H); 7.19 – 7.54 (br. m, 11 arom. H, NCHN); 7.81 (d, 3J ¼ 8.2, 1 arom. H); 12.25 (s,
OH). 13C-NMR (62.9 MHz): 38.2 (br., NCHCH2); 48.8 (br., NCHCH2); 58.8 (CH2OMe) 58.9 (br.,
NCHN); 63.8 (OCH2CH2O); 67.7 (br., CCH2O); 69.9 (OCH2CH2O); 98.0 (NCHCCO); 124.3, 124.5,
126.3 (arom. CH); 126.8 (arom. C); 127.7, 127.9, 128.1, 128.2, 128.5, 128.5 (arom. CH); 134.6, 135.9, 136.1
(arom. C); 152.8, 153.2, 169.9, 173.5 (br., C). EI-MS: 558 (Mþ, 9), 423 (87), 379 (17), 347 (11), 303 (32),
241 (14), 108 (59), 91 (100), 79 (48). HR-EI-MS: 558.20031 (Mþ, C31H30N2O8þ ; calc. 558.19967).
1,11-Dibenzyl 3-Methyl 5,6-Dihydro-4-hydroxy-8,9-dimethyl-2,6-epimino-1-benzazocine-1,3,11(2H)-
tricarboxylate (3g). Starting with 6,7-dimethylquinazoline (1b; 0.316 g, 2.0 mmol), 2b (0.782 g, 3.0 mmol)
and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3g (0.467 g, 43%) was obtained. Yellow, highly
viscous oil. IR (ATR): 3063w, 3031w, 2923w, 1702m, 1652m, 1615w, 1445m, 1383m, 1326m, 1248s (br.),
1
1220s, 1170w, 1110m (br.), 1065m, 1011m, 951w, 783w, 730m, 695s, 597w. H-NMR (250 MHz): 2.19 (s,
Me); 2.21 (s, Me); 2.40 (d, 2J ¼ 18.0, 1 H, NCHCH2); 2.94 (br. d, 2J ¼ 13.5, 1 H, NCHCH2); 3.48, 3.50 (s,
MeO); 5.07 – 5.65 (m, 2 CH2O, NCHCH2); 6.80 (br., s, 1 arom. H); 7.27 – 7.60 (m, 11 arom. H, NCHN);
12.26, 12.29 (s, OH). 13C-NMR (75.5 MHz): 19.1 (Me); 19.8 (Me); 38.2 (NCHCH2); 48.5 (br.)
(NCHCH2); 51.5, 51.6 (MeO, rotamers); 58.9 (br., NCHN); 67.5, 67.8 (CH2O); 98.0 (NCHCCO); 125.1,
127.0, 127.2, 127.6, 128.0, 128.1, 128.2, 128.3, 128.4, 128.6, 128.7, 128.9 (arom. C); 131.9, 132.8, 136.0 (br.);
136.2, 136.3 (arom. C); 152.9, 153.4 (br.); 170.6, 173.5 (C). EI-MS: 542 (Mþ, 9), 407 (72), 363 (10), 331
(13), 91 (100), 65 (8). HR-EI-MS: 542.20540 (Mþ, C31H30N2O7þ ; calc. 542.20475).
1,11-Dibenzyl 3-Ethyl 5,6-Dihydro-4-hydroxy-8,9-dimethyl-2,6-epimino-1-benzazocine-1,3,11(2H)-
tricarboxylate (3h). Starting from 1b (0.316 g, 2.0 mmol), 2c (0.822 g, 3.0 mmol), and BnOCOCl (1.365 g,
8.0 mmol) in CH2Cl2 (20 ml), 3h (0.467 g, 42%) was obtained. Yellowish, highly viscous oil. IR (ATR):
3032w, 2923w, 1702s, 1650m, 1620w, 1384m, 1368w, 1325m, 1247s (br.), 1219s, 1176m, 1150w, 1110m (br.),
1064m, 1013m, 994m, 953w, 820m, 785m, 695s, 597w. EI-MS: 556 (Mþ, 18), 421 (99), 377 (20), 331 (26),
286 (19), 249 (14), 91 (100), 65 (11). HR-EI-MS: 556.22088 (Mþ, C32H32N2O7þ ; calc. 556.22040).
1,12-Dibenzyl 3-Methyl 2,5,6,8,9,10-Hexahydro-4-hydroxy-1H-2,6-epiminoindeno[5,6-b]azocine-
1,3,12-tricarboxylate (3i). Starting with 7,8-dihydro-6H-cyclopenta[g]quinazoline (1c; 0.340 g, 2.0 mmol),
2b (0.782 g, 3.0 mmol), and BnOCOCl (1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3i (0.588 g, 53%) was
obtained. Yellow, highly viscous oil. IR (ATR): 3031w, 2951w, 1699s, 1651m, 1488w, 1427m, 1326m,
1278m, 1238s, 1108m, 1064m, 1008m, 943w, 823w, 695s, 585w. 1H-NMR (250 MHz): 1.99 – 2.10 (m,
CH2CH2CH2); 2.41 (d, 3J ¼ 17.6, 1 H, NCHCH2); 2.81 – 2.98 (m, CH2CH2CH2, 1 H of NCHCH2); 3.48 (s,
MeO); 5.07 – 5.43 (br. m, 2 CH2O, NCHCH2); 6.91 (s, 1 arom. H); 7.26 – 7.45 (br. m, 11 arom. H, NCHN);
7.67 (s, 1 arom. H); 12.30 (s, OH). 13C-NMR (62.9 MHz): 25.5 (CH2CH2CH2); 32.2, 32.8 (CH2CH2CH2);
38.4 (br., NCHCH2); 48.7 (br., NCHCH2); 51.5 (MeO); 58.8 (br., NCHN); 67.4, 67.7 (CCH2O); 97.9
(NCHCCO); 120.2, 121.8 (arom. CH); 124.6 (arom. C); 127.9, 128.0, 128.1, 128.2, 128.4, 128.5 (arom.
CH); 132.3, 135.9, 136.3, 140.4, 144.0, 152.9, 153.4, 170 (C); 173.4 (br., COH). EI-MS: 554 (Mþ, 5), 446
(3), 419 (33), 343 (8), 108 (17), 91 (100), 79 (16). HR-EI-MS: 554.20427 (Mþ, C32H30N2O7þ ; calc.
554.20475).
1,12-Dibenzyl 3-Ethyl 2,5,6,8,9,10-Hexahydro-4-hydroxy-1H-2,6-epiminoindeno[5,6-b]azocine-
1,3,12-tricarboxylate (3j). Starting from 1c (0.340 g, 2.0 mmol), 2c (0.822 g, 3.0 mmol), and BnOCOCl
(1.365 g, 8.0 mmol) in CH2Cl2 (20 ml), 3j (0.591 g, 52%) was obtained. Yellow, highly viscous oil. IR
(ATR): 3063w, 3032w, 2842w, 1702s, 1649m, 1616w, 1426m, 1386m, 1325m, 1280s, 1255s, 1238s, 1219s,
1181m, 1108m, 1086m, 1062m, 945w, 730s (br.), 695s, 585w. 1H-NMR (300 MHz): 1.06 (t, 3J ¼ 7.1,
OCH2Me); 2.04 (m, CH2CH2CH2); 2.39 (d, 3J ¼ 17.7, 1 H, NCHCH2); 2.77 – 2.98 (m, CH2CH2CH2, 1 H of
NCHCH2); 4.04 (q, 3J ¼ 7.1, OCH2Me); 4.97 – 5.41 (br. m, 2 CH2O, NCHCH2); 6.90 (s, 1 arom. H); 7.31 –
7.64 (br. m, 11 arom. H, NCHN); 12.38 (s, OH). 13C-NMR (62.9 MHz): 14.0 (OCH2Me); 25.6
(CH2CH2CH2); 32.3, 32.9 (CH2CH2CH2); 38.4 (br., NCHCH2); 49.0 (br., NCHCH2); 58.9 (br., NCHN);
60.9 (OCH2Me); 67.7 (br., CCH2O); 98.2 (NCHCCO); 120.3, 121.8 (arom. CH); 124.7 (arom. C); 127.9,
128.0, 128.2, 128.4, 128.5 (arom. CH); 132.5, 136.1, 136.2, 140.5, 144.0, 152.6, 153.6, 170.3, 172.9 (br., C).
EI-MS: 568 (Mþ, 6), 433 (39), 389 (8), 343 (8), 298 (8), 237 (10), 108 (47), 91 (100), 79 (50). HR-EI-MS:
568.22012 (Mþ, C33H32N2Oþ7 ; calc. 568.22040).
General Procedure for the Synthesis of 4. The mixture of 3 (1.0 mmol) and Pd/C (10 mol-%) in
MeOH (10 ml) was stirred under H2 at r.t. (208) for 12 h. The mixture was filtered through Celite, washed

Helvetica Chimica Acta – Vol. 94 (2011)
2051
with MeOH (50 ml), and the filtrate was concentrated in vacuo. The residue was purified by
crystallization from AcOEt.
5-Acetyl-2-(2-aminophenyl)-2,3-dihydropyridin-4(1H)-one (4a). Starting from 3a (0.498 g,
1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4a (0.102 g, 44%) was obtained. Colorless solid.
M.p. 163 – 1658. IR (ATR): 3413w, 3335w, 3201w, 2834w, 1614m, 1567s (br.), 1497s, 1459m, 1309m, 1241s,
1153m, 1025m, 957m, 761s, 722m, 656m. 1H-NMR (250 MHz, (D6)DMSO): 2.31 (s, Me); 2.52 – 2.57 (m,
3
3
4
3
CH2); 5.06 (t, J ¼ 8.2, CHCH2); 5.16 (s, NH2); 6.57 (t, J ¼ 7.4, J ¼ 1.1, 1 arom. H); 6.68 (d, J ¼ 7.4, 1
arom. CH); 6.98 – 7.04 (m, 2 arom. H); 8.29 (d, J ¼ 7.4, NHCH); 9.44 (d, J ¼ 7.4, NHCH). 13C-NMR
(75.5 MHz, (D6)DMSO): 30.0 (Me); 41.1 (CHCH2); 51.0 (CHCH2); 108.8 (COCCO); 115.6, 116.2
(arom. CH); 121.4 (arom. C); 126.0, 128.4 (arom. CH); 145.4 (arom. C); 157.3 (CHNH); 188.2, 192.4
(CO). EI-MS: 230 (Mþ, 82), 229 (100), 211 (23), 198 (17), 145 (26), 131 (65), 119 (34), 76 (11). HR-EI-
MS: 230.10438 (Mþ, C13H14N2Oþ2 ; calc. 230.10498).
3
3
Methyl 6-(2-Aminophenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4b). Starting from 3b
(0.514 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4b (0.221 g, 90%) was obtained. Colorless
solid. M.p. 199 – 2008. IR (ATR): 3404w, 3297w, 2802w, 1699s, 1610m, 1592m, 1571s, 1533m, 1364s, 1318m,
1271s, 1209m, 1194m, 1054s, 1006m, 827w, 742s. 1H-NMR (250 MHz, (D6)DMSO): 2.47 – 2.51 (m, CH2);
3
3
3
3.57 (s, MeO); 5.02 (t, J ¼ 8.1, CHCH2); 5.13 (s, NH2); 6.56 (t, J ¼ 7.5, 1 arom. H); 6.67 (d, J ¼ 7.7, 1
arom. H); 6.97 – 7.05 (m, 2 arom. H); 8.25 (s, NHCH); 9.17 (s, NHCH). 13C-NMR (62.9 MHz,
(D6)DMSO): 41.6 (CHCH2); 50.3 (MeO); 51.0 (CHCH2); 98.7 (COCCO); 115.9, 116.4 (arom. CH);
121.9 (arom. C); 126.3, 128.6 (arom. CH); 145.7 (arom. C); 158.0 (CHNH); 165.0 (COO); 186.3 (CO).
EI-MS: 246 (Mþ, 81), 214 (100), 186 (37), 154 (38), 131 (89), 103 (26), 77 (14). HR-EI-MS: 246.09948
(Mþ, C13H14N2Oþ3 ; calc. 246.09989).
Ethyl 6-(2-Aminophenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4c). Starting with 3c
(0.529 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4c (0.242 g, 93%) was obtained. Colorless
solid. M.p. 165 – 1668. IR (ATR): 3306w, 2890w, 1683m, 1615m, 1398m, 1384m, 1323w, 1276s, 1210m,
1090m, 1049m, 950m, 838m, 748s, 622m, 590s. 1H-NMR (500 MHz, (D6)DMSO): 1.19 (t, 3J ¼ 7.2,
OCH2Me); 2.46 (dd, 2J ¼ 15.8, 3J ¼ 6.3, 1 H, CHCH2); 2.52 (dd, 2J ¼ 15.8, 3J ¼ 10.1, 1 H, CHCH2); 4.05 (q,
3J ¼ 7.2, OCH2Me); 5.02 (dd, 3J ¼ 10.1, 3J ¼ 6.3, CHCH2); 5.13 (s, NH2); 6.57 (dꢁtꢂ, 3J ¼ 7.7, 3J ¼ 7.3, 4J ¼ 1.3,
3
4
3
3
4
1 arom. H); 6.68 (dd, J ¼ 7.9, J ¼ 1.3, 1 arom. H); 7.00 (ddd, J ¼ 7.9, J ¼ 7.3, J ¼ 1.5, 1 arom. H); 7.05
(dd, 3J ¼ 7.7, 4J ¼ 1.5, 1 arom. H); 8.24 (s, CHNH); 9.09 (s, NH). 13C-NMR (125.8 MHz, (D6)DMSO): 14.6
(Me); 41.6 (CHCH2); 51.0 (CHCH2); 58.4 (OCH2Me); 98.9 (COCCO); 115.8, 116.4 (arom. CH); 121.9
(arom. C); 126.3, 128.6 (arom. CH); 145.6 (arom. C); 157.8 (CHNH); 164.3 (COO); 186.3 (CO). EI-MS:
260 (Mþ, 33), 214 (74), 186 (19), 168 (17), 145 (28), 131 (100), 103 (37), 76 (17). HR-EI-MS: 260.11536
(Mþ, C14H16N2Oþ3 ; calc. 260.11554).
1-Methylethyl 6-(2-Aminophenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4d). Starting from
3d (0.543 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4d (0.227 g, 83%) was obtained. Colorless
solid. M.p. 107 – 1088. IR (ATR): 3203w, 2977w, 1693m, 1574s, 1495m, 1382m, 1372m, 1276s, 1179m,
1158m, 1036s, 980w, 953w, 922w, 747s, 627m. 1H-NMR (250 MHz, (D6)DMSO): 1.18 (d, 3J ¼ 6.3,
CHMe2); 2.39 – 2.51 (m, CH2); 4.91 (m, 3J ¼ 6.3, CHMe2); 5.00 (dd, 3J ¼ 10.1, 3J ¼ 6.4, CHCH2); 5.14 (s,
3
3
NH2); 6.57 (t, J ¼ 7.5, 4J ¼ 1.1, 1 arom. H); 6.67 (d, J ¼ 8.0, 4J ¼ 1.1, 1 arom. H); 6.97 – 7.06 (m, 2 arom.
H); 8.21 (s, NHCH); 9.08 (br. s, NHCH). 13C-NMR (62.8 MHz, (D6)DMSO): 22.2 (CHMe2); 41.7
(CHCH2); 51.1 (CHCH2); 65.3 (OCHMe2); 99.2 (COCCO); 115.8, 116.4 (arom. CH); 122.0 (arom. C);
126.4, 128.6 (arom. CH); 145.7 (arom. C); 157.7 (CHNH); 163.6 (COO); 186.5 (CO). EI-MS: 274 (Mþ,
12), 215 (35), 187 (24), 155 (100), 128 (21), 91(9), 76 (14). HR-EI-MS: 274.131761 (Mþ, C15H18N2O3þ
;
calc. 274.13174).
2-Methylpropyl 6-(2-Aminophenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4e). Starting
from 3e (0.556 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4e (0.231 g, 80%) was obtained.
Colorless solid. M.p. 199 – 2008. IR (ATR): 3396w, 2967w, 1683m, 1564s, 1494m, 1407m, 1386m, 1365m,
1
1275s, 1235m, 1207m, 1156m, 1045m, 987w, 826m, 747s, 666m, 590s. H-NMR (300 MHz, (D6)DMSO):
3
3
3
0.91 (d, J ¼ 6.7, CHMe2); 1.87 (m, J ¼ 6.7, CHMe2); 2.41 – 2.52 (m, CHCH2); 3.80 (d, J ¼ 6.5, CH2O);
5.00 – 5.05 (m, CHCH2); 5.14 (s, NH2); 6.57 (dꢁtꢂ, 3J ¼ 7.4, 4J ¼ 1.0, 1 arom. H); 6.67 (dd, 3J ¼ 8.1, 4J ¼ 1.0, 1
arom. H); 6.98 – 7.07 (m, 2 arom. H); 8.24 (d, 3J ¼ 7.4, NHCH); 9.05 (d, 3J ¼ 7.4, NHCH). 13C-NMR
(75.5 MHz, (D6)DMSO): 19.3 (CHMe2); 27.7 (CHMe2); 41.7 (CHCH2); 51.1 (CHCH2); 68.6

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Helvetica Chimica Acta – Vol. 94 (2011)
(OCH2CH); 99.0 (COCCO); 115.8, 116.4 (arom. CH); 121.9 (arom. C); 126.3, 128.6 (arom. CH); 145.7
(arom. C); 157.8 (CHNH); 164.4 (COO); 186.3 (CO). EI-MS: 288 (Mþ, 288 (64), 214 (100), 186 (26), 158
(23), 146 (30), 131 (72), 103 (28), 76 (12). HR-EI-MS: 288.14611 (Mþ, C16H20N2O3þ ; calc. 288.14684).
2-Methoxyethyl 6-(2-Aminophenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4f). Starting
from 3f (0.558 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4f (0.235 g, 81%) was obtained.
Colorless solid. M.p. 158 – 1598. IR (ATR): 3388w, 3153m, 2983w, 1681m, 1615m, 1564s, 1495m, 1395m,
1
2
1290m, 1274s, 1204m, 1161m, 1089m, 1050m, 833m, 752s. H-NMR (300 MHz, CD3OD): 2.62 (dd, J ¼
3
2
3
16.2, J ¼ 6.0, 1 H, CHCH2); 2.79 (dd, J ¼ 16.2, J ¼ 11.9, 1 H, CHCH2); 3.38 (s, MeO); 3.63 – 3.66 (m,
CH2OMe); 4.24 – 4.27 (m, COOCH2), 5.08 (dd, 3J ¼ 11.9, 3J ¼ 6.0, CHCH2); 6.69 – 6.78 (m, 2 arom. H);
7.08 (dꢁtꢂ, 3J ¼ 7.5, 4J ¼ 1.5, 1 arom. H); 7.18 (dd, 3J ¼ 7.6, 4J ¼ 1.0, 1 arom. H); 8.46 (s, NHCH). 13C-NMR
(62.9 MHz, CD3OD): 42.4 (CHCH2); 53.4 (CHCH2); 59.1 (MeO); 63.4 (CH2OMe); 71.9 (COOCH2);
100.0 (COCCO); 118.0, 119.3 (arom. CH); 123.5 (arom. C); 127.5, 130.2 (arom. CH); 146.3 (arom.);
160.3 (CHNH); 166.0 (COO); 190.8 (CO). EI-MS: 290 (Mþ, 17), 214 (81), 145 (45), 131 (100), 103 (79),
76 (54). HR-EI-MS: 290.12601 (Mþ, C15H18N2Oþ4 ; calc. 290.12611).
Methyl 6-(2-Amino-4,5-dimethylphenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4g). Start-
ing from 3g (0.542 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4g (0.181 g, 66%) was obtained.
Colorless solid. M.p. 167 – 1698. IR (ATR): 3432w, 3171w, 2950w, 1704m, 1688m, 1614m, 1567s, 1439m,
1320m, 1273s, 1274m, 1194m, 1157m, 1095m, 809w, 773m. 1H-NMR (250 MHz, (D6)DMSO): 2.05 (s,
3
3
Me); 2.07 (s, Me); 2.34 – 2.49 (m, CHCH2); 3.57 (s, MeO); 4.83 (s, NH2); 4.96 (dd, J ¼ 10.8, J ¼ 6.6,
3
3
CHCH2); 6.48 (s, 1 arom. H); 6.82 (s, 1 arom. H); 8.22 (d, J ¼ 7.4, NHCH); 9.07 (d, J ¼ 7.4, NHCH).
13C-NMR (62.9 MHz, (D6)DMSO): 18.7, 19.4 (CMe); 42.0 (CHCH2); 50.3 (MeO); 50.9 (CHCH2); 98.7
(COCCO); 117.4, 119.6 (arom. CH); 123.8, 127.3, 136.2, 143.4 (arom. C); 157.9 (CHNH); 165.0 (COO);
186.4 (CO). EI-MS: 274 (Mþ, 37), 242 (56), 213 (21), 197 (13), 186 (15), 173 (31), 158 (100), 143 (25),
130 (19), 104 (21), 77 (15). HR-EI-MS: 274.13059 (Mþ, C15H18N2O3þ ; calc. 274.13119).
Ethyl 6-(2-Amino-4,5-dimethylphenyl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4h). Starting
from 3h (0.556 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4h (0.172 g, 60%) was obtained.
Colorless solid. M.p. 152 – 1548. IR (ATR): 3369w, 3165w, 2978w, 1694m, 1575m, 1505m, 1404m, 1383m,
1355w, 1319w, 1273s, 1196w, 1164m, 1051m, 1018w. 1H-NMR (250 MHz, CD3OD): 1.29 (t, 3J ¼ 7.1,
2
3
2
3
CH2Me); 2.14 (s, Me); 2.15 (s, Me); 2.57 (dd, J ¼ 16.2, J ¼ 5.8, 1 H, CHCH2); 2.79 (dd, J ¼ 16.2, J ¼
12.5, 1 H, CHCH2); 4.19 (q, 3J ¼ 7.1, CH2Me); 5.03 (dd, 3J ¼ 12.5, 3J ¼ 5.8, CHCH2); 6.61 (s, 1 arom.
H); 6.94 (s, 1 arom. H); 8.40 (d, 3J ¼ 1.1, NHCH). 13C-NMR (62.9 MHz, (D6)DMSO): 14.7 (OCH2Me);
18.7, 19.4 (CMe); 42.0 (CHCH2); 50.9 (CHCH2); 58.4 (OCH2Me); 98.8 (COCCO); 117.4, 119.6 (arom.
CH); 123.8, 127.3, 136.2, 143.4 (arom. C); 157.8 (CHNH); 164.3 (COO); 186.5 (CO). EI-MS: 288 (Mþ,
60), 242 (79), 213 (32), 186 (21), 173 (37), 159 (100), 143 (22), 130 (23), 104 (20), 69 (27). HR-EI-MS:
288.14621 (Mþ, C16H20N2Oþ3 ; calc. 288.14684).
Methyl 6-(6-Amino-2,3-dihydro-1H-inden-5-yl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4i).
Starting from 3i (0.554 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4i (0.187 g, 65%) was
obtained. Colorless solid. M.p. 182 – 1838. IR (ATR): 3405w, 3211w, 2943w, 1705s, 1593s, 1432m, 1364s,
1286s, 1187m, 1050s, 949w, 869w, 769m. 1H-NMR (300 MHz, (D6)DMSO): 1.90 – 2.02 (m, CH2CH2CH2);
2.46 – 2.52 (m, CHCH2); 2.69 – 2.77 (m, CH2CH2CH2); 3.62 (s, MeO); 4.91 (s, NH2); 5.04 (t, 3J ¼ 7.9,
3
3
CHCH2); 6.61 (s, 1 arom. H); 6.94 (s, 1 arom. H); 8.28 (d, J ¼ 6.6, NHCH); 9.27 (d, J ¼ 5.6, NHCH).
13C-NMR (62.9 MHz, (D6)DMSO): 25.5, 31.8, 32.4 (CH2CH2CH2); 41.8 (CHCH2); 50.3 (MeO); 51.1
(CHCH2); 98.5 (COCCO); 112.0 (arom. CH); 120.4 (arom. C); 121.6 (arom. CH); 131.7, 144.0, 144.2
(arom. C); 157.9 (CHNH); 165.0 (COO); 186.6 (CO). EI-MS: 286 (Mþ, 8), 227 (62), 211 (100), 180 (26),
143 (12), 119 (32), 91 (28), 76 (12). HR-EI-MS: 286.131646 (Mþ, C16H18N2O3þ ; calc. 286.131744).
Ethyl 6-(6-Amino-2,3-dihydro-1H-inden-5-yl)-1,4,5,6-tetrahydro-4-oxopyridine-3-carboxylate (4j).
Starting from 3j (0.569 g, 1.0 mmol) and Pd/C (10 mol-%) in MeOH (10 ml), 4j (0.204 g, 68%) was
obtained. Colorless solid. M.p. 163 – 1658. IR (ATR): 3407w, 3307w, 2971w, 2545w, 1699s, 1616m, 1567s,
1
1490m, 1428m, 1368m, 1321m, 1280s, 1150m, 1062m, 1048m, 849m. H-NMR (250 MHz, (D6)DMSO):
1.18 (t, 3J ¼ 7.1, CH2Me); 1.88 – 1.99 (m, CH2CH2CH2); 2.40 – 2.49 (m, CHCH2); 2.66 – 2.73 (m,
3
3
3
CH2CH2CH2); 4.05 (q, J ¼ 7.1, CH2Me); 4.88 (s, NH2); 5.03 (dd, J ¼ 9.9, J ¼ 6.8, CHCH2); 6.57 (s, 1
arom. H); 6.92 (s, 1 arom. H); 8.22 (d, 3J ¼ 7.4, NHCH); 9.06 (d, 3J ¼ 7.4, NHCH). 13C-NMR (62.9 MHz,
(D6)DMSO): 14.7 (OCH2Me); 25.5, 31.8, 32.4 (CH2CH2CH2); 42.0 (CHCH2); 51.2 (CHCH2); 58.4

Helvetica Chimica Acta – Vol. 94 (2011)
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(OCH2Me); 98.8 (COCCO); 111.9 (arom. C); 120.4 (arom. C); 121.7 (arom. CH); 131.6, 144.1, 144.2
(arom. C); 157.7 (CHNH); 164.3 (COO); 186.5 (CO). EI-MS: 300 (Mþ, 5), 255 (15), 211 (100), 186 (16),
116 (23), 76 (12). HR-ESI-MS: 301.15461 ([M þ H]þ, C17H21N2O3þ ; calc. 301.15467).
Financial support from the State of Mecklenburg-Vorpommern (Landesgraduierten scholarship for
V. K. ) and by the DAAD (scholarship for S. M.) is gratefully acknowledged.
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´
˜
[2] J. Barluenga, L. Muniz, F. Lopez, F. Palacios, V. Gotor, J. Heterocycl. Chem. 1984, 21, 539; J.
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Received March 28, 2011