Synthesis of Spiro[benzazepine-2,4′-piperidine]

Full text of DOI:10.1021/jo9803986

4554
J . Org. Chem. 1998, 63, 4554-4557
Sch em e 1
Syn th esis of
Sp ir o[ben za zep in e-2,4′-p ip er id in e]
J . Cossy,* C. Poitevin† and D. Gomez Pardo
Laboratoire de Chimie Organique, Associe´ au CNRS,
ESPCI, 10 rue Vauquelin, 75231, Paris Cedex 05, France
J .-L. Peglion* and A. Dessinges
Institut de Recherches Servier, 11 rue des Moulineaux,
92150 Suresnes Cedex, France
Received March 3, 1998
Interest in spiroheterocycles derives from the varied
biological activity of this class of compounds.1 As part
of our program in heterocyclic chemistry, we needed to
synthesize spiro[benzazepine-2,4′-piperidines] of type A.
Two strategies were conceived to generate this target.
The first would involve a Heck reaction as the key step
from aryl bromide B, while the second would employ an
aldol condensation on compound C. (Scheme 1).
Recently, great attention has been focused on the Heck2
reaction because of its technical simplicity and tolerance
to a variety of functional groups. The intramolecular
Heck3 reaction has been used to build spiroheterocycles
and tetrasubstituted carbon centers.4
Sch em e 2
The synthesis of B (R ) Boc) was planned from the
N-Boc-4-piperidone 1 in two steps (Scheme 2). After
condensation of the N-Boc-4-piperidone 1 with o-bromo-
aniline 2, a solution of the imine 3 in toluene was treated
with homoallylmagnesium bromide. Unfortunately the
corresponding amine 4 could not be isolated.
A second approach based on a Heck reaction and an
intramolecular aldol condensation is outlined in a ret-
rosynthetic scheme (Scheme 3).
In contrast to homoallylmagnesium bromide, allylmag-
nesium bromide reacted readily with imine 3 in toluene
(Scheme 4) and led to the amine 5 [allylmagnesium
bromide (1 equiv), rt, 72% yield]. After deprotection of
5 (HCl/EtOH, reflux, 2 h) and treatment of the resulting
diamine 6 with acetic anhydride (1.1 equiv) in the
presence of DMAP (1 equiv) and Et3N (1.1 equiv), the
monoprotected amine 7 was obtained from 2, with an
Sch em e 3
* To whom the correspondence should be addressed. Phone: (+33)
1 40 79 44 29. Fax: (+33) 1 40 79 44 25. E-mail: janine.cossy@espci.fr.
† Present address: Institut de Recherches Servier, 11 rue des
Moulineaux - 92150 Suresnes Cedex - France.
(1) Chambers, M. S.; Baker, R.; Billigton, D. C.; Knight, A. K.;
Middlemiss, D. N.; Wong, E. H. F. J . Med. Chem. 1992, 35, 2033.
Evans, B. E.; Leighton, J . L.; Ritle, K. E.; Gilbert, K. F.; Lundell, G.
F.; Gould, N. P.; Hobbs, D. W.; DiPardo, R. M.; Veber, D. F.; Pettibone,
D. J .; Clineschmidt, B. V.; Anderson, P. S.; Freidinger, R. M. J . Med.
Chem. 1992, 35, 3919.
(2) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic
Press: London, 1985. Tsuji, J . Synthesis with Palladium Compounds;
Springer-Verlag: Berlin, 1980. Harrington P. J . Transition Metals in
Total Synthesis; Wiley-Interscience: New York, 1990. Heck, R. F. Org.
React. 1982, 27, 345. de Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. Engl. 1994, 33, 2379. Negishi, E.; Cope´ret, C.; Ma, S.; Liou, S. Y.;
Liu, F. Chem. Rev. 1996, 96, 365.
(3) Abelman, M. M.; Oh, T.; Overman, L. E. J . Org. Chem. 1987,
52, 4130. Abelman, M. M.; Overman, L. E.; Tran, V. D. J . Am. Chem.
Soc. 1990, 112, 6959. Negishi, E. I.; Zhnag, Y.; O’Connor, B. Tetrahe-
dron Lett. 1988, 29, 2915. Larock, R. C.; Song, H.; Baker, B. E.; Gong,
W. H. Tetrahedron Lett. 1988, 29, 2919. Neghishi, E. I.; N′Guyen, T.;
O’Connor, B. Heterocycles 1989, 28, 55.
overall yield of 47%. When the Heck reaction was applied
to 7 [Pd(OAc)2 (0.11 equiv), PPh3 (0.22 equiv), Et3N (2.2
equiv)], 8′ was the only observed product when the crude
reaction mixture was analyzed by 1H NMR. After
purification by flash chromatography on silica gel, an
isomerization occurred and two regioisomers 8 and 8′
were obtained in a ratio of 10/90. However, when the
mixture 8/8′ was treated with an excess of acetyl chloride
(16 equiv) in refluxing chloroform for 20 h, the more
thermodynamically stable N,N-diacetylated spiro[benz-
(4) Grigg, R.; Santhakumar, V.; Sridharan, V.; Thornton-Petit, M.;
Bridge, A. W. Tetrahedron 1993, 49, 5177.
S0022-3263(98)00398-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/06/1998

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4555
Sch em e 4
Sch em e 5
Sch em e 6
(Pd/C, 5%; H2, 1 atm; iPrOH), the desired spiro[benza-
zepine-2,4′-piperidine] A was isolated (74% yield).
This synthesis, employing an aldol condensation, is an
efficient entry to spiro[benzazepine-2,4′-piperidine] A.
The target compound was obtained in nine steps from
the N-Boc-piperidinone 1 with an overall yield of 11%.
azepine-2,4′-piperidine] 9, was the only isolated product
(90%). The unsaturated protected compound 9 was
ozonolyzed and the keto aldehyde 10 was isolated after
Me2S reduction of the ozonide (73% yield).
The construction of the seven-membered ring of A was
achieved from 10 by using an intramolecular aldol con-
densation (Scheme 5). When the keto aldehyde 10 was
treated with an aqueous methanolic solution of KOH,
three products, 11 (aldolisation-crotonisation product),
11′ (aldolisation product),5 and 11′′ (addition of methylate
on 11), were isolated in a 8/1/1 ratio (48% yield).
Furthermore, concommitently to the aldolisation a des-
acetylation of the N-arylamine occurred during the
process.
When the reaction was performed in THF in the
presence of an aqueous solution of KOH, only the two
products 11 and 11′ were isolated in a ratio of 8/2 (61%
yield). We point out that 11′ could be transformed to 11
when compound 11′ was treated with mesyl chloride (2.9
equiv) in the presence of DMAP (0.09 equiv) and an
excess of Et3N (4.65 equiv) in CH2Cl2 at room tempera-
ture (Scheme 6). Compound 11 was obtained from 10
with an overall yield of 61%. After hydrogenation of 11
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectra were recorded at
300 and 75 MHz, respectively, using CDCl3 or CD3OD as
solvents. Chemical shifts are reported as δ values in ppm
relative to internal standard tetramethylsilane. Only major
diagnostic IR spectra absorption bands are reported. Mass
spectra were obtained by GC/MS with electron impact ionization
on a 5971 Hewelt Packard instrument at 70 eV; only selected
ions are reported. Uncorrected melting points were taken using
a Kofler bank. Moisture sensitive reactions were conducted in
oven-dried glassware under a nitrogen atmosphere. Analytical
TLC was performed on Merck silica gel 60F-254 plates. Flash
column chromatography was accomplished on Merck Kieselgel
60 (230-400 mesh). Solvents such as chloroform, dichloroeth-
ane, toluene, or acetonitrile were purified by distillation under
N2 from CaH2, and ethanol was distilled from Mg.
1-ter t-Bu toxycar bon yl-4-allyl-4-(2-br om oph en ylam in o)pi-
p er id in e (5). A solution of 2-bromoaniline 2 (8.2 g, 47.7 mmol,
1.0 equiv) and N-tert-butoxycarbonyl-4-piperidone 1 (9.1 g, 45.7
mmol, 1.0 equiv) in benzene (12 mL) was heated at reflux, with
azeotropical removal of water, during 72 h. After cooling and
concentration, the crude ketimine 3 was obtained as an oil. To
(5) 11′ was converted into 11 under basic conditions (KOH, H2O,
MeOH).

4556 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
a solution of 3 in anhydrous toluene (100 mL) was added, during
90 min, a solution of allylmagnesium bromide (45.3 mL, 45.3
mmol, 1.0 equiv, 1 M in diethyl ether). The mixture was stirred
during 24 h. The reaction mixture was poured into a saturated
aqueous NH4Cl solution (50 mL). After extraction with diethyl
ether (3 × 500 mL), the organic phase was dried over MgSO4
and filtered. The solvent was removed in vacuo to afford an oil
which was purified by flash columm chromatography on silica
gel (EtOAc/cyclohexane 15/85) to give 5 as a yellow oil (13.0 g;
32.8 mmol, 72% yield). Rf 0.68 (EtOAc/cyclohexane 15/85); IR
1,1′-Dia cetyl-4′-m eth ylsp ir o[p ip er id in e-4,2′(1′H)-qu in o-
lin e] (9). To a solution of 8 and 8′ (1.0 g, 4.0 mmol, 1.00 equiv)
in anhydrous CHCl3 (10 mL) was added dropwise acetyl chloride
(4.5 mL, 63.3 mmol, 16.0 equiv), and the reaction mixture was
stirred and heated at 70 °C during 20 h. After cooling to 0 °C,
an aqueous sodium hydroxide solution (5 N) was added dropwise
to the reaction mixture with vigorous stirring. The resulting
mixture was stirred at room temperature for 20 min and then
extracted with diethyl ether (2 × 150 mL). The etheral phases
were dried over MgSO4 and concentrated in vacuo to afford an
oil which was purified by flash column chromatography on silica
gel (EtOAc/cyclohexane/MeOH 75/15/10) to give 9 (1.1 g, 3.6
mmol, 90% yield). Rf 0.35 (EtOAc/cyclohexane/MeOH 75/15/10);
(neat) 3400, 1600 cm-1 1H NMR (CDCl3) δ 7.42 (dd, J ) 7.9
;
and 1.5 Hz, 1H), 7.11 (ddd, J ) 8.0, 7.9 and 1.5 Hz, 1H), 6.87
(dd, J ) 8.2 and 1.4 Hz, 1H), 6.55 (ddd, J ) 8.0, 7.9 and 1.4 Hz,
1H), 5.81-5.63 (m, 1H), 5.10-4.95 (m, 2H), 4.21 (s, 1H), 3.95-
3.65 (m, 2H), 3.22-3.08 (m, 2H), 2.55-2.48 (m, 2H), 2.09-1.96
(m, 2H), 1.70-1.44 (m, 11H); 13C NMR (CDCl3) δ 154.6, 142.6,
132.7, 132.6, 127.9, 118.4, 118.0, 114.3, 111.9, 79.3, 54.2, 42.6,
39.2, 34.9, 28.3; EI MS m/z (relative intensity) 396 (M+•, 2), 394
(M+•, 2), 355 (44), 353 (44), 299 (99), 297 (100), 238 (34), 236
(33), 226 (64), 224 (65), 82 (33), 57 (72).
IR (CHCl3) 1680 cm-1 1H NMR (CDCl3) δ 7.28-7.13 (m, 3H),
;
7.10-7.03 (m, 1H), 5.77 (s, 1H), 3.90-3.79 (m, 1H), 3.65-3.20
(m, 3H), 2.80-2.61 (m, 1H), 2.25-2.08 (m, 1H), 2.02 (s, 6H), 1.88
(s, 3H), 1.65-1.48 (m, 1H), 1.45-1.29 (m, 1H); 13C NMR (CDCl3)
δ 173.0, 168.8, 138.0, 133.6, 131.3, 130.6, 127.2, 126.6, 126.3,
123.3, 59.0, 43.5, 38.1, 34.8, 33.6, 26.4, 21.2, 17.7; EI MS m/z
(relative intensity) 298 (M+•, 100), 255 (47), 196 (48), 170 (67),
169 (44), 150 (61), 130 (48), 124 (46), 115 (37).
1-Acetyl-4-a llyl-4-(2-br om op h en yla m in o)p ip er id in e (7).
A solution of 5 (31.5 g, 79.5 mmol, 1.0 equiv) in absolute ethanol
(60 mL) was treated with a 2.5 N ethanolic hydrochloric acid
solution (40 mL). The solution was heated at reflux for 2 h. The
solvent was removed in vacuo. The remaining residue was
treated with an aqueous solution of sodium hydroxide (1 N) to
pH 10, extracted with CH2Cl2 (2 × 75 mL). The organic phase
was dried over MgSO4 and removal of the solvent in vacuo
afforded the crude diamine 6 (20.0 g, 67.9 mmol) as a brown oil.
A solution of 6 (20.0 g, 67.8 mmol, 1.0 equiv) in CH2Cl2 (100
mL) containing DMAP (6.2 g, 69.0 mmol, 1.0 equiv), Ac2O (7.0
mL, 74.2 mmol, 1.1 equiv), and Et3N (10.4 mL, 74.6 mmol, 1.1
equiv) was stirred for 16 h at room temperature. After removal
of the solvent in vacuo, the remaining solid was purified by flash
column chromatography on silica gel (EtOAc/cyclohexane/MeOH
75/15/10) to give 7 as a yellow oil (17.6 g, 52.2 mmol, 65% yield).
Rf 0.75 (EtOAc/cyclohexane/MeOH 75/15/10); IR (neat) 1680
(broad) cm-1; 1H NMR (CD3OD) δ 7.42 (dd, J ) 8.1 and 1.5 Hz,
1H), 7.19-7.01 (m, 1H), 6.96 (dd, J ) 8.1 and 1.5 Hz, 1H), 6.57
(ddd, J ) 8.1, 7.7 and 1.5 Hz, 1H), 5.75-5.59 (m, 1H), 5.05-
4.86 (m, 2H), 4.17-4.05 (m, 1H), 3.68-3.54 (m, 1H), 3.40-3.22
(m, 1H), 3.08-2.94 (m, 1H), 2.55-2.41 (m, 2H), 2.15-1.92 (m,
5H), 1.70-1.42 (m, 2H); 13C NMR (CD3OD) δ 171.7, 144.4, 134.3,
134.2, 129.6, 119.9, 119.4, 116.4, 113.3, 55.8, 43.6, 43.5, 38.7,
36.7, 36.3, 21.6; EI MS m/z (relative intensity) 338 (M+•, 4), 336
(M+•, 4), 297 (50), 295 (52), 238 (96), 236 (100), 124 (17), 82 (18);
HRMS calcd for C16H21BrN2O 336.0837, found 336.0831.
N-(1-Acetyl-4-for m ylp ip er id in -4-yl)-N-(2-a cetylp h en yl)-
a ceta m id e (10). A solution of 9 (6.2 g, 20.8 mmol, 1.0 equiv)
in absolute ethanol (150 mL) was treated with ozone at -78 °C.
After 1 h, dimethyl sulfide (50 mL, 680 mmol, 32.7 equiv) was
added. The reaction mixture was warmed to room temperature
and concentrated in vacuo. The resulting oil was purified by
flash column chromatography on silica gel (EtOAc/cyclohexane/
MeOH 75/15/10) to give 10 as an oil (5.0 g, 15.2 mmol, 73% yield).
Rf 0.33 (EtOAc/cyclohexane/MeOH 75/15/10); IR (neat) 1725,
1685, 1635 cm-1; 1H NMR (CDCl3) (mixture of rotamers) δ 9.59-
9.48 (m, 1H), 7.90-7.82 (m, 1H), 7.65-7.50 (m, 2H), 7.29-7.11
(m, 1H), 4.36-4.17 (m, 1H), 3.85-3.42 (m, 2H), 3.28-3.02 (m,
1H), 2.77-2.31(m, 4H), 2.09-1.78 (m, 4H), 1.69 (s, 3H), 1.62-
1.35 (m, 1H), 1.20-1.00 (m, 1H); 13C NMR (CDCl3) (mixture of
rotamers) δ 199.0, 198.8, 197.6, 171.0, 170.9, 168.7, 168.6, 137.3,
137.1, 136.0, 133.2, 133.1, 131.9, 131.6, 130.6, 130.4, 129.6, 65.1,
65.0, 43.2, 41.7, 38.0, 36.4, 30.9, 30.1, 29.4, 29.1, 28.1, 23.0, 21.0,
20.9; EI MS m/z (relative intensity) 312 (M+• - H2O, 3), 269 (12),
184 (30), 162 (100), 120 (51), 108 (54); HRMS calcd for C18H22N2O4
330.1586, found 330.1584.
1′-Ace t yl-3-h yd r oxy-3,4-d ih yd r osp ir o[5H -1-b e n za ze -
p in e-2(1H),4′-p ip er id in ]-5-on e (11′) a n d 1′-Acetyl-3-m eth -
oxy-3,4-dih ydr ospir o[5H-1-ben zazepin e-2(1H),4′-piper idin ]-
5-on e (11′′). A solution of 10 (0.27 g, 0.81 mmol, 1.0 equiv) in
methanol (2 mL) was added to potassium hydroxide (0.09 g, 1.66
mmol, 2.05 equiv) in water (3 mL) at 0 °C. After 4 h, The
reaction mixture was concentrated in vacuo. The remaining
residue was extracted with CH2Cl2 (2 × 30 mL), the organic
phase was dried over MgSO4, and the solvent was removed in
vacuo. The resulting yellow solid was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane/MeOH 75/15/
10) to give 11 as a yellow solid (0.104 g, 0.38 mmol, 48% yield),
11′ as an amorphous solid (0.02 g, 0.07 mmol, 8% yield), and
11′′ as an oil (0.02 g, 0.06 mmol, 7% yield).
1-Acet yl-4′-m et h ylid en e-3′,4′-d ih yd r osp ir o[p ip er id in e-
4,2′(1′H)-qu in olin e] (8) a n d 1-a cetyl-4′-m eth ylsp ir o[p ip er -
id in e-4,2′(1′H)-qu in olin e] (8′). To a solution of 7 (8.8 g, 26.0
mmol, 1.0 equiv) in anhydrous acetonitrile (200 mL) was added
triethylamine (8.0 mL, 57.4 mmol, 2.2 equiv), triphenylphos-
phine (1.50 g, 5.72 mmol, 0.22 equiv), and palladium acetate
(0.64 g, 2.85 mmol, 0.11 equiv). The reaction mixture was heated
at 80 °C for 72 h. After cooling, palladium was filtered off and
removal of acetonitrile in vacuo afforded a brown residue which
was purified by flash column chromatography on silica gel
(EtOAc/cyclohexane/MeOH 75/15/10). A mixture of 8 and 8′
(5.15 g, 20.11 mmol, 77% yield) in 10/90 ratio was obtained. Rf
0.51 (EtOAc/cyclohexane/MeOH 75/15/10). 8′ “endo”: IR (neat)
An a lytica l d a ta for 11′′: Rf 0.45 (EtOAc/cyclohexane/MeOH
75/15/10); IR (neat) 3400, 1640-1620, 1580 cm-1 1H NMR
;
(CDCl3) (mixture of rotamers) δ 7.75-7.60 (m, 1H), 7.32-7.28
(m, 1H), 6.89-6.78 (m, 1H), 6.77-6.69 (m, 1H), 4.24-3.84 (m,
2H), 3.25-3.35 (m, 3H), 3.12-2.90 (m, 4H), 2.00-1.50 (m, 9H);
13C NMR (CDCl3) (mixture of rotamers) δ 198.7, 198.4, 168.9,
146.7, 133.4, 133.3, 131.1, 128.5, 120.1, 119.9, 87.8, 87.0, 59.0,
58.9, 57.5, 57.4, 45.4, 44.7, 42.0, 37.1, 37.0, 34.5, 33.7, 30.7, 29.0,
21.2.
1
3350, 1680 cm-1; H NMR (CDCl3) δ 6.93 (dd, J ) 7.7 and 1.3
Hz, 1H), 6.85 (ddd, J ) 7.3, 7.3 and 1.5 Hz, 1H), 6.51 (ddd, J )
7.3, 7.7 and 1.1 Hz, 1H), 6.39 (dd, J ) 7.7 and 1.5 Hz, 1H), 5.29
(s, 1H), 4.33 (s broad, 1H), 3.65-3.15 (m, 4H), 1.94 (s, 3H), 1.89
(s, 3H), 1.72-1.40 (m, 4H); 13C NMR (CDCl3) δ 168.8, 142.7,
130.5, 128.4, 124.1, 123.7, 121.6, 117.3, 113.2, 51.4, 41.7, 38.7,
An a lytica l d a ta for 11′: Rf 0.35 (EtOAc/cyclohexane/MeOH
1
75/15/10); IR (CHCl3) 3320, 1705, 1620 (broad) cm-1; H NMR
37.9, 36.9, 21.3, 18.6; EI MS m/z (relative intensity) 256 (M+•
,
(CDCl3) (mixture of rotamers) δ 7.75 (d, J ) 9.0 Hz, 1H), 7.37
(ddd, J ) 9.0, 8.8 and 1.8 Hz, 1H), 6.95 (ddd, J ) 9.0, 8.8 and
1.8 Hz, 1H), 6.83 (d, J ) 8.8 Hz, 1H), 4.30-3.93 (m, 3H), 3.63-
3.40 (m, 1H), 3.29-2.89 (m, 4H), 2.50 (s, 1H); 2.05-1.97 (m, 3H),
1.95-1.55 (m, 4H); 13C NMR (CDCl3) (mixture of rotamers) δ
199.1, 198.6, 169.0, 146.1, 146.0, 133.4, 129.1, 128.9, 127.4, 120.2,
120.1, 119.9, 119.8, 77.2, 76.7, 58.7, 49.9, 41.9, 41.8, 37.0, 36.9,
33.1, 32.3, 31.1, 30.4, 21.2; EI MS m/z (relative intensity) 288
(M+•, 7), 259 (65), 200 (100), 188 (12), 182 (15), 170 (9), 158 (9),
91 (9).
33), 213 (40), 185 (13), 171 (24), 170 (100), 169 (32), 158 (22),
157 (59), 143 (11), 115 (11); HRMS calcd for C16H20N2O 256.1576,
found 256.1575. 8 “exo” (always mixed with 8′): 1H NMR
(CDCl3) δ 7.67-7.30 (m, 4H), 5.39 (s, 1H), 4.75 (s, 1H), 4.33 (s
broad, 1H), 3.65-3.15 (m, 4H), 2.41 (s, 2H), 1.94 (s, 3H), 1.72-
1.40 (m, 4H); 13C NMR (CDCl3) δ 168.8, 142.1, 131.9, 131.1,
124.5, 117.7, 115.1, 108.0, 51.4, 42.3, 41.2, 37.4, 35.8, 35.6, 21.3;
EI MS m/z (relative intensity) 256 (M+•, 46), 213 (24), 170 (90),
169 (100), 157 (52), 143 (11), 115 (11).

Notes
1′-Acet ylsp ir o[5H -1-b en za zep in e-2(1H ),4′-p ip er id in ]-5-
J . Org. Chem., Vol. 63, No. 13, 1998 4557
1.0 equiv) in isopropyl alcohol (180 mL) was hydrogenated over
palladium on charcoal 5% (0.2 g) under 1 atm. After completion
of the reaction, the palladium was filtered off and the crude
product was purified by flash column chromatography on silica
gel (EtOAc/cyclohexane/MeOH 75/15/10), to furnish A as a white
solid (1.5 g, 5.5 mmol, 74% yield): mp 153-154 °C (ethanol); Rf
0.40 (EtOAc/cyclohexane/MeOH 75/15/10); IR (Nujol) 3326, 1668,
on e (11). A solution of 10 (5.0 g, 15.2 mmol, 1.0 equiv) in THF
(5 mL) was added to potassium hydroxide (1.7 g, 30.4 mmol, 2.0
equiv) in water (5 mL) at 0 °C. After 4 h, the resulting
precipitate was filtered, washed with cold water, and then dried
over P2O5 to afford 11 (2.0 g, 7.4 mmol) as a yellow solid. The
filtrate was extracted with methylene chloride (2 × 50 mL), the
organic layer was dried over MgSO4, and the solvent removed
in vacuo to afford a solid (1.0 g, 3.5 mmol) which was dissolved
in methylene chloride (25 mL). To this solution were added
anhydrous triethylamine (2.3 mL, 16.1 mmol, 4.6 equiv) and
DMAP (0.04 g, 0.32 mmol, 0.09 equiv) at 0 °C, and then mesyl
chloride (0.74 mL, 9.56 mmol, 2.90 equiv) was added under
vigorous stirring. After 1 h, the solvent was removed in vacuo,
and the remaining solid was purified to afford 11 as a yellow
solid (0.50 g, 1.85 mmol, 61% yield). Rf 0.40 (EtOAc/cyclohexane/
1626 cm-1 1H NMR (CDCl3) δ 7.72 (d, J ) 8.1 Hz, 1H), 7.21
;
(dd, J ) 7.7 and 7.7 Hz, 1H), 6.84 (dd, J ) 7.7 and 7.7 Hz, 1H),
6.78 (d, J ) 7.7 Hz, 1H), 4.28 (s, 1H), 3.62-3.21 (m, 4H), 2.82-
2.60 (m, 2H), 1.98 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.50 (m, 4H);
13C NMR (CDCl3) δ 201.8, 168.7, 147.3, 133.5, 129.3, 127.4,
121.8, 120.7, 55.2, 42.4, 39.0, 37.5, 37.2, 37.0, 35.8, 21.2; EI MS
m/z (relative intensity) 272 (M+•, 100), 229 (26), 186 (49), 185
(46), 120 (26), 95 (23). Anal. Calcd for C16H20N2O2: C, 70.56;
H, 7.40; N, 10.29. Found C, 70.33; H, 7.13; N, 10.11.
MeOH 75/15/10). IR (CCl4) 3300, 1710, 1680-1530 (broad) cm-1
;
1H NMR (CDCl3) δ 8.05 (dd, J ) 8.1 and 1.8 Hz, 1H), 7.34 (ddd,
J ) 8.1, 7.0 and 1.8 Hz, 1H), 6.92 (ddd, J ) 8.1, 7.0 and 1.1 Hz,
1H), 6.77 (dd, J ) 8.1 and 1.1 Hz, 1H), 6.39 (d, J ) 12.1 Hz,
1H), 6.33 (d, J ) 12.1 Hz, 1H), 4.30 (s, 1H), 3.82-3.57 (m, 2H),
3.47-3.36 (m, 2H), 2.08 (s, 3H), 2.02-1.77 (m, 4H); 13C NMR
(CDCl3) δ 189.9, 169.0, 145.4, 145.2, 134.6, 133.0, 131.2, 123.6,
120.2, 119.9, 53.8, 42.3, 37.2, 35.7, 35.2, 21.3; EI MS m/z (relative
intensity) 270 (M+•, 100), 227 (38), 198 (25), 184 (16), 172 (19),
156(18), 143(18); HRMS calcd for C16H18N2O2 270.1368, found
270.1368.
Ack n ow led gm en t. We thank the Institut de Re-
cherches Servier for financial support.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
for the compounds 5, 7, 8′, 9, 10, 11, 11′, 11′′ (8 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1′-Acetyl-3,4-d ih yd r osp ir o[5H-1-ben za zep in e-2(1H),4′-p i-
p er id in ]-5-on e (A). A suspension of enone 11 (2.0 g, 7.4 mmol,
J O9803986