Synthesis of dibenzo[ b,e ]azepin-11-ones by intramolecular palladium-catalyzed acylation of aryliodides with aldehydes

Article abstract of DOI:10.1021/jo4009244

The paper describes an efficient methodology for the synthesis of diversely functionalized dihydrodibenzo[b,e]azepin-11-ones based on the Pd(0)-catalyzed intramolecular acylation of aryl iodides with aldehydes.

Full text of DOI:10.1021/jo4009244

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Note
Synthesis of Dibenzo[b,e]azepin-11-ones by Intramolecular
Palladium-Catalyzed Acylation of Aryliodides with Aldehydes
Daniel Sole, and Francesco Mariani
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4009244 • Publication Date (Web): 30 Jul 2013
Downloaded from http://pubs.acs.org on August 1, 2013
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Synthesis of Dibenzo[b,e]azepin-11-ones by Intramolecular Palladium-
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Catalyzed Acylation of Aryliodides with Aldehydes
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Daniel Solé,* Francesco Mariani
Laboratori de Química Orgànica, Facultat de Farmàcia, and Institut de
Biomedicina (IBUB), Universitat de Barcelona, 08028-Barcelona, Spain
dsole@ub.edu
Table of Contents
O
R2
I
N
CHO
R1
Pd2(dba)3/ligand
R1
R2
Cs2CO3
toluene, 110 ºC
N
R
R
Pd(0)-catalyzed acylation
Abstract
The paper describes an efficient methodology for the synthesis of diversely
functionalized dihydrodibenzo[b,e]azepinꢀ11ꢀones based on the Pd(0)ꢀcatalyzed
intramolecular acylation of aryl iodides with aldehydes.
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Palladiumꢀcatalyzed coupling reactions are wellꢀestablished as reliable carbonꢀ
carbon bondꢀforming tools both in the research laboratory and in largeꢀscale industrial
production.1 Among the variety of available crossꢀcoupling processes, the palladiumꢀ
catalyzed nucleophilic additions of aryl halides2ꢀ8 and arylboronic acids9ꢀ13 to carbonꢀ
heteroatom multiple bonds have been attracting increasing interest in recent years and
are now emerging as powerful synthetic methodologies.
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As part of our ongoing research on the synthesis of nitrogen heterocycles by means of
palladiumꢀcatalyzed intramolecular coupling reactions of aryl halides and carbonyl
compounds,14 we have been studying the possibility of controlling the ambiphilic
character of the σꢀarylpalladium species involved in these reactions.7,8,15,16 In this
context, we have recently reported that when starting from (2ꢀiodoanilino) aldehydes,
both the enolate arylation and the acylation of the aryl halide can also be selectively
promoted by Pd(0) with only a slight modification of the reaction conditions.17 The
latter acylation reaction seems to proceed through a mechanism involving a
carbopalladation between the σꢀarylpalladium(II) moiety and the carbonyl group,
followed by a βꢀhydride elimination from the resulting Pd(II) alkoxide intermediate.
Besides its mechanistic implications, this reaction has considerable synthetic interest
because it could constitute an alternative to classical acylation methodologies such as
the FriedelꢀCrafts reaction, whose intrinsic problems of regioselectivity often decrease
its effectiveness in the synthesis of unsymmetrically substituted derivatives.18
Moreover, it also provides an alternative to our previously reported palladiumꢀcatalyzed
acylation of aryl halides by esters7 and amides.8 As these palladiumꢀcatalyzed reactions
involve the nucleophilic attack of the σꢀarylpalladium(II) species at the carbonyl group,
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the use of the more electrophilic aldehydes as the acylating agents would result in a
more efficient methodology.
8
9
To demonstrate the potential of the palladiumꢀcatalyzed acylation reaction with
aldehydes,3,19 we envisioned the synthesis of polycyclic compounds containing the
dibenzo[b,e]azepine moiety (Scheme 1). The dibenzo[b,e]azepine system has attracted
considerable attention due to its ubiquitous presence in the molecular structure of
important bioactive compounds.20 Therefore, the development of reliable methodologies
for the construction of the dibenzo[b,e]azepine skeleton would be highly useful in the
field of synthetic organic chemistry.21 In particular, palladiumꢀcatalyzed annulation
reactions have provided some attractive and valuable routes for the synthesis of
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dibenzo[b,e]azepine derivatives.22
O
R2
X
CHO
R2
R1
R1
Pd(0)
N
N
R
R
Scheme 1
We commenced our investigation by studying the acylation reactions of aldehydes 1a
and 1b (Table 1). We were pleased to find that starting from iodoaniline 1a, the
acylation can be smoothly promoted by using 5 mol % of Pd2(dba)3, 10 mol % of the
phosphine ligand, and Cs2CO3 as the base in toluene at high temperature. As also
observed in our initial studies with (2ꢀiodoanilino) aldehydes,17 sterically hindered
phosphines (i. e. dtpf, tBu3P and (oꢀtolyl)3P) proved to be highly efficient ligands for the
acylation, and afforded dihydrodibenzo[b,e]azepinꢀ11ꢀone 1123 in 75% average yield
(table 1, entries 1ꢀ3). The use of the same combination of catalyst and base in either
acetonitrile or DMF was found to be less effective in promoting the acylation reaction
(entries 4 and 5). Bromide 1b was less efficient than iodide 1a in the annulation
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reaction, and longer reaction times were required to reach the total conversion of the
starting material (entries 6ꢀ8).
8
9
Although the acylation can be carried out effectively in toluene under simple thermal
heating, the long reaction times required for the full conversion of the starting material,
especially when starting from bromide 1b, prompted us to also explore the reaction
under microwave irradiation (entries 9ꢀ13).
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TABLE 1. Optimization of Acylation Reaction Conditions
O
X
CHO
Pd2(dba)3/ligand
N
Cs2CO3, Et3N
N
Me
Me
11
X = I, 1a
X = Br, 1b
entry aldehyde
ligand
solvent
tolueneb 24 h
(tBu)3PꢁHBF4 tolueneb 24 h
time
1H NMR ratio yield (%)a
11 (77%)
1
1a
1a
1a
1a
1a
1b
1b
1b
1a
1a
1a
1b
1b
dtpf
2
11 (71%)
3
(oꢀtolyl)3P
dtpf
tolueneb 36 h
CH3CNb 24 h
11 (75%)
4
11 (32%)
5
dtpf
dtpfc
DMFb
tolueneb 36 h
24 h
11 (34%)
6
1b:11 (5:1)
1b:11 (1:1.1)
11 (48%)
c
7
(tBu)3PꢁHBF4 tolueneb 72 h
(oꢀtolyl)3Pc
8
tolueneb 120 h
toluened 60 min 1a:11 (3:1)
dioxaned 60 min 1a:11 (3.5:1)
9
dtpf
10
11
12
dtpf
dtpf
DMFd
DMFd
30 min
11 (35%)
11 (37%)
11 (34%)
dtpf
30 min
13
dtpf
CH3CNd 30 min
a
Yields refer to pure products isolated by flash chromatography. b The reactions were carried
out using Pd2(dba)3 (0.05 equiv), ligand (0.1 equiv), Cs2CO3 (3 equiv) and Et3N (6 equiv) in the
indicated solvent at 110 ºC in a sealed tube. c 0.075 equiv of Pd2(dba)3 and 0.15 equiv of ligand
d
were used. The reactions were carried out using Pd2(dba)3 (0.05 equiv), ligand (0.1 equiv),
Cs2CO3 (1 equiv) and Et3N (3 equiv) in the indicated solvent at 120 ºC in a sealed vessel in a
microwave reactor (fixed temperature, variable pressure).
Under microwaveꢀmediated heating, the use of low absorbing solvents24 such as toluene
and dioxane resulted in poor conversions (entries 9ꢀ10). On the other hand, when using
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DMF as the solvent, although the starting material was completely consumed in 30 min,
dibenzoazepinone 11 was obtained in low yield (entries 11ꢀ12). Similar results were
obtained when using K3PO4 or KOAc as the base instead of Cs2CO3, and (oꢀtolyl)3P or
tBu3P as the ligand (not shown in the table). Performing the reaction in acetonitrile also
resulted in the complete conversion of the starting material, but 11 was again isolated
only in modest yield (entry 13). It should be noted, however, that none of the
experiments summarized in Table 1 yielded any observable products other than ketone
11 or the nonꢀreacted starting material.
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To compare the effectiveness of the palladiumꢀcatalyzed acylation with aldehydes with
our previously reported procedure using esters as the acylating agents, we decided to
prepare ester 1c (Scheme 2). 1c failed to undergo acylation reaction when submitted to
the conditions optimized with esters [Pd(PPh3)4 and K3PO4 in toluene at 110 ºC]7 as
well as to the new reaction conditions [Pd2(dba)3/ligand (dtpf, or (oꢀtolyl)3P) and
Cs2CO3 in toluene at 110 ºC]. In all the experiments only minor amounts of the
hydrodehalogenation product7 were observed together with the unreacted starting
material.
O
I
CO2Me
Pd(0)
N
(see text)
N
Me
Me
11
1c
Scheme 2
As shown in Tables 2 and 3, a variety of diversely substituted substrates was
investigated under the standard thermal heating conditions using toluene as the solvent.
TABLE 2. Synthesis of 5,6-dihydrodibenzo[b,e]azepin-11-onesa
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R2
R3
I
O
CHO
R4
R2
R4
Pd2(dba)3/ligand
N
R1
Cs2CO3, Et3N
R3
N
R1
toluene, 110 ºC
R1 = Bn, R2 = Me, R3 = R4 = H, 2
R1 = Me, R2 = MeO, R3 = R4 = H, 3
R1 = Me, R2 = R4 = H, R3 = F, 4a
R1 = Me, R2 = R4 = H, R3 = Cl, 4b
R1 = Me, R2 = R4 = H, R3 = CH2OH, 4c
R1 = Me, R2 = R4 = H, R3 =CHO, 4d
R1 = Me, R2 = R4 = H, R3 = CH2OAc, 4e
R1 = Me, R2 = R4 = H, R3 = CH2NMe2, 4f
R1 = Me, R2 = R3 = H, R4 = F, 5
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14a
14b
14c
14d
14e
14f
15
R1 = BOC, R2 = R3 = R4 = H, 6
entry aldehyde
ligand
dtpf
time yield (%)b
1
2
24 h 12 (91%)
(tBu)3PꢁHBF4 24 h 12 (77%)c
2
2
3
2
(oꢀtolyl)3P
36 h 12 (62%)
4
3
dtpf
36 h 13 (60%)
(tBu)3PꢁHBF4 48 h 13 (55%)
5
3
6
3
(oꢀtolyl)3P
48 h 13 (51%)
48 h 14a (74%)
(tBu)3PꢁHBF4 60 h 14a (71%)
dtpf
36 h 14b (60%)d
(tBu)3PꢁHBF4 72 h 14b (79%)
7
4a
4a
4b
4b
4b
4c
4c
4d
4d
4e
4e
4f
5
dtpf
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
(oꢀtolyl)3P
72 h 14b (65%)d
24 h 14c (71%)e
dtpf
(tBu)3PꢁHBF4 24 h 14 c (53%)f
dtpf 36 h 14d (53%)
(tBu)3PꢁHBF4 48 h 14d (46%)
dtpf 24 h 14e (59%)
(tBu)3PꢁHBF4 48 h 14e (67%)
dtpf
24 h 14f (69%)
dtpf
36 h 15 (87%)
(tBu)3PꢁHBF4 36 h 15 (72%)
5
5
(oꢀtolyl)3P
dtpf
36 h 15 (55%)
24 h ---
6
23
6
(oꢀtolyl)3P
24 h ---
a
The reactions were carried out using Pd2(dba)3 (0.05 equiv), ligand (0.1 equiv), Cs2CO3 (3
b
equiv) and Et3N (6 equiv) in toluene at 110 ºC in a sealed tube. Yields refer to pure products
isolated by flash chromatography. c Traces of 2 (≤ 5%) were also observed in the crude reaction
mixture. d Traces of 5 (≤ 5%) were also observed in the crude reaction mixture. e 14d (9%) was
also isolated. f 14d (15%) was also isolated.
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In general, the introduction of substituents on the aniline ring (Table 1) had little effect
on the success of the acylation reaction. Thus, the nucleophilicity of the aryl palladium
intermediate does not appear to be significantly affected by the electronic properties of
the substituent on the aromatic ring. Interestingly, the same behavior has also been
observed in the closely related palladiumꢀcatalyzed acylation reaction with esters.7 The
functional group tolerance of the reaction is well illustrated by the fact that halides,
ethers, esters, aldehydes, free hydroxyl and dimethylamino groups all were perfectly
accommodated. I should be noted, however, that in the acylation reactions of 4c, minor
amounts of aldehyde 14d, resulting from the palladiumꢀcatalyzed oxidation of alcohol
14c,17 were also isolated. The successful preparation of 14f indicates that the Pd
catalytic species are not deactivated by the presence of strong coordinating
dialkylamino group.
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The effect of the substituent at the aniline nitrogen atom was also examined. While the
methyl and benzyl groups were well tolerated in the acylation reaction, changing the
substituent at the nitrogen from alkyl to the electronꢀwithdrawing tertꢀbutoxycarbonyl
group resulted in the formation of complex reaction mixtures in which no acylation
compound could be identified (entries 22 and 23).
The palladiumꢀcatalyzed acylation was also extended to the preparation of naphthoꢀ
fused derivatives, which are attractive for their potential antitumor activity.20a As can be
seen in Table 3, both iodoanilines and iodonaphthylamines can be used for this purpose,
although the acylation from the latter proceeded more slowly.
Regarding ligands, as shown in Tables 1ꢀ3, the three sterically hindered phosphines
used in this work proved to be similarly effective in promoting the acylation reaction.
On the whole, dtpf25 seems to be the most versatile ligand, despite not always giving the
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highest yield. On the other hand, the use of (oꢀtolyl)3P as the ligand usually resulted in
lower reaction rates, as reflected in the longer reaction times required for the complete
consumption of the starting material.
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TABLE 3. Synthesis of tetracyclic ketonesa
entry
aldehyde
ligand
yield (%)b
I
O
N
Me
OHC
7
N
16
Me
1
2
7
7
dtpfc
(tBu)3PꢁHBF4
16 (61%)
16 (56%)
c
I
O
CHO
N
8
Me
N
Me
17
3
4
5
8
8
8
dtpfc
(tBu)3PꢁHBF4
17 (58%)
17 (33%)
17 (44%)
(oꢀtolyl)3P
CHO
Me
N
N
I
Me
9
O
18
6
7
8
9
9
9
dtpf
(tBu)3PꢁHBF4
18 (70%)
18 (87%)
18 (90%)
(oꢀtolyl)3P
CHO
Me
Me
N
N
I
O
10
19
9
10
10
10
dtpfc
(tBu)3PꢁHBF4
19 (64%)
19 (63%)
10 + 19 (1.5:1)d
10
11
(oꢀtolyl)3P
a
The reactions were carried out using Pd2(dba)3 (0.05 equiv), ligand (0.1 equiv), Cs2CO3 (3
b
equiv) and Et3N (6 equiv) in toluene at 110 ºC for 72 h in a sealed tube. Yields refer to pure
products isolated by flash chromatography. c 24 h. d 1H NMR ratio, yield not quantified.
In summary, we have demonstrated that the palladiumꢀcatalyzed intramolecular
acylaton of aryl iodides with aldehydes constitutes an efficient methodology for the
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synthesis of dihydrodibenzo[b,e]azepinꢀ11ꢀones. The present reaction is a valuable
synthetic alternative to our previously reported palladiumꢀcatalyzed acylation of aryl
halides by esters and amides.
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Experimental Section
General Methods. Chromatography refers to flash chromatography on silica
1
gel. Hꢀ and 13C NMR spectra were recorded in CDCl3 solution. Chemical shifts are
reported in ppm downfield (δ) from Me4Si.
2-[N-(2-Iodophenyl)-N-methylaminomethyl]benzaldehyde (1a). A mixture of 2ꢀ
iodoꢀNꢀmethylaniline26 (0.25 g, 1.07 mmol), K2CO3 (0.23 g, 1.62 mmol), and 2ꢀ
(bromomethyl)benzonitrile (0.21 g, 1.07 mmol) in acetonitrile (20 mL) was stirred at
reflux for 120 h: every 24 h a new portion of 2ꢀ(bromomethyl)benzonitrile (0.1 g, 0.51
mmol) was added. The mixture was concentrated, and the residue was partitioned
between water and CH2Cl2. The organic layer was dried and concentrated. The residue
was purified by chromatography (from hexanes to 97:3 hexanesꢀEtOAc) to give 2ꢀ[Nꢀ
(2ꢀiodophenyl)ꢀNꢀmethylaminomethyl]benzonitrile (315 mg, 85%).
To a cooled (0ºC) solution of 2ꢀ[Nꢀ(2ꢀiodophenyl)ꢀNꢀmethylaminomethyl]benzonitrile
(315 mg, 0.9 mmol) in CH2Cl2 (5 mL), a 1.0 M solution of DIBALꢀH in hexanes (1.35
mL, 1.35 mmol) was added dropꢀwise under Argon. The resulting solution was stirred
at room temperature for 3 h, cooled again, and poured into a mixture of ice and 6 N
HCl. The mixture was vigorously stirred for 1 h and then extracted with CH2Cl2. The
organic extracts were washed with 1 N NaHCO3 aqueous solution, dried and
concentrated. The residue was purified by chromatography (from hexanes to 97:3
hexanesꢀEtOAc) to give 1a (140 mg, 44%) as a yellow oil. 1H NMR (300 MHz) δ 2.67
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(s, 3H), 4.57 (s, 2H), 6.81 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 7.18 (dd, J = 8.1, 1.5 Hz, 1H),
7.32 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.58 (td, J = 7.5, 1.5 Hz,
1H), 7.77 (d, J = 7.5 Hz, 1H), 7.84ꢀ7.90 (m, 2H), 10.30 (s, 1H). 13C NMR (75.4 MHz) δ
42.8, 57.2, 98.5, 122.4, 125.8, 127.5, 129.0, 130.4, 131.5, 133.5, 134.3, 140.1, 140.6,
153.7, 192.6. IR (NaCl) ν 1693 cmꢀ1. HRMS (ESIꢀTOF) cald for C15H15INO: 352.0193
[M+H]+; found: 352.0191.
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2-[N-(2-Bromophenyl)-N-methylaminomethyl]benzaldehyde (1b). A mixture of 2ꢀ
bromoaniline (0.5 g, 2.9 mmol), K2CO3 (0.6 g, 4.35 mmol), and 2ꢀ
(bromomethyl)benzonitrile (0.57 g, 2.9 mmol) in acetonitrile (40 mL) was stirred at
reflux for 24 h. The mixture was concentrated, and the residue was partitioned between
water and CH2Cl2. The organic layer was dried and concentrated. The residue was
purified
by
chromatography
(CH2Cl2)
to
give
2ꢀ[Nꢀ(2ꢀ
bromophenyl)aminomethyl]benzonitrile (0.54 g, 65%).
A mixture of 2ꢀ[Nꢀ(2ꢀbromophenyl)aminomethyl]benzonitrile (0.54 g, 1.88 mmol),
K2CO3 (0.52 g, 3.76 mmol), and iodomethane (1.0 mL, 16.0 mmol) in acetonitrile (5
mL) was stirred at 80°C in a sealed tube for 2 days. The mixture was concentrated, and
the residue was partitioned between water and CH2Cl2. The organic layer was dried and
concentrated. The residue was purified by chromatography (from hexanes to 95:5
hexanesꢀEtOAc) to give 2ꢀ[Nꢀ(2ꢀbromophenyl)ꢀNꢀmethylaminomethyl]benzonitrile
(0.39 g, 69%).
1b (140 mg, 54%) was obtained starting from 2ꢀ[Nꢀ(2ꢀbromophenyl)ꢀNꢀ
methylaminomethyl]benzonitrile (0.26 g, 0.86 mmol) and operating as in the
preparation of 1a. Chromatography: from hexanes to 95:5 hexanesꢀEtOAc. Brown solid.
1H NMR (400 MHz) δ 2.69 (s, 3H), 4.60 (s, 2H), 6.92 (ddd, J = 8.4, 7.6, 1.6 Hz, 1H),
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7.16 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 (m, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0
Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H),
10.27 (s, 1H). 13C NMR (100.5 MHz) δ 41.5, 57.0, 120.3, 122.3, 124.7, 127.4, 128.1,
129.9, 131.8, 133.6, 133.9, 134.3, 140.9, 150.9, 192.6. IR (NaCl) ν 1693 cmꢀ1. HRMS
(ESIꢀTOF) cald for C15H15BrNO: 304.0332 [M+H]+; found: 304.0333.
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Compounds 1c and 2 were prepared according to the preparation of 1a.
Methyl 2-[N-(2-iodophenyl)-N-methylaminomethyl]benzoate (1c). Chromatography:
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from hexanes to 95:5 hexanesꢀEtOAc. Pale yellow oil. H NMR (300 MHz) δ 2.64 (s,
3H), 3.84 (s, 3H), 4.53 (s, 2H), 6.78 (ddd, J = 8.1, 7.5, 1.5 Hz, 1H), 7.15 (dd, J = 8.1,
1.5 Hz, 1H), 7.25ꢀ7.34 (m, 2H), 7.51 (td, J = 7.5, 1.5 Hz, 1H), 7.83ꢀ7.91 (m, 3H). 13C
NMR (75.4 MHz) δ 42.5, 52.0, 58.4, 98.1, 122.2, 125.3, 126.6, 129.0, 129.7, 130.1,
130.4, 131.8, 140.0, 140.1, 154.4, 168.0. HRMS (ESIꢀTOF) cald for C16H17INO2:
382.0304 [M+H]+; found: 382.0306.
2-[N-Benzyl-N-(2-iodo-4-methylphenyl)aminomethyl]benzaldehyde
(2).
1
Chromatography: from hexanes to 9:1 hexanesꢀEtOAc. Colorless oil. H NMR (300
MHz) δ 2.21 (s, 3H), 4.11 (s, 2H), 4.49 (s, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.98 (dd, J =
7.8, 2.1 Hz, 1H), 7.21ꢀ7.41 (m, 6H), 7.48 (td, J = 7.5, 1.5 Hz, 2H), 7.59 (d, J = 7.8 Hz,
1H), 7.67 (dd, J = 2.1, 0.6 Hz, 1H), 7.80 (dd, J = 7.8, 1.5 Hz, 1H), 10.13 (s, 1H). 13C
NMR (75.4 MHz) δ 20.2, 52.8, 59.0, 99.9, 124.2, 127.3, 127.4, 128.2, 129.1, 129.4,
130.8, 130.9, 133.3, 134.4, 136.2, 137.3, 140.3, 140.4, 148.2, 192.3. IR (NaCl) ν 1693
cmꢀ1. HRMS (ESIꢀTOF) cald for C22H21INO: 442.0662 [M+H]+; found: 442.0655.
Compounds 3, 4a-c, 5 and 8-10 were prepared according to the preparation of 1b
starting from the corresponding oꢀiodoarylamines.27ꢀ30
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2-[N-(2-Iodo-4-methoxyphenyl)-N-methylaminomethyl]benzaldehyde
(3).
1
6
Chromatography: CH2Cl2. Brown solid. H NMR (300 MHz) δ 2.59 (s, 3H), 3.75 (s,
3H), 4.47 (s, 2H), 6.87 (dd, J = 8.7, 3.0 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.37 (d, J =
3.0 Hz, 1H), 7.41 (td, J = 7.5, 0.9 Hz, 1H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.70 (d, J =
7.5 Hz, 1H), 7.87 (dd, J = 7.5, 1.2 Hz, 1H), 10.34 (s, 1H). 13C NMR (75.4 MHz) δ 43.4,
55.6, 57.5, 99.7, 114.8, 122.7, 124.6, 127.5, 130.6, 131.0, 133.4, 134.3, 140.7, 146.7,
158.7, 192.6. IR (NaCl) ν 1693 cmꢀ1. HRMS (ESIꢀTOF) cald for C16H17INO2: 382.0298
[M+H]+; found: 382.0290.
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2-[N-(5-Fluoro-2-iodophenyl)-N-methylaminomethyl]benzaldehyde
(4a).
Chromatography: CH2Cl2. Yellow oil. 1H NMR (300 MHz) δ 2.67 (s, 3H), 4.56 (s, 2H),
6.59 (ddd, J = 8.7, 7.8, 3.0 Hz, 1H), 6.90 (dd, J = 10.5, 3.0 Hz, 1H), 7.45 (td, J = 7.5,
1.2 Hz, 1H), 7.59 (td, J = 7.5, 1.5 Hz, 1H), 7.77 (dd, J = 8.7, 6.3 Hz, 1H), 7.78 (d, J =
7.8 Hz, 1H), 7.87 (dd, J = 7.5, 1.5 Hz, 1H), 10.27 (s, 1H). 13C NMR (75.4 MHz) δ 42.5,
57.2, 90.3 (d, J = 4.1 Hz), 109.9 (d, J = 23.0 Hz), 112.8 (d, J = 21.9 Hz), 127.6, 130.2,
132.2, 133.6, 134.2, 140.1, 140.6 (d, J = 9.2 Hz), 155.5 (d, J = 8.1 Hz), 163.6 (d, J =
248.0 Hz), 192.7. IR (NaCl) ν 1692 cmꢀ1. HRMS (ESIꢀTOF) cald for C15H14FINO:
370.0099 [M+H]+; found: 370.0110.
2-[N-(5-Cloro-2-iodophenyl)-N-methylaminomethyl]benzaldehyde
(4b).
1
Chromatography: from hexanes to 95:5 hexanesꢀEtOAc. Yellow oil. H NMR (300
MHz) δ 2.66 (s, 3H), 4.55 (s, 2H), 6.81 (dd, J = 8.1, 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz,
1H), 7.47 (td, J = 7.8, 1.2 Hz, 1H), 7.59 (td, J = 7.8, 1.5 Hz, 1H), 7.75 (d, J = 8.1 Hz,
1H), 7.78 (d, J = 7.8 Hz, 1H), 7.87 (dd, J = 7.8, 1.5 Hz, 1H), 10.27 (s, 1H). 13C NMR
(75.4 MHz) δ 42.5, 57.2, 95.0, 122.8, 125.7, 127.6, 130.2, 132.2, 133.6, 134.2, 134.9,
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140.2, 140.7, 155.1, 192.6. IR (NaCl) ν 1699 cmꢀ1. HRMS (ESIꢀTOF) cald for
C15H14ClINO: 385.9803 [M+H]+; found: 385.9797.
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2-[N-(5-Hydroxymethyl-2-iodophenyl)-N-methylaminomethyl]benzaldehyde (4c).
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Chromatography: from CH2Cl2 to CH2Cl2ꢀMeOH 1%. Colorless oil. H NMR (400
MHz) δ 1.98 (broad s, 1H), 2.65 (s, 3H), 4.55 (s, 2H), 4.63 (s, 2H), 6.81 (dd, J = 8.0, 2.0
Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.43 (td, J = 7.6, 0.8 Hz, 1H), 7.58 (td, J = 7.6, 1.6
Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.6, 1.6 Hz,
1H), 10.25 (s, 1H). 13C NMR (100.5 MHz) δ 42.6, 57.2, 64.6, 96.9, 120.9, 124.3, 127.6,
130.5, 131.5, 133.5, 134.3, 140.1, 140.6, 142.3, 153.9, 192.6. IR (NaCl) ν 1682, 3400
cmꢀ1. HRMS (ESIꢀTOF) cald for C16H17INO2: 382.0298 [M+H]+; found: 382.0298.
2-[N-(5-Formyl-2-iodophenyl)-N-methylaminomethyl]benzaldehyde
(4d)
was
1
prepared from 4c (Swern oxidation). Chromatography: CH2Cl2. Yellow oil. H NMR
(400 MHz) δ 2.72 (s, 3H), 4.63 (s, 2H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (td, J = 7.6,
0.8 Hz, 1H), 7.58 (td, J = 7.6, 1.6 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.0 Hz,
1H), 7.88 (dd, J = 7.6, 1.6 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 9.95 (s, 1H), 10.29 (s, 1H).
13C NMR (100.5 MHz) δ 42.5, 57.3, 106.7, 121.5, 126.8, 127.7, 130.3, 132.1, 133.6,
134.2, 137.2, 140.0, 141.2, 154.9, 191.3, 192.6. IR (NaCl) ν 1681, 1704 cmꢀ1. HRMS
(ESIꢀTOF) cald for C16H15INO2: 380.0142 [M+H]+; found: 380.0135.
2-[N-(5-Acetoxymethyl-2-iodophenyl)-N-methylaminomethyl]benzaldehyde
(4e)
was prepared from 4c (AcCl). Chromatography: CH2Cl2. Pale yellow oil. 1H NMR (400
MHz) δ 2.11 (s, 3H), 2.67 (s, 3H), 4.56 (s, 2H), 5.03 (s, 2H), 6.81 (dd, J = 8.0, 1.6 Hz,
1H), 7.15 (d, J = 1.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.57 (td, J = 7.6, 1.6 Hz, 1H),
7.77 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 7.6, 1.2 Hz, 1H), 10.28
(s, 1H). 13C NMR (100.5 MHz) δ 20.9, 42.6, 57.2, 65.5, 97.8, 122.1, 125.5, 127.5,
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130.4, 131.6, 133.5, 134.3, 137.2, 140.3, 140.4, 153.9, 170.6, 192.6. IR (NaCl) ν 1693,
1738 cmꢀ1. HRMS (ESIꢀTOF) cald for C18H19INO3: 424.0404 [M+H]+; found:
424.0394.
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2-[N-(5-Dimethylaminomethyl-2-iodophenyl)-N-methylaminomethyl]benzaldehyde
(4f) was prepared from 4c (a. MsCl, b. Me2NH). Chromatography: from CH2Cl2 to
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CH2Cl2ꢀMeOH 8%. Brown oil. H NMR (400 MHz) δ 2.29 (s, 6H), 2.68 (s, 3H), 3.46
(s, 2H), 4.58 (s, 2H), 6.77 (dd, J = 8.0, 2.0 Hz, 1H), 7.22 (s, 1H), 7.42 (t, J = 7.6 Hz,
1H), 7.55 (td, J = 7.6, 1.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H),
7.87 (dd, J = 7.6, 1.6 Hz, 1H), 10.32 (s, 1H). 13C NMR (100.5 MHz) δ 42.8, 45.2, 57.1,
63.6, 96.5, 123.0, 126.5, 127.5, 130.5, 131.1, 133.4, 134.3, 139.8, 140.0, 140.7, 153.6,
192.5. IR (NaCl) ν 1693 cmꢀ1. HRMS (ESIꢀTOF) cald for C18H22IN2O: 409.0771
[M+H]+; found: 409.0774.
4-Fluoro-2-[N-(2-iodophenyl)-N-methylaminomethyl]benzaldehyde
(5).
1
Chromatography: CH2Cl2. Green oil. H NMR (400 MHz) δ 2.69 (s, 3H), 4.57 (s, 2H),
6.82 (ddd, J = 8, 7.2, 1.6 Hz, 1H), 7.10 (td, J = 8, 2.8 Hz, 1H), 7.19 (dd, J = 8, 1.6 Hz,
1H), 7.32 (ddd, J = 8, 7.2, 1.6 Hz, 1H), 7.66 (dd, J = 10.4, 2.4 Hz, 1H), 7.87 (m, 2H),
10.18 (s, 1H). 13C NMR (100.5 MHz) δ 42.7, 57.2 (d, J = 1.5 Hz), 98.4, 114.4 (d, J =
21.4 Hz), 117.4 (d, J = 22.9 Hz), 122.4, 126.0, 129.2, 130.6 (d, J = 2.3 Hz), 135.2 (d, J
= 9.9 Hz), 140.2, 144.8 (d, J = 8.4 Hz), 153.6, 166.0 (d, J = 255.8 Hz), 191.1. IR (NaCl)
ν 1694 cmꢀ1. HRMS (ESIꢀTOF) cald for C15H14FINO: 370.0099 [M+H]+; found:
370.0096.
2-[N-(tert-Butoxycarbonyl)-N-(2-iodophenyl)aminomethyl]benzaldehyde (6).
A
solution of Nꢀ(tertꢀbutoxycarbonyl)ꢀ2ꢀiodoaniline (0.4 g, 1.25 mmol) in THF (2 mL)
was added at 0ºC under Argon to a suspension of NaH (60% in oil, 65 mg, 1.63 mmol)
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in THF (8 mL). After 15 min at 25ºC, the mixture was cooled again to 0ºC. DMF (2
mL) and 2ꢀ(bromomethyl)benzaldehyde (325 mg, 1.63 mmol) were added and the
mixture was stirred for 10 min at 0ºC and at 25ºC overnight. Saturated aqueous NH4Cl
was added and the mixture was extracted with EtOAc. The organic extracts were dried
and concentrated. The residue was purified by chromatography (from hexanes to 8:2
hexanesꢀEtOAc) to give 6 (265 mg, 48%) as an orange oil. 1H NMR (400 MHz, mixture
of rotamers) δ 1.38 (s, 9H), 4.91 (d, J = 16 Hz, 1H), 5.48 (d, J = 16 Hz, 1H), 6.77ꢀ7.84
(m, 8H), 10.12 (s, 1H). 13C NMR (100.5 MHz, major rotamer) δ 28.2, 48.6, 80.8, 100.3,
127.9, 128.6, 128.8, 129.8, 130.7, 130.9, 133.7, 134.3, 139.6, 143.5, 153.9, 192.1.
HRMS (ESIꢀTOF) cald for C19H21INO3: 438.0561 [M+H]+; found: 438.0549.
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3-[N-(2-Iodophenyl)-N-methylaminomethyl]-2-naphthaldehyde (7). A mixture of 2ꢀ
iodoꢀNꢀmethylaniline (150 g, 0.68 mmol), 3ꢀ(bromomethyl)ꢀ2ꢀnaphthaldehyde31 (115
mg, 0.46 mmol) and 2,6ꢀlutidine (80 ꢀL ,0.68 mmol) was stirred at 100ºC for 6 h. The
reaction mixture was partitioned between water and Et2O. The organic layer was dried
and concentrated. The residue was purified by chromatography (from hexanes to 95:5
hexanesꢀEtOAc) to give 7 (130 mg, 70%) as an orange oil. 1H NMR (300 MHz) δ 2.72
(s, 3H), 4.70 (s, 2H), 6.80 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 7.25 (dd, J = 7.8, 1.5 Hz, 1H),
7.33 (ddd, J = 7.8, 7.2, 1.5 Hz, 1H), 7.54 (td, J = 7.2, 1.2 Hz, 1H), 7.62 (td, J = 7.2, 1.2
Hz, 1H), 7.86 (dd, J = 7.8, 1.5 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.8 Hz,
1H), 8.17 (s, 1H), 8.39 (s, 1H), 10.36 (s, 1H). 13C NMR (75.4 MHz) δ 43.0, 57.8, 98.5,
122.4, 125.7, 126.7, 127.8, 129.1 (2 CH), 129.2, 129.4, 131.7, 132.7, 135.2, 135.3,
135.5, 140.1, 154.0, 192.9. IR (NaCl) ν 1692 cmꢀ1. HRMS (ESIꢀTOF) cald for
C19H17INO: 402.0349 [M+H]+; found: 402.0355.
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2-[N-(3-Iodo-2-naphthyl)-N-methylaminomethyl]benzaldehyde
(8).
1
Chromatography: from hexanes to 95:5 hexanesꢀEtOAc. Yellow solid. H NMR (300
MHz) δ 2.73 (s, 3H), 4.66 (s, 2H), 7.35ꢀ7.48 (m, 3H), 7.52 (s, 1H), 7.57 (ddd, J = 7.8,
7.2, 1.5 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 7.8 Hz,
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1H), 7.87 (dd, J = 7.8, 1.2 Hz, 1H), 8.40 (s, 1H), 10.32 (s, 1H). C NMR (75.4 MHz) δ
43.3, 57.5, 98.0, 119.0, 125.4, 126.4, 126.7, 127.0, 127.5, 130.4, 131.7, 132.1, 133.5,
133.6, 134.3, 139.7, 140.6, 150.5, 192.7. IR (NaCl) ν 1691 cmꢀ1. HRMS (ESIꢀTOF)
cald for C19H17INO: 402.0349 [M+H]+; found: 402.0342.
2-[N-(1-Iodo-2-naphthyl)-N-methylaminomethyl]benzaldehyde
(9).
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Chromatography: from hexanes to 1:1 hexanesꢀCH2Cl2. Yellow oil. H NMR (400
MHz) δ 2.79 (s, 3H), 4.69 (s, 2H), 7.40ꢀ7.48 (m, 3H), 7.52ꢀ7.58 (m, 2H), 7.75 (dd, J =
7.6, 0.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.89 (dd, J = 7.6,
1.2 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 10.40 (s, 1H). 13C NMR (100.5 MHz) δ 43.6,
57.4, 103.5, 121.4, 125.7, 127.6, 127.8, 128.0, 129.8, 130.7, 131.5, 132.0, 132.9, 133.6,
134.3, 135.9, 140.7, 152.3, 192.8. IR (NaCl) ν 1692 cmꢀ1. HRMS (ESIꢀTOF) cald for
C19H17INO: 402.0349 [M+H]+; found: 402.0350.
2-[N-(2-Iodo-1-naphthyl)-N-methylaminomethyl]benzaldehyde
(10).
Chromatography: from hexanes to 9:1 hexanesꢀEtOAc. Yellow oil. 1H NMR (300 MHz)
δ 3.02 (s, 3H), 4.91 (d, J = 13.5 Hz, 1H), 4.97 (d, J = 13.5 Hz, 1H), 7.39 (d, J = 8.4 Hz,
1H), 7.41ꢀ7.51 (m, 3H), 7.54 (td, J = 7.5, 1.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.82 (m,
1H), 7.85 (d, J = 9 Hz, 1H), 7.87 (m, 1H), 8.05 (m, 1H), 20.21 (s, 1H). 13C NMR (100.5
MHz) δ 40.6, 56.2, 97.3, 124.0, 126.2, 126.4, 127.5, 127.6, 128.5, 130.8, 131.2, 133.4,
133.6, 134.3, 134.6, 136.5, 141.6, 149.5, 192.1. IR (NaCl) ν 1691 cmꢀ1. HRMS (ESIꢀ
TOF) cald for C19H17INO: 402.0349 [M+H]+; found: 402.0340.
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Representative Procedure for the Pd(0)-Catalyzed Acylation (Table 1, Entry 1). A
mixture of aldehyde 1a (70 mg, 0.2 mmol), Cs2CO3 (195 mg, 0.6 mmol), Et3N (0.17
mL, 1.2 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), and dtpf (9.5 mg, 0.02 mmol) in toluene
(8 mL) was stirred at 110°C in a sealed tube for 24 h. The reaction mixture was
partitioned between water and Et2O. The organic extracts were washed with brine,
dried, and concentrated. The residue was purified by chromatography (from hexanes to
hexanesꢀEtOAc 2.5%) to give 11 (34 mg, 77%).
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6-Methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (11). Yellow solid: mp 109ꢀ110 ºC
1
(recrystallized from Et2O). H NMR (300 MHz) δ 3.24 (s, 3H), 4.26 (s, 2H), 6.85 (m,
1H), 6.87 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.2, 1.5 Hz, 1H), 7.34ꢀ7.43 (m, 2H), 7.49
(td, J = 7.5, 1.5 Hz, 1H), 7.76 (dd, J = 7.5, 1.5 Hz, 1H), 8.30 (dd, J = 8.4, 1.5 Hz, 1H).
13C NMR (75.4 MHz) δ 40.1, 58.4, 115.7, 117.5, 123.5, 125.6, 128.0, 128.9, 131.9,
132.3, 134.1, 136.9, 140.5, 150.9, 193.4. IR (NaCl) ν 1629 cmꢀ1. HRMS (ESIꢀTOF)
cald for C15H14NO: 224.1070 [M+H]+; found: 224.1069.
6-Benzyl-9-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (12). Chromatography:
from hexanes to hexanesꢀEtOAc 3%. Yellow solid: mp 85ꢀ90 ºC (recrystallized from
1
Et2O). Yield: 91% (48 mg). H NMR (300 MHz) δ 2.30 (s, 3H), 4.30 (s, 2H), 4.70 (s,
2H), 6.80 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 7.5, 1.2 Hz, 1H), 7.15 (dd, J = 8.4, 2.4 Hz,
1H), 7.22 (d, J = 7.2 Hz, 2H), 7.30ꢀ7.43 (m, 4H), 7.46 (td, J = 7.5, 1.5 Hz, 1H), 7.78
(dd, J = 7.5, 1.2 Hz, 1H), 8.12 (d, J = 1.2 Hz, 1H). 13C NMR (75.4 MHz) δ 20.2, 55.4,
55.9, 117.2, 123.5, 125.9, 126.7, 127.3, 127.4, 128.0, 128.8, 129.0, 131.5, 131.8, 135.6,
136.7, 137.6, 140.7, 149.2, 193.6. IR (NaCl) ν 1633 cmꢀ1. HRMS (ESIꢀTOF) cald for
C22H20NO: 314.1545 [M+H]+; found: 314.1548.
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9-Methoxy-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (13). Chromatography:
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from hexanes to hexanesꢀEtOAc 5%. Brown solid: mp 95ꢀ97 ºC (recrystallized from
8
9
1
Et2O). Yield: 60% (30 mg). H NMR (300 MHz) δ 3.19 (s, 3H), 3.84 (s, 3H), 4.23 (s,
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2H), 6.88 (d, J = 9.0 Hz, 1H), 7.08 (dd, J = 9.0, 3.3 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H),
7.38 (ddd, J = 7.8, 7.5, 1.2 Hz, 1H), 7.50 (dd, J = 7.8, 7.5, 1.5 Hz, 1H), 7.78 (d, J = 3.3
Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H). 13C NMR (75.4 MHz) δ 40.2, 55.6, 58.5, 112.1,
118.2, 123.7, 124.3, 125.8, 127.9, 129.1, 131.9, 137.0, 139.9, 146.5, 151.8, 192.7. IR
(NaCl) ν 1630 cmꢀ1. HRMS (ESIꢀTOF) cald for C16H16NO2: 254.1176 [M+H]+; found:
254.1182.
8-Fluoro-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (14a). Chromatography:
from hexanes to hexanesꢀEtOAc 10%. Yellow gum. Yield: 74% (36 mg). 1H NMR (300
MHz) δ 3.23 (s, 3H), 4.28 (s, 2H), 6.51 (dd, J = 12.0, 2.4 Hz, 1H), 6.90 (ddd, J = 9.6,
7.5, 2.4 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.39 (td, J = 7.5, 1.2 Hz, 1H), 7.51 (td, J =
7.5, 1.5 Hz, 1H), 7.76 (dd, J = 7.5, 1.2 Hz, 1H), 8.32 (dd, J = 9.0, 7.5 Hz, 1H). 13C
NMR (75.4 MHz) δ 40.3, 58.5, 101.2 (d, J = 25.9 Hz), 106.0 (d, J = 23.0 Hz), 120.4,
125.7, 128.3, 129.0, 132.0, 135.4 (d, J = 11.5 Hz), 136.5, 140.3, 152.5 (d, J = 12.1 Hz),
166.7 (d, J = 252.5 Hz), 192.0. IR (NaCl) ν 1633 cmꢀ1. HRMS (ESIꢀTOF) cald for
C15H13FNO: 242.0976 [M+H]+; found: 242.0981.
8-Cloro-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (14b). Chromatography:
from hexanes to hexanesꢀEtOAc 8%. Brown solid: mp 86ꢀ88 ºC. Yield: 79% (35 mg).
1H NMR (400 MHz) δ 3.24 (s, 3H), 4.26 (s, 2H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.85 (s,
1H), 7.25 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 8.0, 7.2 Hz, 1H), 7.51 (ddd, J = 7.6, 7.2, 1.2
Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H). 13C NMR (100.5 MHz) δ
40.2, 58.4, 115.1, 118.1, 122.0, 125.8, 128.3, 129.0, 132.2, 134.0, 136.6, 140.2, 140.3,
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151.3, 192.3. IR (NaCl) ν 1630 cmꢀ1. HRMS (ESIꢀTOF) cald for C15H13ClNO:
258.0680 [M+H]+; found: 258.0678.
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8-(Hydroxymethyl)-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one
(14c).
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Chromatography: from CH2Cl2 to CH2Cl2ꢀMeOH 1%. Yellow oil. Yield: 71% (32 mg).
1H NMR (400 MHz) δ 2.39 (broad s, 1H), 3.22 (s, 3H), 4.20 (s, 2H), 4.67 (s, 2H), 6.77
(dd, J = 8.0, 1.6 Hz, 1H), 6.89 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.36 (td, J = 7.6, 1.2
Hz, 1H), 7.48 (td, J = 7.6, 1.2 Hz, 1H), 7.74 (dd, J = 7.2, 1.2 Hz, 1H), 8.24 (d, J = 8.0
Hz, 1H). 13C NMR (100.5 MHz) δ 40.1, 58.4, 64.7, 113.0, 115.8, 122.5, 125.7, 128.0,
128.8, 132.0, 132.7, 136.8, 140.3, 147.6, 151.1, 193.1. IR (NaCl) ν 1623, 3406 cmꢀ1.
HRMS (ESIꢀTOF) cald for C16H16NO2: 254.1176 [M+H]+; found: 254.1166.
8-(Formyl)-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (14d). Chromatography:
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from hexanes to CH2Cl2. Yellow oil. Yield: 49% (22 mg). H NMR (400 MHz) δ 3.35
(s, 3H), 4.32 (s, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 8.4, 1.6 Hz, 1H), 7.40 (s,
1H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.55 (td, J = 7.6, 1.6 Hz, 1H), 7.75 (dd, J = 7.6, 1.2
Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H). 13C NMR (100.5 MHz) δ 40.3, 58.4, 117.2, 117.4,
125.9, 126.8, 128.4, 129.0, 132.5, 133.5, 136.7, 139.8, 140.2, 150.8, 192.4, 193.3. IR
(NaCl) ν 1633, 1693 cmꢀ1. HRMS (ESIꢀTOF) cald for C16H14NO2: 252.1019 [M+H]+;
found: 252.1016.
8-(Acetoxymethyl)-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one
(14e).
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Chromatography: from hexanes to CH2Cl2. Yellow oil. Yield: 69% (32 mg). H NMR
(400 MHz) δ 2.12 (s, 3H), 3.26 (s, 3H), 4.26 (s, 2H), 5.08 (s, 2H), 6.83 (d, J = 7.6 Hz,
1H), 6.85 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.38 (td, J = 7.6, 1.2 Hz, 1H), 7.50 (td, J =
7.6, 1.2 Hz, 1H), 7.75 (dd, J = 7.2, 1.2 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H). 13C NMR
(100.5 MHz) δ 20.9, 40.1, 58.4, 65.8, 114.8, 116.9, 123.1, 125.7, 128.1, 128.9, 132.0,
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132.9, 136.8, 140.3, 142.1, 150.8, 170.7, 192.9. IR (NaCl) ν 1632, 1738 cmꢀ1. HRMS
(ESIꢀTOF) cald for C18H18NO3: 296.1281 [M+H]+; found: 296.1276.
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8-(Dimethylaminomethyl)-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one
(14f).
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Chromatography (SiO2, from CH2Cl2 to CH2Cl2ꢀMeOH 3%). Yellow oil. Yield: 69%
1
(28 mg). H NMR (400 MHz) δ 2.27 (s, 6H), 3.27 (s, 3H), 3.44 (s, 2H), 4.26 (s, 2H),
6.81 (dd, J = 8.4, 1.6 Hz, 1H), 6.89 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.38 (td, J = 7.6,
1.2 Hz, 1H), 7.49 (td, J = 7.6, 1.2 Hz, 1H), 7.76 (dd, J = 7.6, 1.2 Hz, 1H), 8.25 (d, J =
8.4 Hz, 1H). 13C NMR (100.5 MHz) δ 40.2, 45.4, 58.4, 64.2, 115.8, 118.6, 122.7, 125.7,
128.0, 128.9, 131.9, 132.5, 136.9, 140.5, 145.1, 151.0, 193.0. IR (NaCl) ν 1633 cmꢀ1.
HRMS (ESIꢀTOF) cald for C18H21N2O: 281.1654 [M+H]+; found: 281.1654.
4-Fluoro-6-methyl-5,6-dihydrodibenzo[b,e]azepin-11-one (15). Chromatography:
from hexanes to hexanesꢀCH2Cl2 80%. Yellow solid: mp 82ꢀ84 ºC. Yield: 87% (34 mg).
1H NMR (400 MHz) δ 3.24 (s, 3H), 4.23 (s, 2H), 6.88 (m, 2H), 6.95 (dd, J = 8.8, 2.4
Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz, 1H), 7.41 (ddd, J = 8.8, 7.2, 1.2 Hz, 1H), 7.79 (dd, J
= 8.8, 5.6 Hz, 1H), 8.31 (dd, J = 8.8, 1.2 Hz, 1H). 13C NMR (100.5 MHz) δ 40.2, 58.0
(d, J = 1.5 Hz), 112.6 (d, J = 21.8 Hz), 115.1 (d, J = 21.0 Hz), 115.9, 117.9, 123.5,
131,7 (d, J = 9.2 Hz), 132.4, 134.2, 136.7 (d, J = 3.1 Hz), 139.3 (d, J = 7.0 Hz), 150.9,
165.0 (d, J = 252.8 Hz), 191.6. IR (NaCl) ν 1633 cmꢀ1. HRMS (ESIꢀTOF) cald for
C15H13FNO: 242.0975 [M+H]+; found: 242.0976.
5-Methyl-5,6-dihydrobenzo[b]naphtho[2,3-e]azepin-13-one (16). Chromatography:
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from hexanes to hexanesꢀEtOAc 8%. Yellow oil. Yield: 61% (21 mg). H NMR (300
MHz) δ 3.25 (s, 3H), 4.43 (s, 2H), 6.84ꢀ6.91 (m, 2H), 7.40 (ddd, J = 8.7, 6.9, 1.5 Hz,
1H), 7.46ꢀ7.58 (m, 2H), 7.67 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H),
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8.29 (s, 1H), 8.35 (dd, J = 8.7, 1.5 Hz, 1H). C NMR (75.4 MHz) δ 39.9, 58.8, 115.8,
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117.6, 123.7, 123.9, 126.3, 127.3, 127.8, 129.2, 129.7, 132.3, 132.6, 134.1, 134.4,
134.9, 139.0, 151.2, 193.4. IR (NaCl) ν 1619, 1639 cmꢀ1. HRMS (ESIꢀTOF) cald for
C19H16NO: 274.1226 [M+H]+; found: 274.1223.
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6-Methyl-6,7-dihydrobenzo[e]naphtho[2,3-b]azepin-12-one (17). Chromatography:
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from hexanes to 1:1 hexanesꢀCH2Cl2. Red oil. Yield: 58% (30 mg). H NMR (300
MHz) δ 3.28 (s, 3H), 4.30 (s, 2H), 7.08 (s, 1H), 7.22 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H),
7.27 (dd, J = 7.5, 0.9 Hz, 1H), 7.36ꢀ7.45 (m, 2H), 7.51 (td, J = 7.5, 1.5 Hz, 1H), 7.62 (d,
J = 8.4 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.84 (dd, J = 7.5, 3.3 Hz, 1H), 8.29 (s, 1H).
13C NMR (75.4 MHz) δ 40.9, 58.5, 109.7, 123.0, 125.7, 125.9, 126.6, 126.8, 128.0,
128.8, 129.2, 129.8, 132.2, 134.5, 137.3, 138.2, 139.8, 147.4, 194.0. IR (NaCl) ν 1619,
1643 cmꢀ1. HRMS (ESIꢀTOF) cald for C19H16NO: 274.1226 [M+H]+; found: 274.1224.
7-Methyl-7,8-dihydrobenzo[e]naphtho[2,1-b]azepin-13-one (18). Chromatography:
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from hexanes to 1:1 hexanesꢀEtOAc. Yellow oil. Yield: 90% (46 mg). H NMR (400
MHz) δ 3.29 (s, 3H), 4.32 (s, 2H), 7.10 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H),
7.32 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.37 (td, J = 7.6, 1.2 Hz, 1H), 7.46 (td, J = 7.6, 1.6
Hz, 1H), 7.58 (ddd, J = 8.8, 7.2, 1.2 Hz, 1H), 7.65 (dd, J = 8.0, 1.2 Hz, 1H), 7.72 (d, J =
9.2 Hz, 1H), 7.82 (dd, J = 8.0, 1.2 Hz, 1H), 9.32 (d, J = 8.4 Hz, 1H). 13C NMR (100.5
MHz) δ 39.7, 58.0, 114.4, 117.0, 123.4, 124.8, 126.9, 127.7, 128.1, 128.2, 128.6, 129.0,
130.8, 134.1, 135.1, 137.1, 142.1, 152.4, 191.9. IR (NaCl) ν 1603, 1635 cmꢀ1. HRMS
(ESIꢀTOF) cald for C19H16NO: 274.1226 [M+H]+; found: 274.1228.
13-Methyl-12,13-dihydrobenzo[e]naphtho[1,2-b]azepin-7-one
(19).
Chromatography: from hexanes to 1:1 hexanesꢀCH2Cl2. Yellow oil. Yield: 64% (30
mg). 1H NMR (400 MHz) δ 2.93 (s, 3H), 4.60 (s, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.43 (t,
J = 7.6 Hz, 1H), 7.49ꢀ7.59 (m, 4H), 7.80 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H),
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8.36 (m, 2H). 13C NMR (100.5 MHz) δ 41.4, 59.0, 123.5, 125.9, 126.7, 127.2, 127.5,
128.0, 128.2, 128.3, 128.5, 129.7, 130.5, 132.0, 137.5, 138.0, 139.9, 152.7, 192.4. IR
(NaCl) ν 1615, 1633 cmꢀ1. HRMS (ESIꢀTOF) cald for C19H16NO: 274.1226 [M+H]+;
found: 274.1225.
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Acknowledgments
Support for this work by grants CTQ2009ꢀ07175 and CTQ2012ꢀ31391 from the
Ministerio de Economia y Competitividad, Spain, is gratefully acknowledged.
Supporting Information: 1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org/.
References and Notes.
1 (a) Negishi, E. Ed.; Handbook of Organopalladium Chemistry for Organic
Synthesis; WileyꢀVCH: New York, 2002; Vols. I and II. (b) Tsuji, J. Ed.;
Palladium in Organic Synthesis, in Topics in Organometallic Chemistry;
SpringerꢀVerlag: Berlin; 2005. (c) de Meijere, A.; Diederich, F. Eds.; Metal-
Catalyzed Cross-Coupling Reactions, WileyꢀVCH: New York, 2004.
2 For selected examples on the addition to ketones, see: (a) Quan, L. G.; Lamrani,
M.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4827. (b) Solé, D.; Vallverdú,
L.; Solans, X.; FontꢀBardia, M.; Bonjoch, J. J. Am. Chem. Soc. 2003, 125, 1587.
(c) Jia, Y.ꢀX.; Katayev, D.; Kündig, E. P. Chem. Commun. 2010, 130.
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3 Aldehydes: (a) ÁlvarezꢀBercedo, P.; FloresꢀGaspar, A.; Correa, A.; Martin, R. J.
Am. Chem. Soc. 2010, 132, 466. (b) FloresꢀGaspar, A.; GutiérrezꢀBonet, A.;
Martin, R. Org. Lett. 2012, 14, 5234.
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4 Nitriles: (a) Yang, C.ꢀC.; Sun, P.ꢀJ.; Fang, J.ꢀM. J. Chem. Soc.; Chem. Commun.
1994, 2629. (b) Pletnev, A. A.; Larock, R. C. J. Org. Chem. 2002, 67, 9428.
5 Imines: Ohno, H.; Aso, A.; Kadoh, Y.; Fujii, N.; Tanaka, T. Angew. Chem. Int.
Ed. 2007, 46, 6325.
6 Anhydrides: Cacchi, S.; Fabrizi, G.; Gavazza, F.; Goggiamani, A. Org. Lett.
2003, 5, 289.
7 Esters: Solé, D.; Serrano, O. Angew. Chem. Int. Ed. 2007, 46, 7270.
8 Amides: Solé, D.; Serrano, O. J. Org. Chem. 2008, 73, 9372.
9 For a review, see: Miyaura, N. Synlett. 2009, 2039.
10 Ketones: Liu, G.; Lu, X. J. Am. Chem. Soc. 2006, 128, 16504.
11 For selected recent references on the reaction with aldehydes, see: (a) Liao, Y.ꢀ
X.; Xing, C.ꢀH.; Israel, M.; Hu, Q.ꢀS. Tetrahedron Lett. 2011, 52, 3324. (b) Luo,
F.; Pan, S.; Pan, C.; Qian, P.; Cheng, J. Adv. Synth. Catal. 2011, 353, 320.
12 Nitriles, see for example: Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
13 For selected recent examples on the reaction with imines, see: (a) Marques, C.
S.; Burke, A. J. Eur. J. Org. Chem. 2010, 1639. (b) Chen, J.; Lu, X.; Lou, W.;
Ye, Y.; Jiang, H.; Zeng, W. J. Org. Chem. 2012, 77, 8541.
14 (a) Solé, D.; Serrano, O. J. Org. Chem. 2008, 73, 2476. (b) Solé, D.; Serrano, O.
Org. Biomol. Chem. 2009, 7, 3382. (c) Solé, D.; Serrano, O. J. Org. Chem.
2010, 75, 6267. (d) Solé, D.; Bennasar, M.ꢀL.; Jiménez, I. Org. Biomol. Chem.
2011, 9, 4535.
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15 (a) Fernández, I.; Solé, D.; Sierra, M. A. J. Org. Chem. 2011, 76, 1592. (b) Solé,
D.; Fernández, I.; Sierra, M. A. Chem. Eur. J. 2012, 18, 6950.
16 Recently, the control of the divergent reactivity of these intermediates has been
exploited to develop efficient domino processes, see: Zhao, Y.ꢀB.; Mariampillai,
B.; Candito, D. A.; Laleu, B.; Li, M.; Lautens, M. Angew. Chem. Int. Ed. 2009,
48, 1849.
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