Synthesis of dibenzazepinones by palladium-catalyzed intramolecular arylation of o -(2′-Bromophenyl)anilide enolates

Article abstract of DOI:10.1021/jo101137r

A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an anilide enolate. T'e reactions were completed in 10 min at 100 °C with moderate to excellent yields. Aminodibenzazepinone 1, the core structure in the γ-secretase inhibitor LY411575, can be prepared in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis reported here compares favorably with presently available approaches to this interesting ring system.

Full text of DOI:10.1021/jo101137r

pubs.acs.org/joc
Synthesis of Dibenzazepinones by Palladium-Catalyzed Intramolecular
Arylation of o-(20-Bromophenyl)anilide Enolates
Xiaohong Pan and Craig S. Wilcox*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
daylite@pitt.edu
Received June 10, 2010
A new approach for the convenient synthesis of dibenzazepinones is reported. The key step is the
formation of the seven-membered ring through palladium-catalyzed intramolecular arylation of an
anilide enolate. The reactions were completed in 10 min at 100 °C with moderate to excellent yields.
Aminodibenzazepinone 1, the core structure in the γ-secretase inhibitor LY411575, can be prepared
in five steps from 2-bromophenylboronic acid and 2-iodoaniline in 60% overall yield. The synthesis
reported here compares favorably with presently available approaches to this interesting ring system.
Introduction
produce byproducts that are difficult to separate from the target
molecule. The palladium-catalyzed intramolecular arylation
of anilide enolates has been developed for the synthesis of
oxindoles6 and other five- and six-membered ring compounds.7
We became interested in exploring the potential of this method
for seven-member ring formation and its utility in the synthesis
of aminodibenzazepinone 1. In this paper, we describe the
results of our investigations and detail a new synthesis of diben-
zazepinones by the palladium-catalyzed intramolecular aryla-
tion of o-phenylanilide enolates.
γ-Secretase inhibitor LY411575,1,2 a potential drug can-
didate for Alzheimer’s disease, is known to reduce brain and
CSF levels of Aβ-peptides. As the core structure of LY411575,
R-substituted dibenzazepinones have an interesting gear-like
structure.3,4 Prior syntheses of dibenzazepinones have been
based upon Friedel-Crafts alkylation,5a,b palladium-catalyzed
borylation-Suzuki reaction,4 the cyclization of a hydroxyla-
mide in neat trifluoromethanesulfonic acid,5c the intramolecular
Staudinger-aza-Wittig reaction of an azido pentafluorophenyl
ester,5d and the hydrogenation of methyl 2-nitro-20-biphenyl-
acetate.5e Some of these methods suffer from low yields or
Results and Discussion
Synthesis of Dibenzazepinone Precursors (Scheme 1). The
Suzuki coupling of 2-bromophenylboronic acid and 2-io-
doaniline afforded 2-amino-20-bromobiphenyl 2 in 90%
yield. Amidation of 2 with acyl chlorides or carboxylic acids
gave amides 3-9 in generally excellent yields. Methylation of
3-9 with methyl iodide or benzylation of 3 with benzyl
(1) Fauq, A. H.; Simpson, K.; Maharvi, G. M.; Golde, T.; Das, P. Bioorg.
Med. Chem. Lett. 2007, 17, 6392.
(2) (a) Wu, J. T.; Tung, J. S.; Thorsett, E. D.; Pleiss, M. A.; Nissen, J. S.;
Neitz, J.; Latimer, L. H.; John, V.; Freedman, S.; Britton, T. C.; Audia, J. E.;
Reel, J. K.; Mabry, T. E.; Dressman, B. A.; Cwi, C. L.; Droste, J. J.; Henry,
S. S.; McDaniel, S. L.; Scott, W. L.; Stucky, R. D.; Porter, W. PCT Int. Appl.
WO 9828268 A 2:889, 1998. (b) Audia, J. E.; Hyslop, P. A.; Nissen, J. S.;
Thompson, R. C.; Tung, J. S.; Tanner, L. I. WO 00/19210, 2000.
(3) Tabata, H.; Akiba, K.; Lee, S.; Takahashi, H.; Natsugari, H. Org.
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Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631. (c) Watson, E. L.;
Marsden, S. P.; Raw, S. A. Tetrahedron Lett. 2009, 50, 3318. (d) Ackermann,
(4) Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem.
2002, 67, 1199.
(5) (a) Wiesner, K.; Valenta, C.; Manson, A. J.; Stonner, F. W. J. Am.
Chem. Soc. 1955, 77, 675. (b) Dewar, M. J. S.; Kaneko, C.; Bhattacharjee,
M. K. J. Am. Chem. Soc. 1962, 84, 4884. (c) Endo, Y.; Ohta, T.; Shudo, K.;
Okamoto, T. Heterocycles 1977, 8, 367. (d) Fuwa, H.; Okamura, Y.; Morohashi,
Y.; Tomita, T.; Iwatsubo, T.; Kan, T.; Fukuyama, T.; Natsugari, H. Tetrahedron
Lett. 2004, 45, 2323. (e) Muth, C. W.; Sung, W.-L.; Papanastassiou, Z. B. J. Am.
Chem. Soc. 1955, 77, 3393.
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L.; Vicente, R.; Hofmann, N. Org. Lett. 2009, 11, 4274. (e) Sole., D.; Serrano,
O. J. Org. Chem. 2008, 73, 9372. (f) Marsden, S. P.; Watson, E. L.; Raw,
S. A. Org. Lett. 2008, 10, 2905. (g) Durbin, M. J.; Willis, M. C. Org. Lett.
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DOI: 10.1021/jo101137r
r
Published on Web 09/07/2010
J. Org. Chem. 2010, 75, 6445–6451 6445
2010 American Chemical Society

Pan and Wilcox
JOCArticle
SCHEME 1. Synthesis of Amides 10-17
SCHEME 2. Synthesis of Dibenzazepinone 19 from Chloroaryl
Substrates
was explored. As shown in Scheme 2, the synthesis of
20-chloro-2-aminobiphenyl 21 from 2-chlorophenylboronic
acid and 2-bromoaniline, which are less expensive starting
materials, proceeded with the same efficiency as found for
the bromoaryl analogue (82% yield). Following amidation
of 21 with acetyl chloride and methylation of amide 22 with
methyl iodide gave N-methyl amide 23 in quantitative overall
yield. Unfortunately, with chloroaryl substrate 23, the catal-
ysis system of tricyclohexylphosphonium tetrafluoroborate
provided no product; N-heterocyclic carbene ligand pre-
cursor 18 under the same conditions for 20 min gave 19 in
only 21% yield.
TABLE 1. Optimization of the Synthesis of Dibenzazepinone 19
Exploration of the Substrate Scope. The optimized cycliza-
tion conditions were applied to seven more substrates (Table 2).
A phenyl group in the R position of the amide was well
tolerated; the yield of R-phenyldibenzazepinone 24 was al-
most quantitative (entry 2). In contrast, R-methyl and
R-methoxy substrates 12 and 13 (entry 3 and 4) afforded
relatively low yields of the dibenzazepinone and the product
was accompanied by the byproduct 9-methyl-9H-carbazole.
The incorporation of two methyl groups at the R position
inhibited the reaction; R,R-dimethyldibenzazepinone 27 was
formed in only 8% yield and 54% conversion (entry 5). The
N-benzyl amide 17 was investigated as an alternative to
N-methyl amide 10 because the product amide may be read-
ily deprotected. The benzyl and methyl amides behaved
similarly. N-Benzyl protected dibenzazepinone 28 was iso-
lated in 84% yield along with 9-benzyl-9H-carbazole in 16%
yield (entry 6).
Under the standard conditions using 3 equiv of base, an
interesting byproduct was formed (54% yield) in the reaction
of R-benzyloxyamide 15. This side product was also pro-
duced by the reaction of product 29 with NaOt-Bu alone
in toluene at 100 °C (Scheme 3) and therefore could be
R-hydroxy-R-benzyl dibenzazepinone 30, a 1,2-Wittig rear-
rangement product.8 To confirm the structure of 30, 29 was
reduced to amine 31(Scheme 3). Following debenzylation of
31, Dess-Martin oxidation of alcohol 32 and treatment of
aldehyde 33 with benzylmagnesium chloride afforded amine
34, which was identical to the amide reduction product of 30.
The reaction conditions were then modified for the forma-
tion of 29. R-Benzyloxydibenzazepinone 29 was formed in
81% yield with 4% 30 when the amount of NaOt-Bu was
reduced to 1.5 equiv, and the reaction was run in toluene for
10 min (Table 2, entry 7).
aYield of 19 was calculated from isolated product after chromato-
graphy. bReaction run with 5 mol % of the catalyst and 1.5 equiv of
NaOt-Bu.
bromide provided the desired N-alkyl amides 10-17 as
dibenzazepinone precursors in uniformly excellent yields.
Optimization of Reaction Conditions. As shown in Table 1,
two general catalysis systems were screened with acetamide
10. Treatment of 10 with N-heterocyclic carbene precursor
18,6 palladium acetate, and sodium tert-butoxide (NaOt-Bu)
in toluene at 100 °C for 20 min gave dibenzazepinone 19 in
78% yield (entry 1). The use of tricyclohexylphosphonium
tetrafluoroborate7a with palladium acetate increased the
yield of 19 to 90% in 10 min (entry 2) and generated a by-
product identified as 9-methyl-9H-carbazole 20 (6% yield).
This byproduct is presumed to arise by cleavage of the amide
to the aniline by NaOt-Bu followed by the palladium-
catalyzed intramolecular amination. Changing the solvent
to dioxane decreased the yield of 19 to 45% (entry 3). To
further explore the efficiency of the catalysis system of
tricyclohexylphosphonium tetrafluoroborate, the catalytic
loading was lowered to 5 mol % with 1.5 equiv of NaOt-Bu
(entry 4). However, the yield of 19 dropped to 61%.
Exploration of the Reaction with Chloroaryl Substrates.
For reasons related to materials cost, the possibility of using
a chloroaryl substrate in place of the bromoaryl substrate
(8) Bertrand, M. B.; Wolfe, J. P. Org. Lett. 2006, 8, 4661.
6446 J. Org. Chem. Vol. 75, No. 19, 2010

Pan and Wilcox
JOCArticle
TABLE 2. Scope of the Intramolecular Arylation Pathway to Diben-
zazepinones
SCHEME 3. Rearrangement of R-Benzyloxydibenzazepinone 29
in 93% yield (entry 8). Lowering the catalyst loading to
3 mol % had little effect and provided the desired product in
15 min in 91% yield (entry 9).
Completion of the Synthesis of r-Aminodibenzazepinone 1.
R-Dibenzylaminodibenzazepinone 35 was debenzylated
quantitatively through hydrogenolysis to afford R-aminodi-
benzazepinone 1 (eq 1). The complete synthesis of R-amino-
dibenzazepinone 1 by this approach requires five steps from
2-bromophenylboronic acid and 2-iodoaniline and proceeds
in 60% overall yield. Significant increases in overall yield
can be achieved by optimizing the step involving coupling of
20-bromo-2-aminobiphenyl 2 with dibenzylaminoacetic acid.
Conclusion
The intramolecular R-arylation of amide enolates has been
applied successfully to the formation of seven-membered
ring compounds. These reactions provide a new route to the
synthesis of substituted dibenzazepinones. The procedure is
efficient and especially useful for the synthesis of R-amino-
dibenzazepinone. We anticipate that with the appropriate
asymmetric ligand or chiral amino protecting group, R-amino-
dibenzazepinone may be made directly with high enantiomeric
excess, thus eliminating the need for resolution of this impor-
tant target.
Experimental Section
[1,10-Biphenyl]-2-amine, 20-Bromo- (2). A solution of 2-iodoa-
niline (3.48 g, 15.89 mmol), 2-bromophenylboronic acid (3.67 g,
18.27 mmol), Pd(PPh3)4 (550 mg, 0.48 mmol), and NaHCO3
(4.0 g, 47.7 mmol) in DME (45 mL) was stirred at room
temperature for 5 min. H2O (23 mL) was added, and the
resulting mixture was degassed by oil pump in a dry ice-acetone
bath, sealed, and stirred at 120 °C for 3 h. After being cooled to
room temperature, the mixture was extracted with Et2O. The
extracts were combined, dried over MgSO4, and filtered. After
removal of volatile components from the filtrate, the resulting
crude product was purified by flash chromatography (SiO2,
hexanes/EtOAc = 3/1) to give 2 (3.53 g, 90%) as a pale yellow
solid:9 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J = 8.1 Hz, 1H),
7.47-7.31 (m, 2H), 7.27-7.19 (m, 2H), 7.06 (dd, J = 7.5, 1.5 Hz,
1H), 6.87 (td, J = 7.5, 0.9 Hz, 1H), 6.81 (dd, J = 8.1, 0.9 Hz, 1H),
3.54 (br, 2H); 13C NMR (75 MHz, CDCl3) δ 143.7, 140.2, 133.3,
132.0, 130.4, 129.4, 129.3, 128.0, 127.3, 124.4, 118.4, 115.7.
aYield was calculated from isolated product after chromatography.
bConversion was based on the isolated starting material. cReaction run
with 1.5 equiv of NaOt-Bu. dReaction run with 3 mol % of the catalyst
for 15 min.
Because of our interest in the γ-secretase inhibitor, it was
significant to find that R-dibenzylaminoamide 16 cyclized
efficiently to afford R-dibenzylaminodibenzazepinone 35
(9) Sandin, R. B.; Hay, A. S. J. Am. Chem. Soc. 1952, 74, 274.
J. Org. Chem. Vol. 75, No. 19, 2010 6447

Pan and Wilcox
JOCArticle
[1,10-Biphenyl]-2-amine, 20-Chloro- (21). A solution of 2-bro-
moaniline (516 mg, 3.0 mmol), 2-chlorophenylboronic acid (562
mg, 3.6 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol), and NaHCO3
(756 mg, 9.0 mmol) in DME (7 mL) was stirred at room
temperature for 5 min. H2O (7 mL) was added, and the resulting
mixture was degassed by oil pump in a dry ice-acetone bath,
sealed, and stirred at 120 °C for 2 h. After being cooled to room
temperature, the mixture was extracted with Et2O. The extracts
were combined, dried over MgSO4, and filtered. After removal
of volatile components from the filtrate, the resulting crude
product was purified by flash chromatography (SiO2, hexanes/
2968, 1676, 1517, 1285, 754; 1H NMR (300 MHz, CDCl3) δ 8.22
(d, J = 8.1 Hz, 1H), 7.72-7.67 (m, 1H), 7.43-7.36 (m, 2H),
7.29-7.24 (m, 2H), 7.19-7.12 (m, 2H), 6.92 (br, 1H), 2.36
(heptet, J = 6.9 Hz, 1H), 1.06 (d, J = 6.9 Hz, 3H), 1.03 (d,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.8, 138.8,
135.1, 133.1, 132.0, 131.9, 129.9, 129.7, 129.0, 128.0, 124.2,
123.9, 121.9, 36.5, 19.3; HRMS (EI) m/e calcd for C16H16NOBr
(Mþ) 317.0415, found 317.0410.
[1,10-Biphenyl]-2-acetamide, 20-Chloro- (22). By the general
procedure, 21 (475 mg, 2.33 mmol), Et3N (0.39 mL, 2.8 mmol),
acetyl chloride (0.2 mL, 2.8 mmol) in CH2Cl2 (10 mL) for 5 min
provided 22 (570 mg, 99%) as an oil after flash chromatography
(SiO2, hexanes/EtOAc = 3/1): IR (cm-1) 3421, 3283, 3058,
1670, 1521, 1442, 1293, 1036, 754; 1H NMR (300 MHz, CDCl3)
δ 8.09 (d, J = 8.1 Hz, 1H), 7.49-7.46 (m, 1H), 7.39-7.23 (m,
4H), 7.18-7.15 (m, 2H), 7.10 (br, 1H), 1.91 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.4, 136.7, 135.2, 133.5, 131.9, 130.5,
130.2, 129.8, 129.6, 128.8, 127.3, 124.4, 122.5, 24.2; HRMS (EI)
m/e calcd for C14H12NOCl (Mþ) 245.0607, found 245.0610.
[1,10-Biphenyl]-2-phenylacetamide, 20-Bromo- (4). To a solu-
tion of 2 (350 mg, 1.4 mmol), phenylacetic acid (209 mg, 1.54
mmol), and 1-hydroxybenzotriazole (HOBT) (209 mg, 1.54
mmol) in CH2Cl2 (10 mL) was added a solution of DCC (318
mg, 1.54 mmol) in CH2Cl2 (4 mL) slowly at room temperature in
1 h, and the mixture was stirred for 36 h and filtered. After
removal of volatile components from the filtrate, the resulting
crude product was purified by flash chromatography (SiO2,
hexanes/EtOAc = 3/1) to give 4 (490 mg, 96%) as an oil: IR
(cm-1) 3381, 3307, 3060, 1685, 1519, 1443, 1303, 754; 1H NMR
(300 MHz, CDCl3) major conformer: δ 8.32 (d, J = 8.1 Hz, 1H),
7.48 (dd, J = 7.5, 1.5 Hz, 1H), 7.41 (td, J = 7.2, 1.5 Hz, 1H),
7.25-7.08 (m, 6H), 7.13-6.93 (m, 4H), 6.80 (br, 1H), 3.59 (s,
1H), 3.58 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 169.0, 138.3,
135.0, 133.7, 133.2, 131.6, 131.2, 129.7, 129.4, 129.3, 129.1,
127.8, 127.6, 124.2, 123.8, 121.0, 45.1; HRMS (EI) m/e calcd
for C20H16NOBr (Mþ) 365.0415, found 365.0410.
[1,10-Biphenyl]-2-benzyloxyacetamide, 20-Bromo- (8). To a
solution of 2 (744 mg, 3.0 mmol), benzyloxyacetic acid (600
mg, 3.6 mmol) and HOBT (492 mg, 3.6 mmol) in CH2Cl2
(24 mL) was added a solution of DCC (750 mg, 3.6 mmol) in
CH2Cl2 (6 mL) slowly at room temperature in 1 h, and the
mixture was stirred for 1 h and filtered. After removal of volatile
components from the filtrate, the resulting crude product was
purified by flash chromatography (SiO2, hexanes/EtOAc = 3/1)
to give 8 (1.11 g, 94%) as an oil: IR (cm-1) 3376, 3065, 2869,
1693, 1526, 1026, 738; 1H NMR (300 MHz, CDCl3) δ 8.41 (d,
J = 8.1 Hz, 1H), 8.20 (br, 1H), 7.55 (dd, J = 8.1, 0.9 Hz, 1H),
7.44-7.37 (m, 1H), 7.33-7.09 (m, 8H), 7.06-6.98 (m, 2H),
4.39-4.29 (m, 2H), 4.03-3.91 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 167.5, 138.5, 136.6, 134.6, 133.1, 131.7, 131.5, 129.9,
129.2, 128.5, 128.0, 127.9, 127.6, 124.3, 124.0, 120.9, 73.2, 69.7;
HRMS (EI) m/e calcd for C21H18NO2Br (Mþ) 395.0521, found
395.0538.
EtOAc = 3/1) to provide 21 (501 mg, 82%) as a white solid:9 1
H
NMR (300 MHz, CDCl3) δ 7.50 (m, 1H), 7.38-7.23 (m, 3H),
7.22 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.84 (t, J = 7.5
Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 3.52 (br, 2H); 13C NMR
(75 MHz, CDCl3) δ 143.9, 138.1, 134.0, 133.1, 131.6, 131.0,
130.3, 129.5, 128.9, 128.4, 128.2, 128.1, 126.3, 125.4, 119.5,
117.3, 116.6, 114.6.
General Procedure for the Acylation of 2-Arylanilines with
Acyl Chlorides. To a solution of 2-arylaniline (2.0 mmol) and
Et3N (0.34 mL, 2.4 mmol) in CH2Cl2 (10 mL) was added acyl
chloride (2.4 mmol) slowly at 0 °C, and the mixture was stirred at
room temperature for 5 min. Saturated NH4Cl solution was
added, and the resulting mixture was stirred for 10 min. The
organic layer was separated, dried over MgSO4, and filtered.
After removal of volatile components from the filtrate, the
resulting crude product was purified by flash chromatography.
[1,10-Biphenyl]-2-acetamide, 20-Bromo- (3). By the general
procedure, 2 (1.0 g, 4.0 mmol), Et3N (0.67 mL, 4.8 mmol), acetyl
chloride (0.34 mL, 4.8 mmol) in CH2Cl2 (20 mL) for 5 min
provided 3 (1.15 g, 99%) as an oil after flash chromatography
(SiO2, hexanes/EtOAc = 1/1): IR (cm-1) 3421, 3286, 3056,
1
1670, 1520, 1442, 1369, 1294, 1027, 1005, 754; H NMR (300
MHz, CDCl3) δ 8.18 (d, J = 8.1 Hz, 1H), 7.71-7.69 (m, 1H),
7.42-7.37 (m, 2H), 7.29-7.25 (m, 2H), 7.21-7.13 (m, 2H), 6.86
(br, 1H), 1.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4,
138.9, 135.1, 133.3, 132.0, 130.1, 130.0, 129.3, 129.1, 128.1,
124.4, 124.0, 122.2, 24.6; HRMS (EI) m/e calcd for C14H12NOBr
(Mþ) 289.0102, found 289.0101.
[1,10-Biphenyl]-2-propionamide, 20-Bromo- (5). By the general
procedure, 2 (248 mg, 1.0 mmol), Et3N (0.17 mL, 1.2 mmol),
propionyl chloride (0.10 mL, 1.2 mmol) in CH2Cl2 (10 mL) for
5 min provided 5 (278 mg, 92%) as an oil after flash chroma-
tography (SiO2, hexanes/EtOAc = 3/1): IR (cm-1) 3296, 2976,
1672, 1442, 754; 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J = 7.8
Hz, 1H), 7.70-7.67 (m, 1H), 7.41-7.34 (m, 2H), 7.28-7.22 (m,
2H), 7.18-7.11(m, 2H), 6.92 (br, 1H), 2.20 (q, J = 7.5 Hz, 2H),
1.05 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.8,
138.8, 135.1, 133.1, 131.9, 129.9, 129.0, 128.0, 124.1, 123.9,
121.9, 30.7, 9.5; HRMS (EI) m/e calcd for C15H14NOBr (Mþ)
303.0259, found 303.0270.
[1,10-Biphenyl]-2-methoxyacetamide, 20-Bromo- (6). By the
general procedure, 2 (248 mg, 1.0 mmol), Et3N (0.17 mL, 1.2
mmol), methoxyacetyl chloride (0.11 mL, 1.2 mmol) in CH2Cl2
(10 mL) for 5 min provided 6 (298 mg, 93%) as an oil after flash
[1,10-Biphenyl]-2-dibenzylaminoacetamide, 20-Bromo- (9). To
a solution of 2 (124 mg, 0.5 mmol), dibenzylaminoacetic acid
(153 mg, 0.6 mmol) and HOBT (82 mg, 0.6 mmol) in CH2Cl2
(4 mL) was added a solution of DCC (125 mg, 0.6 mmol) in
CH2Cl2 (1 mL) at room temperature in 1 h, and the mixture was
stirred for 72 h and filtered. After removal of volatile components
from the filtrate, the resulting crude product was purified by
flash chromatography (SiO2, hexanes/EtOAc = 3/1) to give 9
(176 mg, 73%) as an oil: IR (cm-1) 3336, 3061, 3029, 2923, 2831,
chromatography (SiO2, hexanes/EtOAc = 3/1): IR (cm-1
)
1
3369, 2936, 1693, 1526, 1303, 1111, 757; H NMR (300 MHz,
CDCl3) δ 8.37 (d, J = 8.1 Hz, 1H), 8.08 (br, 1H), 7.71-7.68 (m,
1H), 7.46-7.37 (m, 2H), 7.29-7.24 (m, 2H), 7.17-7.14 (m, 2H),
3.84 (d, J = 1.2 Hz, 2H), 3.14 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.6, 138.5, 134.5, 133.0, 131.7, 131.5, 129.8, 129.7,
129.0, 127.9, 124.2, 124.0, 120.9, 72.1, 59.3; HRMS (EI) m/e
calcd for C15H14NO2Br (Mþ) 319.0208, found 319.0207.
1
2246, 1692, 1583, 1514, 1445, 910, 750; H NMR (300 MHz,
[1,10-Biphenyl]-2-isobutyramide, 20-Bromo- (7). By the general
procedure, 2 (248 mg, 1.0 mmol), Et3N (0.17 mL, 1.2 mmol),
isobutyryl chloride (0.13 mL, 1.2 mmol) in CH2Cl2 (10 mL) for
5 min provided 7 (289 mg, 91%) as an oil after flash chroma-
tography (SiO2, hexanes/EtOAc = 3/1): IR (cm-1) 3424, 3298,
CDCl3) δ 8.73 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.82 (dd, J =
7.2, 0.6 Hz, 1H), 7.54 (td, J = 6.9, 1.2 Hz, 1H), 7.43-7.33 (m,
3H), 7.31-7.19 (m, 6H), 7.17-7.13 (m, 2H), 6.99-6.94 (m, 4H),
3.52 (d, J = 13.5 Hz, 2H), 3.44 (d, J = 13.5 Hz, 2H), 3.18 (d, J =
16.5 Hz, 1H), 3.04 (d, J = 16.5 Hz, 1H); 13C NMR (75 MHz,
6448 J. Org. Chem. Vol. 75, No. 19, 2010

Pan and Wilcox
JOCArticle
CDCl3) δ 169.3, 139.4, 136.9, 135.2, 133.4, 132.1, 131.4, 130.3,
130.1, 129.2, 129.1, 128.7, 128.0, 127.6, 124.7, 124.1, 121.2, 58.9,
57.6; HRMS (EI) m/e calcd for C28H26N2OBr (MHþ) 485.1228,
found 485.1217.
General Procedure for the Methylation of Amides with Methyl
Iodide. A mixture of amide (1.0 mmol) and NaH (60% in mineral
oil, 42 mg, 1.05 mmol) in THF (10 mL) was stirred at room
temperature for 10 min. MeI (0.075 mL, 1.2 mmol) was added,
and the resulting mixture was stirred for 10 min. After removal of
volatile components from the mixture, the resulting crude pro-
duct was purified by flash chromatography.
128.0, 127.9, 127.4, 127.1, 126.9, 123.1, 122.8, 71.0, 70.6, 70.2, 59.1,
58.7, 38.2, 36.7, 35.7; HRMS (EI) m/e calcd for C16H16NO2Br
(Mþ) 333.0364, found 333.0377.
[1,10-Biphenyl]-2-(N-methyl-isobutyramide), 20-Bromo- (14). By
the general procedure, 7 (260 mg, 0.82 mmol), NaH 60% in
mineral oil (35 mg, 0.86 mmol), MeI (140 mg, 0.99 mmol) in
THF (10 mL) for 10 min afforded 14 (268 mg, 99%) as a white
solid after flash chromatography (SiO2, hexanes/EtOAc = 1/1):
IR (cm-1) 2968, 1658, 1466, 1386, 1102, 752; 1H NMR (300 MHz,
CDCl3) δ 7.66 (m, 1H), 7.48-7.24 (m, 5H), 7.24-7.09 (m, 2H),
3.21 (s, 1.2H), 3.07 (s, 0.3H), 2.89 (s, 1.5H), 2.76 (heptet, J = 6.9
Hz, 0.1H), 2.62-2.46 (m, 0.9H), 1.13 (d, J = 6.6 Hz, 1.5H), 1.09
(d, J = 6.6 Hz, 1.5H), 0.94 (d, J = 6.6 Hz, 1.37H), 0.81 (d, J = 6.6
Hz, 0.35H), 0.69 (d, J = 6.6 Hz, 1.28H); 13C NMR (75 MHz,
CDCl3) δ 177.6, 177.2, 142.4, 142.2, 141.8, 139.8, 139.2, 138.9,
138.5, 133.5, 133.0, 132.8, 132.1,131.8, 131.3, 130.9, 130.6, 129.6,
129.4, 129.3, 129.1, 128.0, 127.8, 127.3, 127.2, 126.9, 123.3, 38.8,
37.9, 36.2, 31.5, 30.9, 30.3, 20.6, 20.1, 19.6,18.9,18.8, 18.7; HRMS
(EI) m/e calcd for C17H18NOBr (Mþ) 331.0572, found 331.0565.
[1,10-Biphenyl]-2-(N-methyl-benzyloxyacetamide), 20-Bromo-
(15). By the general procedure, 8 (1.04 g, 2.63 mmol), NaH
60% in mineral oil (110 mg, 2.77 mmol), MeI (448 mg, 3.16
mmol) in THF (30 mL) for 10 min afforded 15 (1.056 g, 98%) as
an oil after flash chromatography (SiO2, hexanes/EtOAc =
3/1): IR (cm-1) 3060, 2925, 1673, 1026, 751; 1H NMR (300
MHz, CDCl3) δ 7.65-7.58 (m, 1H), 7.42-7.14 (m, 11.4H), 7.05
(dd, J = 7.2, 1.8 Hz, 0.6H), 4.63-4.33 (m, 2H), 4.14-3.87 (m,
2H), 3.12 (s, 1H), 3.00 (s, 0.4H), 2.86 (s, 1.6H); 13C NMR (75
MHz, CDCl3) δ 169.7, 169.0, 141.6, 140.6, 140.2, 139.8, 139.0,
138.9, 138.7, 138.6, 137.9, 137.5, 133.6, 133.1, 132.7, 132.5,
131.6, 131.5, 131.2, 130.3, 129.6, 129.4, 128.8, 128.4, 128.3,
128.1, 128.0, 127.9, 127.6, 127.4, 127.3, 127.2, 123.3, 123.1,
73.2, 73.0, 72.9, 69.0, 68.2, 38.5, 37.2, 36.0; HRMS (EI) m/e
calcd for C22H20NO2NaBr (MNaþ) 432.0575, found 432.0548.
[1,10-Biphenyl]-2-(N-methyl-dibenzylaminoacetamide), 20-Bromo-
(16). By the general procedure, 9(166 mg, 0.34 mmol), NaH 60% in
mineral oil (15 mg, 0.36 mmol), MeI (58 mg, 0.41 mmol) in THF
(4 mL) for 10 min afforded 16 (170 mg, 99%) as an oil after flash
chromatography (SiO2, hexanes/EtOAc = 3/1): IR (cm-1) 3060,
3027, 2919, 1664, 1464, 749; 1H NMR (300 MHz, CDCl3) δ 7.60 (d,
J = 7.8 Hz, 0.5H), 7.48 (d, J = 8.1 Hz, 0.3H), 7.43-7.07 (m,
15.7H), 6.96-6.89 (m, 0.5H), 6.88 (d, J = 7.5 Hz, 0.5H), 6.60 (d,
J = 7.2 Hz, 0.5H), 3.98-3.01 (m, 7.5H), 2.82 (s, 1.50H); 13C NMR
(75 MHz, CDCl3) δ 171.3, 171.0, 170.7, 142.1, 141.3, 140.6, 140.1,
139.9, 139.8, 139.1, 138.9, 138.8, 138.7, 133.7, 133.1, 132.8, 132.3,
131.5, 131.0, 130.3, 130.1, 129.5, 129.4, 129.3, 129.0, 128.7, 128.5,
128.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.2, 127.1, 126.8, 123.4,
123.2, 123.0, 77.4, 58.3, 58.0, 57.4, 56.2, 53.5, 53.2, 38.7, 37.9, 35.9;
HRMS (EI) m/e calcd for C29H28N2OBr (MHþ) 499.1385, found
499.1381.
[1,10-Biphenyl]-2-(N-methyl-acetamide), 20-Bromo- (10). By
the general procedure, 3 (1.01 g, 3.48 mmol), NaH 60% in
mineral oil (147 mg, 3.65 mmol), MeI (593 mg, 4.18 mmol) in
THF (25 mL) for 10 min afforded 10 (1.05 g, 99%) as a white
solid after flash chromatography (SiO2, hexanes/EtOAc = 1/1):
1
IR (cm-1) 3066, 1658, 1467, 1373, 757; H NMR (300 MHz,
CDCl3) δ 7.69-7.63 (m, 1H), 7.48-7.38 (m, 2H), 7.38-7.30 (m,
2H), 7.29-7.09 (m, 3H), 3.09 (s, 1.04H), 2.96 (s, 0.31H), 2.84
(s, 1.65H), 2.17 (s, 0.14H), 2.01 (s, 0.32H), 1.98 (s, 1.54H), 1.86
(s, 1.0H); 13C NMR (75 MHz, CDCl3) δ 171.3, 170.5, 142.7,
142.3, 142.0, 139.3, 138.8, 133.6, 133.3, 132.7, 132.5, 131.9,
131.4, 130.3, 129.7, 129.5, 129.4, 129.3, 128.7, 128.5, 128.4,
127.9, 127.7, 127.3, 123.5, 123.3, 77.43, 38.9, 38.4, 36.0, 31.1,
22.7, 22.0; HRMS (EI) m/e calcd for C15H14NOBr (Mþ)
303.0259, found 303.0268.
[1,10-Biphenyl]-2-(N-methyl-phenylacetamide), 20-Bromo- (11).
By the general procedure, 4 (480 mg, 1.32 mmol), NaH 60% in
mineral oil (53 mg, 1.32 mmol), MeI (225 mg, 1.59 mmol) in THF
(5 mL) for 10 min afforded 11 (451 mg, 90%) as a white solid after
flash chromatography (SiO2, hexanes/EtOAc = 3/1): IR (cm-1
)
3060, 1658, 1373, 753; 1H NMR (300 MHz, CDCl3) δ 7.71-7.58
(m, 1H), 7.45-7.09 (m, 11.4H), 6.85-6.80 (m, 0.6H), 3.70-3.50
(m, 1.6H), 3.37-3.32 (m, 0.4H), 3.15 (s, 1H), 2.99 (s, 0.3H), 2.86
(s, 1.7H); 13C NMR (75 MHz, CDCl3) δ171.6, 170.9, 142.1, 142.0,
141.6, 139.1, 139.0, 138.9, 135.8, 135.3, 134.5, 133.8, 133.2, 132.9,
132.5, 131.7, 131.4, 130.4, 129.8, 129.7, 129.5, 129.4, 129.1, 129.0,
128.8, 128.7, 128.6, 128.4, 128.1, 127.9, 127.6, 127.5, 127.4, 127.0,
126.8, 126.6, 123.5, 123.3, 77.43, 41.1, 41.0, 38.9, 36.4; HRMS (EI)
m/e calcd for C21H18NOBr (Mþ) 379.0572, found 379.0575.
[1,10-Biphenyl]-2-(N-methyl-propionamide), 20-Bromo- (12). By
the general procedure, 5 (249 mg, 0.82 mmol), NaH 60% in
mineral oil (35 mg, 0.86 mmol), MeI (140 mg, 0.99 mmol) in
THF (10 mL) for 10 min afforded 12 (257 mg, 99%) as a white
solid after flash chromatography (SiO2, hexanes/EtOAc = 1/1):
IR(cm-1) 3058, 2974, 2936, 1660, 1464, 1378, 1285, 753; 1H NMR
(300 MHz, CDCl3) δ 7.67-7.60 (m, 1H), 7.45-7.37 (m, 2H),
7.37-7.28 (m, 2H), 7.27-7.05 (m, 3H), 3.11 (s, 1.08H), 2.97 (s,
0.35H), 2.85 (s, 1.57H), 2.35-2.18 (m, 0.7H), 2.18-2.04 (m,
1.3H), 1.14 (t, J = 7.2 Hz, 1.54H), 1.03 (t, J = 7.2 Hz, 0.40H),
0.95 (t, J = 6.9 Hz, 1.06H); 13C NMR (75 MHz, CDCl3) δ 174.3,
173.7, 142.3, 142.2, 141.7, 139.8, 139.1, 139.0, 138.7, 133.4, 133.1,
132.5, 132.3, 131.5, 131.2, 130.1, 129.5, 129.4, 129.2, 129.1, 128.5,
128.3, 128.2, 127.7, 127.4, 127.1, 127.0, 123.3, 123.1, 38.3, 38.0,
35.9, 27.6, 27.4, 26.9, 9.9, 9.7, 9.1; HRMS (EI) m/e calcd for
C16H16NOBr (Mþ) 317.0415, found 317.0421.
[1,10-Biphenyl]-2-(N-methyl-acetamide), 20-Chloro- (23). By the
general procedure, 22 (271 mg, 1.1 mmol), NaH 60% in mineral
oil (47 mg, 1.155 mmol), MeI (188 mg, 1.32 mmol) in THF (7 mL)
for 10 min afforded 23 (280 mg, 98%) as a white solid after flash
chromatography (SiO2, hexanes/EtOAc = 1/1): IR (cm-1) 3069,
1658, 1373, 1031, 760; 1H NMR (300 MHz, CDCl3) δ 7.48-7.33
(m, 5H), 7.33-7.23 (m, 3H), 7.15 (br, 1H), 3.04 (s, 1.15H), 2.96 (s,
0.44H), 2.85 (s, 1.41H), 2.01-2.00 (m, 0.25H), 1.94 (s, 1.50H),
1.86 (s, 1.25H); 13C NMR (75 MHz, CDCl3) δ 171.0, 170.3, 142.4,
142.0, 137.2, 136.9, 133.0, 132.2, 131.5, 131.2, 130.3, 129.9, 129.4,
129.1, 128.4, 128.2, 127.8, 127.2, 126.9, 126.5, 37.9, 35.9, 22.5, 22.2,
21.9; HRMS (EI) m/e calcd for C15H14NOCl (Mþ) 259.0764,
found 259.0763.
[1,10-Biphenyl]-2-(N-methyl-methoxyacetamide), 20-Bromo- (13).
By the general procedure, 6 (275 mg, 0.86 mmol), NaH 60% in
mineral oil (36 mg, 0.90 mmol), MeI (147 mg, 1.03 mmol) in THF
(8 mL) for 10 min afforded 13 (286 mg, 99%) as an oil after flash
chromatography (SiO2, hexanes/EtOAc = 1/1): IR (cm-1) 3058,
2925, 2820,1676, 1465, 1330, 1103, 754; 1H NMR (300 MHz,
CDCl3) δ 7.68-7.63 (m, 1H), 7.48-7.40 (m, 2H), 7.39-7.17 (m,
5H), 4.09-3.93 (m, 0.75H), 3.88- 3.79 (m, 1.25H), 3.37 (s, 1.45H),
3.28 (s, 0.52H), 3.27 (s, 1.0H), 3.13 (s, 1.1H), 2.98 (s, 0.40H), 2.85 (s,
1.53H); 13C NMR (75 MHz, CDCl3) δ 169.3, 168.7, 141.3, 140.3,
139.8, 139.5, 138.8, 138.6, 138.5, 138.4, 133.4, 133.0 132.6, 132.4,
131.4, 131.2, 131.0, 129.9, 129.5, 129.2, 129.1, 129.0, 128.6, 128.1,
[1,10-Biphenyl]-2-(N-benzyl-acetamide), 20-Bromo- (17). A
mixture of 3 (290 mg, 1.0 mmol) and NaH (60% in mineral
oil, 42 mg, 1.05 mmol) in THF (10 mL) was stirred at room
temperature for 10 min. Benzyl bromide (205 mg, 1.2 mmol) was
added, and the resulting mixture was stirred for 12 h. After
J. Org. Chem. Vol. 75, No. 19, 2010 6449

Pan and Wilcox
JOCArticle
removal of volatile components from the mixture, the resulting
crude product was purified by flash chromatography (SiO2,
hexanes/EtOAc = 1/1) to give 17 (371 mg, 99%) as a white solid:
IR (cm-1) 3060, 1658, 1386, 751; 1H NMR (300 MHz, CDCl3) δ
7.74-7.65 (m, 1H), 7.40-7.32 (m, 3H), 7.32-7.22 (m, 3H),
7.21-7.16 (m, 5H), 6.88 (d, J = 7.8 Hz, 0.24H), 6.75 (d, J = 7.8
Hz, 0.76H), 5.44 (d, J = 18.0 Hz, 0.22H), 5.27 (d, J = 14.1 Hz,
0.78H), 3.90 (d, J = 14.4 Hz, 0.22H), 3.45 (d, J = 14.4 Hz,
0.78H), 2.10 (s, 0.21H), 2.04 (s, 2.14H), 1.95 (s, 0.65H); 13C
NMR (75 MHz, CDCl3) δ 170.4, 139.9, 139.1, 138.7, 137.4,
133.6, 132.8, 131.4, 130.8, 130.4, 130.1, 129.8, 129.4, 129.1,
128.9, 128.5, 128.3, 128.0, 127.8, 127.4, 123.4, 52.9, 50.7, 23.4,
23.0; HRMS (EI) m/e calcd for C21H18NOBr (Mþ) 379.0572,
found 379.0556.
General Procedure for the Palladium-Catalyzed Cyclization of
Dibenzazepinones. A solution of Pd(OAc)2 (3.4 mg, 0.015 mmol),
HPCy3BF4 (5.6 mg, 0.015 mmol) and NaOt-Bu (44 mg, 0.45
mmol) in toluene (1 mL) was stirred at room temperature for
10 min and cooled in a dry ice-acetone bath. The amide as
dibenzazepinone precursor (0.15 mmol) in toluene (0.5 mL) was
added, and the resulting mixture was degassed by oil pump and
refilled with argon. After being stirred at 100 °C for 10 min, the
mixture was cooled to room temperature and purified by flash
chromatography.
5-Phenyl-N-methyl-dibenzazepin-6-one (24). By the general
procedure, 11 (57 mg, 0.15 mmol) gave 24 (44.5 mg, 99%) as a
film after flash chromatography (SiO2, hexanes/EtOAc = 3/1):
IR (cm-1) 2920, 1662, 1366, 705; 1H NMR (300 MHz, CDCl3) δ
7.73-7.70 (m, 0.7H), 7.66-7.59 (m, 1.3H), 7.53-7.46 (m, 2.4H),
7.46-7.28 (m, 3.6H), 7.21-7.18 (m, 0.4H), 7.10-7.04 (m, 0.6H),
6.99-6.87 (m, 3H), 6.71-6.66 (m, 1H), 5.35 (s, 0.6H), 4.65 (s,
0.4H), 3.40 (s, 1.9H), 3.36 (s, 1.1H); 13C NMR (75 MHz, CDCl3)
δ 172.7, 170.8, 142.2, 140.7, 139.3, 138.0, 136.7, 136.6, 136.0,
135.7, 134.6, 134.3, 131.8, 130.7, 130.3, 129.8, 129.4,128.9,
128.7, 128.6, 128.5, 128.2, 128.1, 127.9, 127.6, 127.3, 126.4,
126.2, 125.6, 125.0, 122.7, 122.4, 60.5, 51.5, 37.3, 36.7, 29.9;
HRMS (EI) m/e calcd for C21H17NO (Mþ) 299.1310, found
299.1309.
5-Methoxy-N-methyl-dibenzazepin-6-one (26). By the general
procedure, 13 (50 mg, 0.15 mmol) gave 26 (21 mg, 56%) as a film
after flash chromatography (SiO2, hexanes/EtOAc = 1/2): IR
(cm-1) 3066, 2926, 2831, 1680, 1440, 1212, 1092, 984, 767, 743;
1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 7.5 Hz, 1H), 7.63
(dd, J=7.8, 1.5 Hz, 1H), 7.58 (dd, J=7.5, 1.2 Hz, 1H), 7.54-7.32
(m, 5H), 5.03 (s, 0.05H), 4.54 (s, 0.95H), 3.56 (s, 2.86H), 3.42
(s, 0.14H), 3.35 (s, 2.86H), 3.03 (s, 0.14H); 13C NMR (75
MHz, CDCl3) δ 169.9, 140.8, 137.3, 133.8, 133.5, 130.0, 129.5,
129.0, 128.9, 128.1, 127.9, 125.8, 122.9, 122.8, 78.7, 58.4, 36.5;
HRMS (EI) m/e calcd for C16H15NO2 (Mþ) 253.1103, found
253.1100.
131.3, 131.2, 130.1, 130.0, 129.6, 129.5, 129.2, 129.1, 129.0,
128.9, 128.2, 128.1, 128.0, 127.8, 127.5, 127.4, 127.0, 126.9,
126.8, 126.7, 126.0, 125.9, 124.9, 124.8, 124.7, 124.5, 124.4,
122.3, 122.2, 53.8, 51.9, 50.0, 44.1, 42.4, 42.3, 40.6; HRMS
(EI) m/e calcd for C21H17NO (Mþ) 299.1310, found 299.1301.
5-Benzyloxy-N-methyl-dibenzazepin-6-one (29). By the gener-
al procedure, Pd(OAc)2 (13.6 mg, 0.06 mmol), HPCy3BF4 (22.4
mg, 0.06 mmol), 15 (248 mg, 0.6 mmol) and NaOt-Bu (86.4 mg,
0.9 mmol) in toluene (6 mL) gave 29 (160 mg, 81%) as a film
after flash chromatography (SiO2, hexanes/EtOAc = 3/1): IR
1
(cm-1) 3063, 2926, 1680, 743; H NMR (300 MHz, CDCl3) δ
7.83 (d, J = 7.8 Hz, 1H), 7.60-7.22 (m, 12H), 4.97 (d, J = 11.7
Hz, 1H), 4.75 (s, 1H), 4.59 (d, J = 11.7 Hz, 1H), 3.35 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 169.9, 140.8, 138.0, 137.5, 133.8,
133.5, 130.0, 128.9, 128.9, 128.5, 128.0, 127.9, 127.9, 127.8,
125.8, 123.4, 122.8, 76.7, 72.2, 36.6; HRMS (EI) m/e calcd for
C22H19NO2 (Mþ) 329.1416, found 329.1416.
5-Dibenzylamino-N-methyl-dibenzazepin-6-one (35). By the
general procedure, 16 (75 mg, 0.15 mmol) gave 35 (58 mg,
93%) as a film after flash chromatography (SiO2, hexanes/
EtOAc = 3/1): IR (cm-1) 3061, 3027, 2925, 2245, 1656, 732;
1H NMR (300 MHz, CDCl3) δ 7.58-7.24 (m, 7H), 7.17-7.08
(m, 7H), 6.73-6.67 (m, 4H), 4.67 (s, 1H), 3.42 (d, J = 14.1 Hz,
2H), 3.19 (s, 3H), 3.17 (d, J = 14.4 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 170.7, 141.4, 137.1, 137.0, 136.4, 134.0, 130.4, 129.8,
129.7, 129.4, 129.0, 128.7, 128.0, 127.0, 124.6, 121.9, 77.9, 54.9,
37.5; HRMS (EI) m/e calcd for C29H26N2O (Mþ) 418.2045,
found 418.2042.
5-Benzyl-5-hydroxy-N-methyl-dibenzazepin-6-one (30). In the
cyclization reaction of 15, 30 (4% yield) was separated as a film
after flash chromatography (SiO2, hexanes/EtOAc = 3/1): IR
1
(cm-1) 3387, 2926, 1644, 1352, 763, 736; H NMR (300 MHz,
CDCl3) δ 8.00 (m, 1H), 7.69 (dd, J=7.5, 1.5 Hz, 1H), 7.60-7.41
(m, 4H), 7.41 (td, J = 8.1, 1.2 Hz, 2H), 7.17-7.12 (m, 3H),
6.91-6.86 (m, 2H), 5.27 (s, 1H), 3.39 (s, 3H), 2.73-2.60 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 174.1, 143.0, 140.6, 136.6, 135.0,
134.0, 130.4, 130.0, 129.4, 128.9, 128.9, 128.4, 128.0, 126.8,
126.3, 125.6, 122.7, 78.2, 41.2, 38.6; HRMS (EI) m/e calcd for
C22H19NO2 (Mþ) 329.1416, found 329.1409.
5-Benzyloxy-N-methyl-dihydrodibenzazepine (31). To a solu-
tion of 29 (160 mg, 0.486 mmol) in THF (6 mL) was added a
solution of BH3 Me2S in THF (2 M, 1 mL) at room tempera-
3
ture, and the mixturre was stirred for 2 h. NaOH solution in
H2O (1 M, 2 mL) was added, and the mixture was stirred for
10 min. THF was evaporated under reduced pressure, and the
residue was extracted with Et2O. The extracts were combined,
dried over MgSO4, and filtered. After removal of volatile
components from the filtrate, the resulting crude product was
purified by flash chromatography (SiO2, hexanes/EtOAc = 3/1)
to give 31 (150 mg, 98%) as an oil: IR (cm-1) 3062, 2860,
1596, 1492, 1444, 1181, 755, 698; 1H NMR (300 MHz, CDCl3)
δ 7.57-7.54 (m, 1H), 7.40-7.19 (m, 10H), 7.12 (td, J = 7.5,
1.8 Hz, 1H), 7.04 (dd, J = 7.8, 0.6 Hz, 1H), 4.55 (d, J = 11.4 Hz,
1H), 4.50 (m, 1H), 4.29 (d, J = 11.7 Hz, 1H), 3.62-3.47 (m,
2H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.1,
139.2, 138.5, 138.4, 134.9, 129.0, 128.9, 128.7, 128.5, 127.8,
127.7, 127.5, 127.4, 123.6, 122.7, 118.3, 77.4, 71.8, 68.8, 41.8;
HRMS (EI) m/e calcd for C22H21NO (Mþ) 315.1623, found
315.1609.
5,5-Dimethyl-N-methyl-dibenzazepin-6-one (27). By the gen-
eral procedure, 14 (50 mg, 0.15 mmol) gave 27 (3 mg, 8%) as a
film after flash chromatography (SiO2, hexanes/EtOAc = 1/1):
IR (cm-1) 2926, 1651, 1598, 758, 735; 1H NMR (300 MHz,
CDCl3) δ 7.58-7.52 (m, 3H), 7.45-7.38 (m, 3H), 7.29-7.24 (m,
2H), 3.37 (s, 3H), 1.79 (s, 3H), 0.95 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 175.4, 143.9, 141.9, 136.8, 135.4, 130.0, 129.9, 128.6,
128.5, 127.5, 125.3, 125.1, 122.0, 46.2, 38.5, 26.8, 23.2; HRMS
(EI) m/e calcd for C17H17NO (Mþ) 251.1310, found 251.1305.
N-Benzyl-dibenzazepin-6-one (28). By the general procedure,
17 (57 mg, 0.15 mmol) gave 28 (38 mg, 84%) as a film after flash
chromatography (SiO2, hexanes/EtOAc = 3/1): IR (cm-1)3063,
3029, 1669, 1440, 763, 738; 1H NMR (300 MHz, CDCl3) δ
7.52-7.48 (m, 2H), 7.43-7.37 (m, 3H), 7.37-7.20 (m, 3H),
7.14-7.08 (m, 3H), 6.92-6.87 (m, 2H), 5.19 (d, J = 15.6 Hz,
1H), 4.94 (d, J = 15.6 Hz, 1H), 3.68 (d, J = 12.3 Hz, 1H), 3.55
(d, J = 12.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 171.2,
140.7, 137.6 137.5, 136.7, 135.5, 135.4, 135.1, 135.0, 134.9, 131.4,
5-Hydroxy-N-methyl-dihydrodibenzazepine (32). To a solu-
tion of 31 (90 mg, 0.285 mmol) in 95% ethanol (3 mL) was added
10% palladium on carbon (30 mg, 0.0285 mmol), and the
mixture was stirred at 80 °C under H2 (1 atm) for 14 h. After
being cooled to room temperature, the mixture was filtered
through Celite. After removal of volatile components from the
filtrate, the resulting crude product was purified by flash chro-
matography (SiO2, hexanes/EtOAc = 3/1) to give 32 (54 mg,
85%) as an oil: IR (cm-1) 3345, 2803, 1485, 1443, 1065, 756, 733;
6450 J. Org. Chem. Vol. 75, No. 19, 2010

Pan and Wilcox
JOCArticle
1H NMR (300 MHz, CDCl3) δ 7.53-7.47 (m, 1H), 7.36-7.28
(m, 5H), 7.12 (td, J = 7.8, 1.5 Hz, 1H), 7.05 (dd, J = 8.1, 0.9 Hz,
1H), 4.71 (m, 1H), 3.51 (m, 1H), 3.38 (m, 1H), 2.71 (s, 3H), 2.18
(br, 1H); 13C NMR (75 MHz, CDCl3) δ 149.1, 141.3, 137.7,
134.7, 129.3, 129.0, 128.5, 127.8, 127.7, 122.9, 122.8, 118.4, 70.2,
70.0, 41.8; HRMS (EI) m/e calcd for C15H15NO (Mþ) 225.1154,
found 225.1145.
4.8, 1.2 Hz, 1H), 7.16-7.11 (m, 4H), 7.08 (d, J = 4.8 Hz, 1H),
6.75-6.74 (m, 2H), 3.56 (d, J = 6.9 Hz, 1H), 3.37 (d, J = 6.9 Hz,
1H), 2.98 (d, J = 8.4 Hz, 1H), 2.78 (s, 3H), 2.69 (d, J = 8.1 Hz,
1H), 2.11 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 148.9, 143.0,
137.6, 136.4, 136.2, 130.7, 130.0, 129.2, 128.9, 128.3, 128.0, 127.5,
127.0, 124.6, 123.1, 118.0, 75.4, 74.2, 46.5, 42.1; HRMS (EI) m/e
calcd for C22H22NO (MHþ) 316.1701, found 316.1692.
N-Methyl-dibenzazepin-5-one (33). To a solution of Dess-
Martin reagent (122 mg, 0.289 mmol) in CH2Cl2 (3 mL) was
added a solution of 32 (50 mg, 0.22 mmol) in CH2Cl2 (2 mL) at
0 °C, and the mixture was stirred for 30 min. NaOH solution in
H2O (1 M, 1 mL) was added, and the resulting mixture was
stirred at room temperature for 5 min and extracted with
EtOAc. The extracts were combined, dried over MgSO4, and
filtered. After removal of volatile components from the filtrate,
the resulting crude product was purified by flash chromatogra-
phy (SiO2, hexanes/EtOAc = 3/1) to give 33 (46 mg, 93%) as a
solid: IR (cm-1) 3062, 2830, 1680, 1596, 1300, 757, 732; 1H
NMR (300 MHz, CDCl3) δ 7.86-7.82 (m, 1H), 7.64-7.58 (m,
1H), 7.52-7.36 (m, 4H), 7.23-7.16 (m 2H), 3.95 (s, 2H), 2.90
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 204.5, 150.2, 139.2, 137.4,
133.6, 133.0, 130.9, 130.3, 129.6, 128.6, 127.8, 124.3, 117.3, 72.2,
42.0; HRMS (EI) m/e calcd for C15H13NO (Mþ) 223.0997,
found 223.0995.
The synthesis from 33: to a solution of 33 (28 mg, 0.125 mmol)
in THF (2 mL) was added a solution of benzylmagnesium
chloride (2 M in THF, 69 μL, 0.138 mmol) slowly at rt, the
mixture was stirred for 15 min, and a drop of H2O was added.
After removal of volatile components from the mixture, the
resulting crude product was purified by flash chromatography
(SiO2, hexanes/EtOAc=3/1) to give 34 (23.6 mg, 60%) as an oil.
5-Amino-N-methyl-dibenzazepin-6-one (1). A solution of 35
(30 mg, 0.072 mmol) and 10% palladium on carbon (6.5 mg,
0.0061 mmol) in ethanol (95%, 6 mL) was stirred under H2
(1 atm, balloon) at 90 °C for 12 h. After being cooled to rt, the
mixture was filtered, and the filtrate was extracted with Et2O.
The extracts were combined, dried over MgSO4, and filtered.
After removal of volatile components from the filtrate, the
resulting crude product was purified by flash chromatography
(SiO2, Et2O/EtOH = 10/1) to give 1 (16.7 mg, 98%) as an oil: 1H
NMR (300 MHz, CDCl3) δ 7.65-7.30 (m, 8H), 4.36 (s, 1H), 3.35
(s, 3H), 2.25 (br, 2H).
5-Benzyl-5-hydroxy-N-methyl-dihydrodibenzazepine (34). The
synthesis from 30: to a solution of 30 (6 mg, 0.0183 mmol) in
THF (0.5 mL) was added BH3 Me2S (7.3 μL) at room tempera-
3
Acknowledgment. We thank the Department of Chemistry
and the University of Pittsburgh for support of this investi-
gation.
ture, and the mixture was stirred for 1.5 h. NaOH solution in H2O
(1 M, 1 drop) was added, and the mixture was stirred for 10 min.
After removal of volatile components from the mixture, the
resulting crude product was purified by flash chromatography
(SiO2, hexanes/EtOAc = 3/1) to give 34 (5.7 mg, 99%) as an oil:
IR (cm-1) 3556, 2924, 1496, 1443, 761, 737; 1H NMR (500 MHz,
CDCl3) δ 7.51 (d, J = 4.8 Hz, 1H), 7.47 (dd, J = 4.5, 0.6 Hz, 1H),
7.42-7.39 (m, 2H), 7.37 (td, J = 5.1, 0.9 Hz, 1H), 7.31 (td, J =
Supporting Information Available: General experimental
procedures and copies of 1H/13C NMR spectra for all products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 19, 2010 6451