Synthesis of Pyridobenzazepines Using a One-Pot Rh/Pd-Catalyzed Process

Article abstract of DOI:10.1021/acs.joc.7b00568

In recent years, our group has been developing multicatalytic reactions for the synthesis of biologically relevant heterocyclic compounds. An efficient dual-metal catalyzed reaction of electron-deficient o-chlorovinylpyridines with o-aminophenylboronic esters to access pyridobenzazepines is described. Combining a Rh^I-catalyzed arylation followed by a Pd⁰-catalyzed C-N coupling, in a one-pot procedure, provides a simplified method to access heterocycles without workup and purification after each step. The substrate scope encompasses a variety of N-H and N-alkylated pyridobenzazepine variants with yields up to 93%.

Full text of DOI:10.1021/acs.joc.7b00568

Article
pubs.acs.org/joc
Synthesis of Pyridobenzazepines Using a One-Pot Rh/Pd-Catalyzed
Process
Heather Lam, Jennifer Tsoung, and Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street Toronto, ON Canada, M5S 3H6
S
* Supporting Information
ABSTRACT: In recent years, our group has been developing
multicatalytic reactions for the synthesis of biologically
relevant heterocyclic compounds. An efficient dual-metal
catalyzed reaction of electron-deficient o-chlorovinylpyridines
with o-aminophenylboronic esters to access pyridobenzaze-
pines is described. Combining a RhI-catalyzed arylation
followed by a Pd0-catalyzed C−N coupling, in a one-pot
procedure, provides a simplified method to access heterocycles without workup and purification after each step. The substrate
scope encompasses a variety of N-H and N-alkylated pyridobenzazepine variants with yields up to 93%.
INTRODUCTION
■
Multicatalytic reactions offer an alternative to traditional step-
by-step sequences and can reduce the amount of time, effort,
and solvent used to construct useful products. Our objective is
to learn about the compatibility of different catalysts and
substrates in multicatalytic scenarios. This knowledge could be
of use for others interested in developing new multicatalytic
reactions. One variant uses several substrates and catalysts in a
multicomponent-multicatayst reaction, (MC)2R. Our group has
applied this approach in various syntheses of heterocyclic
Figure 1. Examples of drugs that contain the dibenzazepine motif.
scaffolds including dihydroquinolinones, oxindoles, and fully
substituted triazoles.1−4 Ideally, all the starting materials,
reagents, and catalysts are added simultaneously, and the
building blocks will react in a productive sequential manner
under the same reaction conditions. To ensure successful
application of this strategy, orthogonal reactivity of the metals
and “time resolution” of the individual steps are necessary.5
In recent years, our group has synthesized functionalized
seven-membered fused heterocyclic rings using dual-metal
catalyzed processes to combine readily available vinylpyridines
and ortho-functionalized phenylboronic acids. Recently, we
reported a method for the synthesis of pyridobenzoxepines
(Scheme 1a).6 The analogous nitrogen-containing dibenzaze-
pine is prevalent in many pharmaceutically relevant com-
pounds, used as tricyclic antidepressants, and was recently
reengineered as an anticancer agent, which exhibited efficacy on
xenograft models of EFGR-driven cancer (Figure 1).7−10
Although the core structure of these tricyclic motifs is readily
available, substituted analogues are difficult to access. Diversity
in scaffolds is typically obtained by electrophilic aromatic
substitution, which is often low-yielding and with limited
control over site selectivity. Additionally, there are relatively few
de novo syntheses of these structures.11−15
high yields from vinylpyridines, o-chlorophenylboronic acids,
and anilines by combining a Rh-catalyzed arylation reaction and
two Pd-catalyzed C−N bond-forming reactions in one pot. The
N-alkylated analogues could also be accessed by adopting a
one-pot, two-step procedure where the Rh-catalyzed arylation
was allowed to take place before the components for the Pd-
catalyzed C−N bond forming reactions were added. While this
protocol allowed for the synthesis of several N-alkylated
products in moderate yields, we were interested in pursuing a
more expedient procedure to access these highly valuable
targets.
We herein report that N-alkylated as well as N-H
pyridobenzazepine motifs can be synthesized by coupling o-
aminophenylboronic esters to o-chlorovinylpyridines with a
new approach using Rh-catalyzed 1,4-arylation followed by a
Pd-catalyzed C−N coupling between a secondary amine and an
aryl chloride (Scheme 1c). Compared to the arylated analogues,
N-alkylated analogues are more relevant in pharmacophores,
and the N-H motifs can be further derivatized at the secondary
amine.17 Furthermore, the products can be obtained using a
one-step protocol compared to the previous two-step protocol,
We recently reported the synthesis of the N-arylated
pyridobenzazepine motif using a Rh/Pd-catalyzed (MC)2R
(Scheme 1b).16 These complex products could be obtained in
Received: March 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00568
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Scheme 1. Previous Approaches to Seven-Membered Heterocycles with Dual-Metal Catalysis
Scheme 2. Synthesis of Pyridobenzazepines
and the yields obtained were generally higher than the previous
method, making this method advantageous for the synthesis of
these motifs.
yield (Table 1, entry 6), although the G2 and G3 versions of
the same catalyst gave poorer yields under these conditions
(Table 1, entries 7 and 8). A survey of bases showed that KOH
afforded the highest isolated yield of 87% (Table 1, entry 9).
Running the reaction without an excess of the XPhos ligand
gave lower yields (Table 1, entry 10).
RESULTS AND DISCUSSION
■
To access N-H pyridobenzazepines, we used the Rhl-catalyzed
arylation with [Rh(cod)Cl]2 as the catalyst and K2CO3 as the
base. This process afforded 91% yield of intermediate 3a, which
was subjected to the Pd0-catalyzed C−N bond formation using
Pd(OAc)2 with XPhos as the ligand and NaOtBu as the base. A
95% yield of the desired product 4a was isolated (Scheme 2).
Although the two steps can be telescoped in a one-pot, two-
step procedure, molecular sieves had to be added to attain
comparable yields. Consequently, a convenient one-pot
procedure with a single addition of all the reagents at the
start of the reaction is more desirable. However, simply
combining the reagents from these individual steps gave a poor
yield of 4a (Table 1, entry 1), though switching the base to
KOH showed an improvement in yield (Table 1, entry 2).18
Changing the ligand to tBuBrettPhos did not improve the yield
(Table 1, entry 3). Bidentate ligands such as Josiphos or
Xantphos also fared worse (Table 1, entries 4 and 5). A variety
of Buchwald precatalysts and ligands were screened (Figure 2).
Changing the palladium source to Pd-G1-XPhos improved the
A screen of other bulky monophosphine ligands such as
tBuXPhos, SPhos, and RuPhos demonstrated that XPhos was
the best ligand for this domino reaction (Table 1, entries 11−
14). This result is in alignment with reports from Buchwald on
the efficiency of the XPhos ligand for the coupling of primary
amines.19 When we ran experiments with a mixed ligand system
(Table 1, entries 15 and 16), slightly better yields were
obtained. Finally, as a control study, running the reaction
without palladium and ligand gave a >95% yield of 3a (Table 1,
entry 17), showing that C−N bond formation occurs via
palladium catalysis and not through an SNAr mechanism. Due
to the similarity of the results of the mixed vs single ligand
system (Table 1, entry 9 and 15), we examined the substrate
scope using a single ligand to simplify the system (Table 2).
However, it became apparent that using substrates other than
2a gave much poorer yields in all cases. Similarly, running the
reactions with Pd-G1-RuPhos and excess RuPhos ligand gave
B
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a
Table 1. Optimization of Domino Reaction of N-H Pyridobenzazepine
c
c
entry
[Pd]/L1
Pd(OAc)2
L2
XPhos
base
yield of 4a (%)
yield of 3a (%)
b
1
K2CO3
KOH
13
72
b
2
Pd(OAc)2
XPhos
b
3
Pd(OAc)2
tBuBrettPhos
Josiphos
Xantphos
XPhos
KOH
66
b
4
Pd(OAc)2
KOH
36
b
5
Pd(OAc)2
KOH
52
6
Pd-G1-XPhos
Pd-G2-XPhos
Pd-G3-XPhos
Pd-G1-XPhos
Pd-G1-XPhos
Pd-G1-tBuXPhos
Pd-G1-SPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-XPhos
K2CO3
K2CO3
K2CO3
KOH
58
7
XPhos
10
8
XPhos
18
9
XPhos
89 (87)
63
10
11
12
13
14
15
16
17
KOH
tBuXPhos
SPhos
K2CO3
K2CO3
K2CO3
KOH
6
12
26
RuPhos
RuPhos
XPhos
65
70 (75)
93 (90)
90
KOH
RuPhos
KOH
KOH
>95
a
b
c
1a (1.0 equiv, 0.2 mmol), 2a (1.5 equiv). 15 mol % L2 used. 1H NMR yields with p-nitroacetophenone as the internal standard with isolated
yields in parentheses.
Figure 2. Buchwald palladacycle precatalysts and various ligands.
equally poor yields of the cyclized product. Hence, we settled
on the mixed ligand system.
ring, possibly due to competing oxidative addition to the Pd
catalyst. Electron-donating groups (4h,i) worked well, but an
electron-withdrawing cyano group (4j) fared much worse.
Next, we wanted to explore the conditions for synthesizing
N-alkylated pyridobenzazepines. We optimized the conditions
for the synthesis of N-alkylated pyridobenzazepines using an N-
benzylated derivative 2b as the standard substrate. When
reacting 1a with 2b, we found that [Rh(cod)Cl]2, K2CO3, and
Pd-G1-RuPhos with excess RuPhos ligand in a 10:1 mixture of
1,4-dioxane and H2O gave an 85% yield of 4b (Table 3, entry
1). This outcome is in line with reports from Buchwald on the
high efficiency of RuPhos for the coupling of secondary
amines.19 [Rh(cod)OH]2 gave comparable yields, while
[Rh(C2H4)2Cl]2 gave lower yields (Table 3, entries 2 and 3).
It was found that K2CO3 was the optimal base. The use of other
Based on our previous work with vinylpyrazines in
multicatalytic reactions, we envisioned that these substrates
would work well in the present reaction.20 When we subjected
o-chlorovinylpyrazine 1b and 2a to the domino catalysis
conditions, 4c was isolated in excellent yield. Running the
reaction in the absence of the palladium gave none of the
cyclization product, showing that cyclization did not occur
through a base-mediated reaction. In place of the CF3 group,
vinylpyridines with Ms 1c or CN 1d were tolerated in the
reaction to give 4d and 4e respectively.
In the absence of an electron-withdrawing R group on the
vinylpyridine (i.e., R = CH3 or H), the desired transformation
failed to occur. Halides were tolerated on the ring (4f,g);
however, the yield was much lower with a chloro on the aniline
C
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Table 2. Scope of N-H Pyridobenzazepines
a
b
c
d
Pd-G1-XPhos instead of Pd-G1-RuPhos. RuPhos instead of XPhos. Uncyclized intermediate was isolated in 35% yield. Uncyclized intermediate
was isolated in 20% yield.
a
Table 3. Optimization of One-Pot Domino Reaction of N-Benzylated Pyridobenzazepine
b
b
entry
[Pd]/L1
L2
base
yield of 4b (%)
yield of 3b (%)
1
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-XPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd(OAc)2
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
XPhos
K2CO3
K2CO3
K2CO3
KOH
85 (80)
c
2
79 (71)
d
3
2
42
8
4
5
6
CsCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
13
30
30
60
e
7
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
RuPhos
75
f
8
e
8
60
60
9
86 (81)
g
10
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
Pd-G1-RuPhos
h
11
59
9
i
12
j
13
18
9
k
14
40
12
l
15
11
a
b
1a (1.0 equiv, 0.3 mmol), 2a (1.5 equiv), 0.1 M in dioxane, 110 °C, 16 h. 1H NMR yields with p-nitroacetophenone as the internal standard with
c
d
e
f
isolated yields in parentheses. [Rh(cod)OH]2 instead of [Rh(cod)Cl]2. [Rh(C2H4)2Cl]2 instead of [Rh(cod)Cl]2. 10 mol % of L2 used. 2.5 mol
% of [Pd]/L1 used. Run at 100 °C. Run at 120 °C. Run at 0.05 M. Run at 0.2 M. Dioxane/H2O = 10:0.5. MeOH instead of H2O.
g
h
i
j
k
l
inorganic bases such as KOH or Cs2CO3 fared poorly under
otherwise identical conditions (Table 3, entries 4 and 5).
The domino reaction did not give full conversion to 4b using
the combination of Pd-G1-XPhos with excess XPhos ligand
(Table 3, entry 6). In analogy to the N-H case, the second- and
third-generation Pd-XPhos palladacycles, with added XPhos,
afforded negligible yields. Increasing the amount of excess
ligand to 10 mol % or decreasing the palladium catalyst loading
to 2.5 mol % significantly decreased the yield (Table 3, entries 7
and 8). We also wanted to determine if simple palladium
sources could be used rather than the specialized precatalysts
mentioned above. When the reaction was performed with the
free ligand and Pd(OAc)2, comparable yields (81%) to Pd-G1-
RuPhos with an equivalent ligand loading (Table 3, entry 9)
were obtained.21 PdCl2, Pd(dppf)Cl2, Pd2(dba)3, or Pd-
(PhCN)2Cl2 led to low yields and incomplete conversion to
the desired product under otherwise standard conditions.
D
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Table 4. Scope of N-Substituted Pyridobenzazepine
a
KOH (3 equiv) used instead of K2CO3.
Figure 3. Proposed mechanism for the Rh/Pd-catalyzed formation of benzazepines.
When the temperature of the reaction was lowered to 100
°C, only 60% of intermediate 3b and none of 4b was observed
(Table 3, entry 10). Running the reaction at 120 °C led to a
lower yield of 4b (Table 3, entry 11). A concentration of 0.1 M
was found to be the optimal value, as reactions run at either
0.05 or 0.20 M proceeded in low yield (Table 3, entries 12 and
13). Halving the amount of water in the reaction led to lower
yields of 3b and incomplete conversion to 4b (Table 3, entry
14). Using MeOH in place of H2O led to incomplete
conversion of 3b to the desired product (Table 3, entry 15).
Hence, the best conditions used a combination of 2.5 mol %
of [Rh(cod)Cl]2, 3 equiv of K2CO3, and 5 mol % of Pd-G1-
RuPhos precatalyst with 5 mol % excess RuPhos ligand in a
10:1 mixture of 1,4-dioxane and H2O. With these optimized
conditions, we studied the scope of the reaction (Table 4).
Substrates bearing a para substituent on the N-benzyl group
gave good yields of the desired products 4k,l. Deborylation of 2
was the major side reaction when coupling the N-benzyl
substrates to 1. An analysis of the aniline component showed
that electron-donating groups such as methoxy and methyl
provided good yields (Table 4, 4m,n). However, electron-
withdrawing groups such as a methyl ester or cyano in that
position generally gave lower yields of the product (Table 4,
4o−q). Compounds 4o and 4p gave the intermediates in 71%
and 80% yield, respectively. For 4q, switching the base to KOH
allowed for cyclization to the product, but 67% of the
intermediate remained uncyclized. When the Rh-catalyzed
step was run on its own, the intermediates could be obtained in
good yields. The lowered yields for the Pd-catalyzed step could
be due to the reduced nucleophilicity of the aniline. Alkyl
chains of different lengths were incorporated in good yields
(Table 4, 4r−t) with around 15−20% of the dechlorinated
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Scheme 3. Three-Component (MC)2R
intermediate as the major side product. Bulky N-substituents on
the aniline (i.e., iPr) would lead to formation of the
intermediate, without cyclizing, instead undergoing partial
dechlorination.
zazepines from easily accessible vinylpyridines and amino-
phenylboronic esters that affords up to 93% yield. It was also
shown that a three-component (MC)2R could be performed
under similar conditions to access both N-arylated and N-
alkylated products in a one-pot procedure. These compounds
are pharmaceutically relevant as many tricyclic scaffolds with
the dibenzazepine motif contains an N-alkyl chain and N-H
analogues can be further functionalized. Furthermore, the
compounds presented are all novel and could show interesting
biological reactivity. With our previously reported (MC)2R
conditions to access N-aryl pyridobenzazepines, we now offer a
suite of modular and efficient methods to access these diverse
and highly functionalized heterocyclic structures.
We propose that the formation of the pyridobenzazepines
occurs through a Rh-catalyzed 1,4-arylation followed by a Pd-
catalyzed amination (Figure 3). First, [Rh(cod)Cl]2 is
converted to the more active [Rh]-OH species. [Rh]-OH
then transmetalates with the 2-aminophenylboronic ester 2,
which reacts with the vinylpyridine 1 to give an aza-
allylrhodium species. Protodemetalation gives intermediate 3,
and water regenerates [Rh]-OH. Oxidative addition of 3 to the
Pd-catalyst occurs and the Pd coordinates to the aniline. In the
presence of base, HCl is lost, and a reductive elimination gives
rise to pyridobenzazepine 4.
A limitation of the current process is that an electron-
withdrawing substituent must be present in the 5 position of
the vinylpyridine for the transformation to occur. This includes
either a CF3 or CN group. Subjecting 1d with 2-(N-
methylamino)phenylboronic acid pinacol ester gave moderate
yields of 4v along with 44% of unreacted vinylpyridine, using
KOH. This reaction did not work with an unsubstituted
vinylpyridine nor with a Ms or NO2 group in the 5-position.
Subjecting these unsuccessful substrates to the rhodium-
catalyzed arylation conditions in the absence of palladium
was also unsuccessful, leading only to deborylation of 2. As an
alternative strategy, we attempted to use a more electron-rich
aminophenylboronic ester, but it was not found to be a viable
solution to allow electron-neutral pyridines to react. When we
attempted to react 1b with 2b, none of the N-substituted
product was obtained. Instead, 40% yield of the intermediate
was formed. It was re-subjected to the Pd-catalyzed conditions,
but no reaction was observed.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under an
argon atmosphere in oven- or flame-dried flasks or vials with magnetic
stirring. Organic solutions were concentrated using a rotary evaporator
at 30−45 °C under reduced pressure unless otherwise stated.
Analytical TLC was performed on silica gel plates (0.2 mm, 60 Å
pore size). Visualization was done under a 254 nm UV light source and
by immersion in potassium permanganate solution. Flash chromatog-
raphy was performed employing 230−400 mesh silica gel. All reagents,
catalysts, and ligands were purchased from commercial sources and
used without further purification. Prior to use, THF were distilled over
Na/benzophenone, while 1,2-dichloroethane and propionitrile were
distilled over CaH2. Reagent-grade 1,4-dioxane was used straight from
the bottle. 1H, 13C, and 19F NMR were recorded at 25 °C in CDCl3 on
a Varian Mercury 400 MHz, 500 MHz, or Bruker Avance III 400 MHz
spectrometer. 1H spectra were referenced to residual protium
resonances relative to Me4Si (CHCl3 δ 7.26). 13C spectra were
referenced to solvent carbon resonances (CDCl3 δ 77.16). Chemical
shifts are reported in parts per million (ppm) and coupling constants
1
as scalar values in hertz. Data for H NMR are reported as follows:
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, tt
= triplet of triplets, qd = quartet of doublets, m = multiplet), coupling
constant (J, Hz), and integration. High-resolution mass spectra
(HRMS) were obtained from an SI2Micromass 70S-250 spectrometer
operating at 70 eV in EI mode, or an AB/Sciex QStar spectrometer
operating in positive ESI mode. Mass analyzer type is TOF. FTIR
spectra were recorded using an ATR method unless otherwise stated.
General Procedure for Benzylation. N-(4-Methylbenzyl)-2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2h). In an
oven-dried scintillation vial with a stir bar were added 2-aminoboronic
acid pinacol ester 2a (138 mg, 1.5 mmol, 1 equiv) and 4-tolualdehyde
(396 mg, 1.8 mmol, 1.2 equiv) and the mixture dissolved in anhydrous
MeOH (1.5 mL) for 4 h. NaBH4 (68 mg, 1.8 mmol, 1.2 equiv) was
added portionwise, and the reaction was allowed to stir for 1 h. The
reaction was partitioned in a 1:1 mixture of EtOAc (25 mL) and
distilled water (25 mL). The organic layer was collected, the aqueous
Finally, we were also interested in seeing if we could extend
this strategy to a three-component reaction (Scheme 3). We
expected that compound 4a, formed in situ from 1a and 2a,
would undergo a second Pd-catalyzed C−N coupling with an
external coupling partner. Using 3 equiv of an electron-deficient
aryl chloride, we obtained 52% yield of the cyclized product 4w
under our standard domino reaction conditions. Using BnBr,
Pd-G1-RuPhos, and XPhos gave 3b (90% yield) exclusively as
4a was not formed. We hypothesized that only cyclization of
the secondary amine 3b afforded 4b. Hence, changing the
excess ligand to RuPhos afforded 4b in 46% yield (Scheme 3).
CONCLUSION
■
In summary, we have reported a Rh/Pd-catalyzed two-
component protocol to access N-alkylated or N-H pyridoben-
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layer was extracted with EtOAc (25 mL × 2), and the organic layers
were combined. The organic layers were washed with saturated NaCl
solution and then dried over MgSO4. The mixture was concentrated in
vacuo and then purified by column chromatography (1% EtOAc in
hexanes) to obtain 110 mg (23% yield, mp = 62−63 °C) of the desired
product as a clear colorless solid. 1H NMR (500 MHz, CDCl3): δ 7.65
(dd, J = 7.3, 1.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 4H), 7.14 (d, J = 7.8 Hz,
2H), 6.63 (t, J = 7.4 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 6.33 (s, 1H),
4.36 (s, 2H), 2.34 (s, 3H), 1.32 (s, 12H). 13C NMR (500 MHz,
CDCl3): δ 154.4, 137.0, 136.7, 136.3, 133.1, 129.3, 129.1, 127.5, 126.8,
117.5, 115.6, 112.8, 109.8, 83.5, 48.1, 47.2, 24.9, 21.1. FT-IR: 3422,
2977, 2927, 1694, 1578, 1515, 1455, 1356, 1323, 1265, 1142, 1088,
1040, 962, 861, 835, 801, 752, 673, 657 cm−1. HRMS (DART): m/z
[M + H]+ calcd for C20H27BNO2 324.2129, found 324.2135.
1527, 1424, 1371, 1325, 1294, 1249, 1140, 1113, 1053, 983, 852, 774,
732, 698, 662 cm−1. HRMS (DART): m/z [M + H]+ calcd for
C21H27BNO4 368.2028, found 368.2033.
N-Benzyl-4-cyano-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline (2m). 4-(Benzylamino)-3-bromobenzonitrile (286 mg, 1
mmol, 1 equiv) was used. The crude mixture was purified by column
chromatography (5% EtOAc in hexanes) to obtain 274 mg (82% yield,
mp = 68−69 °C) of the product as a pink solid. 1H NMR (500 MHz,
CDCl3): δ 7.96−7.87 (m, 1H), 7.44 (ddd, J = 8.7, 2.1, 0.5 Hz, 1H),
7.39−7.28 (m, 1H), 6.87 (s, 1H), 6.47 (d, J = 8.7 Hz, 1H), 4.43 (d, J =
5.6 Hz, 2H), 1.33 (s, 12H). 13C NMR (126 MHz, CDCl3): δ 156.6,
141.7, 138.2, 136.6, 128.7, 127.3, 126.7, 120.4, 109.7, 97.8, 84.3, 47.0,
24.9. FT-IR: 3395, 2979, 2214, 1604, 1580, 1524, 1452, 1421, 1392,
1367, 1329, 1281, 1194, 1139, 1056, 965, 898, 852, 817, 735, 696, 669
cm−1. HRMS (DART): m/z [M + H]+ calcd for C20H24BN2O2
335.1925, found 335.1931.
N-(4-Methoxybenzyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)aniline (2i). Compound 2a (138 mg, 1.5 mmol, 1 equiv) and 4-
anisaldehyde (449 mg, 1.8 mmol, 1.2 equiv) were used. The crude
mixture was purified by column chromatography (5% EtOAc in
hexanes) to obtain 220 mg (43% yield, mp = 69−70 °C) of the
N-Benzyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-tri-
fluoromethylaniline (2n). Methyl 4-(benzylamino)-3-iodobenzoate
(367 mg, 1 mmol, 1 equiv) was used. The crude mixture was purified
by column chromatography (5% EtOAc in hexanes) to obtain the
desired product (279 mg, mp = 72−73 °C) as a white solid in 74%
1
product as a clear yellow solid. H NMR (500 MHz, CDCl3): δ7.65
(dd, J = 7.4, 1.6 Hz, 1H), 7.32−7.26 (m, 3H), 7.25 (ddd, J = 8.4, 7.2,
1.8 Hz, 1H), 6.91−6.85 (m, 2H), 6.63 (td, J = 7.3, 0.9 Hz, 1H), 6.55−
6.50 (m, 1H), 6.28 (s, 1H), 4.33 (d, J = 3.3 Hz, 2H), 3.81 (s, 3H), 1.33
(s, 12H). 13C NMR (500 MHz, CDCl3: δ 158.5, 154.4, 137.0, 133.1,
131.8, 128.1, 115.6, 113.9, 109.8, 83.5, 55.3, 46.9, 24.9. FT-IR: 3415,
2927, 2846, 1605, 1578, 1513, 1457, 1358, 1325, 2346, 1144, 1010,
862, 828, 755, 659 cm−1. HRMS (DART): m/z [M + H]+ calcd for
C20H27BNO3 340.2079, found 340.2084.
1
yield. H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 2.1 Hz, 1H), 7.43
(dd, J = 8.5, 2.1 Hz, 1H), 7.35 (d, J = 1.0 Hz, 1H), 7.34 (s, 2H),
7.37−7.28 (m, 1H), 6.71 (s, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.43 (d, J =
4.1 Hz, 2H), 1.34 (s, 12H). 13C NMR (500 MHz, CDCl3): δ 156.3,
138.8, 134.3 (q, J(C−F) = 3.8 Hz), 129.9 (q, J(C−F) = 3.6 Hz), 128.6,
127.1, 126.8, 125.1 (q, J(C−F) = 270.4 Hz), 117.3 (q, J(C−F) = 32.4 Hz),
109.2, 84.0, 47.1, 24.9. 19F NMR (500 MHz, CDCl3): δ 60.95. FT-IR:
3416, 2980, 1617, 1588, 1533, 1453, 1373, 1319, 1266, 1169, 1143,
1108, 1078, 963, 850, 818, 731, 697, 680 cm−1. HRMS (DART): m/z
[M + H]+ calcd for C20H24BF3NO2 378.1847, found 378.1852.
General Procedure for the Synthesis of N-Alkylated o-
Anilineboronic Acid Pinacol Esters. N-Methyl-2-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)aniline (2o). In a flame-dried round-
bottomed flask equipped with a stirbar was dissolved 2-aminoboronic
acid pinacol ester, 2a, (1.0 g, 6 mmol, 2 equiv) in dry THF (6 mL)
under argon and then the mixture cooled to −40 °C. n-BuLi (2.5 M in
hexanes, 1.2 mL, 1 equiv) was added dropwise, and the solution was
stirred for 30 min. The solution was further cooled to −78 °C, and
MeI (188 μL, 3 mmol, 1 equiv) was added dropwise. This was stirred
for 12 h with warming to room temperature. The reaction was
quenched by the addition of water (4 mL), and the organic layer was
separated. The aqueous layer was extracted with EtOAc (50 mL × 3),
and then the organic layer was washed with NaHCO3, dried over
anhydrous MgSO4, and concentrated in vacuo. The compound was
isolated by column chromatography (5% EtOAc/hexanes) to obtain
General Procedure for Borylation of o-Halo N-Substituted
Anilines. N-Benzyl-5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)aniline (2j). In a flame-dried 3 dram vial that was
purged with argon, N-benzyl-2-bromo-5-methoxyaniline (291 mg, 1
mmol, 1 equiv) was dissolved in dry 1,4-dioxane (4 mL). Et3N (0.43
mL, 4 mmol, 4 equiv) and Pd(dppf)Cl2 (43 mg, 0.1 mmol, 10 mol %)
were added. Pinacolborane (0.44 mL, 3 mmol, 3 equiv) was added
dropwise under argon. The crude mixture was purified by column
chromatography (5% EtOAc in hexanes) to obtain the desired product
1
(237 mg, mp = 89−91 °C) as a clear colorless solid in 70% yield. H
NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.2 Hz, 1H), 7.33−7.20 (m,
4H), 7.21−7.12 (m, 1H), 6.32 (s, 1H), 6.13 (dd, J = 8.3, 2.3 Hz, 1H),
5.96 (d, J = 2.2 Hz, 1H), 4.30 (d, J = 5.2 Hz, 2H), 3.64 (s, 3H), 1.23
(s, 12H). 13C NMR (400 MHz, CDCl3): δ 144.5, 138.8, 138.5, 132.0,
128.7, 127.3, 127.3, 118.9, 112.3, 106.5, 48.0, 21.5. FT-IR: 3413, 2986,
2920, 1605, 1570, 1450, 1261, 1201, 1093, 1053, 860, 800, 735, 697,
660 cm−1. HRMS (DART): m/z [M + H]+ calcd for C20H27BNO3
340.2079, found 340.2084.
1
the desired product (643 mg) as a clear colorless oil in 92% yield. H
N-Benzyl-4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline (2k). N-Benzyl-2-bromo-4-methylaniline (275 mg, 1 mmol,
1 equiv) was used. The crude mixture was purified by column
chromatography (5% EtOAc in hexanes) to obtain the desired product
(242 mg, mp = 74−75 °C) as pale yellow solid in 75% yield. 1H NMR
(500 MHz, CDCl3): δ 7.6 (d, J = 7.5 Hz, 1H), 7.4−7.3 (m, 4H), 7.3 (t,
J = 7.2 Hz, 1H), 6.5 (d, J = 7.5 Hz, 1H), 6.4 (s, 1H), 6.3 (s, 1H), 4.4
(s, 2H), 2.3 (s, 3H), 1.3 (s, 12H). 13C NMR (500 MHz, CDCl3): δ
154.6, 143.5, 139.9, 137.1, 134.8, 128.5, 127.0, 126.8, 117.0, 110.5,
83.4, 47.5, 24.9, 22.2. FT-IR: 3423, 2977, 2919, 2867, 1614, 1571,
1450, 1350, 1313, 1261, 1093, 1053, 963, 860, 801, 735, 697, 657
cm−1. HRMS (DART): m/z [M + H]+ calcd for C20H27BNO2
324.2129, found 324.2135.
Methyl 4-(Benzylamino)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzoate (2l). Methyl 4-(benzylamino)-3-iodobenzoate (367
mg, 1 mmol, 1 equiv) was used. The crude mixture was purified by
column chromatography (5% EtOAc in hexanes) to obtain the desired
product (315 mg, mp = 105−107 °C) as a pink solid in 86% yield. 1H
NMR (500 MHz, CDCl3): δ 8.34 (d, J = 2.2 Hz, 1H), 7.91 (dd, J =
8.8, 2.3 Hz, 1H), 7.34 (d, J = 4.4 Hz, 4H), 7.28 (s, 1H), 6.83 (d, J = 5.8
Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 5.5 Hz, 2H), 3.84 (s,
3H), 1.33 (s, 12H). 13C NMR (500 MHz, CDCl3): δ 167.3, 157.5,
139.5, 138.7, 134.9, 128.6, 127.1, 126.8, 117.1, 83.9, 77.3, 77.0, 76.7,
47.1, 24.9, 14.2. FT-IR: 3396, 2979, 2940, 2858, 1705, 1605, 1480,
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 7.3 Hz, 1H), 7.33 (t, J = 7.8
Hz, 1H), 6.63 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 5.79 (s,
1H), 2.85 (s, 3H), 1.33 (s, 12H). 13C NMR (500 MHz, CDCl3-insert):
δ 155.4, 137.1, 133.2, 115.4, 108.9, 83.5, 30.2, 24.9. FT-IR: 3433, 2979,
2934, 2810, 1606, 1582, 1524, 1467, 1430, 1358, 1325, 1273, 1173,
1143, 1106, 1086, 1049, 1034, 964, 837, 756, 677, 662 cm−1. HRMS
(DART): m/z [M + H]+ calcd for C13H21BNO2 234.1660, found
234.1665.
N-Propyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(2q). 1-Iodopropane (291 μL, 3 mmol, 1 equiv) was added. The
compound was isolated by column chromatography (5% EtOAc/
hexanes) to obtain the desired product (705 mg) as a clear colorless
oil in 90% yield. 1H NMR (400 MHz, CDCl3): δ 7.66 (dd, J = 7.3, 1.8
Hz, 1H), 7.32 (ddd, J = 8.6, 7.2, 1.8 Hz, 1H), 6.63 (td, J = 7.3, 1.0 Hz,
1H), 6.58 (d, J = 8.3 Hz, 1H), 5.90 (s, br 1H), 3.13 (t, J = 6.8 Hz, 2H),
1.71 (h, J = 7.2 Hz, 2H), 1.36 (s, 12H), 1.05 (t, J = 7.4 Hz, 3H). 13C
NMR (400 MHz, CDCl3): δ 154.8, 137.1, 133.1, 115.2, 109.4, 83.4,
45.1, 25.0, 22.4, 11.7. FT-IR: 3414, 2967, 2925, 2858, 1605, 1579,
1521, 1455, 1356, 1323, 1264, 1104, 1060, 1039, 962, 864, 753, 674,
658 cm−1. HRMS (DART): m/z [M + H]+ calcd for C15H24BNO2
262.1973, found 262.1978.
2-(2-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)ethyl)aniline (3a).
In a 2 dram vial equipped with a stir bar were added 3-chloro-5-
G
DOI: 10.1021/acs.joc.7b00568
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The Journal of Organic Chemistry
Article
trifluoro-2-vinylpyridine 1a (42 mg, 0.2 mmol), 2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)aniline 2a (66 mg, 0.3 mmol, 1.5 equiv),
[Rh(cod)Cl]2 (2.5 mg, 0.01 mmol, 0.05 equiv), and KOH (34 mg,
0.06 mmol, 3.0 equiv). The product was isolated by column
chromatography (15% EtOAc/hexanes) as a colorless solid (38 mg,
equiv), RuPhos (4.7 mg, 0.01 mmol, 0.05 equiv), and KOH (34 mg,
0.06 mmol, 3.0 equiv). The vial was flushed with argon gas. Then 1,4-
dioxane (2 mL, 0.1 M) was added followed by distilled H2O (0.2 mL)
and benzyl bromide (71 μL, 0.6 mmol, 3 equiv). The vial was sealed
with a Teflon screw cap, and then the seal was wrapped with Teflon
tape. The mixture was placed into a 110 °C oil bath and heated for 16
h. Upon cooling to room temperature, the reaction mixture was
partitioned between EtOAc (25 mL) and water (10 mL). The organic
layer was kept, and the aqueous layer was extracted again with EtOAc
(25 mL × 2). The organic fractions were combined, washed with
saturated NaCl (1 M solution, dried over anhydrous MgSO4), and
concentrated in vacuo. The product was isolated using column
chromatography (5% EtOAc in hexanes) to give the desired
compound (33 mg, mp = 60−62 °C) as a peach crystalline solid in
46% yield. 1H NMR (500 MHz, CDCl3): δ 8.27 (s, 1H), 7.47 (s, 1H),
7.36 (s, 1H), 7.35 (s, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.23−7.15 (m,
4H), 7.08−7.01 (m, 1H), 4.96 (s, 2H), 3.44−3.37 (m, 2H), 3.36−3.29
(m, 2H). 13C NMR (126 MHz, CDCl3): δ 155.8 (q, J(C−F) = 1.4 Hz),
148.0, 143.0, 137.6 (q, J(C−F) = 4.2 Hz), 136.64, 136.61, 128.8, 128.6,
128.0, 127.5, 127.0, 124.7, 124.1 (q, J(C−F) = 32.7 Hz), 123.5 (q, J(C−F)
= 272.4 Hz), 122.6 (q, J(C−F) = 3.5 Hz), 121.5, 117.1, 55.7, 37.5, 29.9.
19F NMR (377 MHz, CDCl3): δ −62.32. FT-IR (NaCl, neat): 3065,
1
mp = 57−62 °C) in 91% yield. H NMR (400 MHz, CDCl3): δ 8.72
(s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.15−7.00 (m, 2H), 6.83−6.64 (m,
2H), 3.86 (s, 2H), 3.41−3.20 (m, 2H), 3.05−2.84 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 162.6 (q, J(C−F) = 1.4 Hz), 144.4, 144.0 (q,
J(C−F) = 4.2 Hz), 133.8 (q, J(C−F) = 3.6 Hz), 131.3, 129.7, 129.3, 127.5,
125.7 (q, J(C−F) = 33.6 Hz), 122.8 (q, J(C−F) = 272.6 Hz), 118.8, 115.8,
34.9, 29.4. 19F NMR (377 MHz, CDCl3): δ −62.17. IR (NaCl, thin
film): 3387, 3337, 3225, 3067, 3024, 2930, 2862, 1605, 1497, 1456,
1397, 1323, 1175, 1132, 1092, 1059, 916, 750 cm−1. HRMS (DART):
m/z [M + H]+ calcd for C14H13ClF3N2 301.0719, found 301.0723.
General Procedure 1 for the Synthesis of N-H Benzazepines.
3-(Trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido[2,3-f ]azepine
(4a). In a 2 dram vial equipped with a stir bar were added 3-chloro-5-
trifluoro-2-vinylpyridine 1a (42 mg, 0.2 mmol), 2-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)aniline 2a (66 mg, 0.3 mmol, 1.5 equiv),
[Rh(cod)Cl]2 (2.5 mg, 0.01 mmol, 0.05 equiv), Pd-G1-RuPhos (7.4
mg, 0.01 mmol, 0.05 equiv), XPhos (7.1 mg, 0.01 mmol, 0.05 equiv),
and KOH (34 mg, 0.06 mmol, 3.0 equiv). The vial was flushed with
argon gas. Then 1,4-dioxane (0.2 mL, 0.1 M) was added followed by
distilled H2O (0.02 mL). The vial was sealed with a Teflon screw cap,
and then the seal was wrapped with Teflon tape. The mixture was
placed into a 110 °C oil bath and heated for 16 h. Upon cooling to
room temperature, the reaction mixture was partitioned between
EtOAc (25 mL) and water (10 mL). The organic layer was kept, and
the aqueous layer was extracted again with EtOAc (25 mL × 2). The
organic fractions were combined, washed with saturated NaCl (1 M
solution, dried over anhydrous MgSO4), and concentrated in vacuo.
NMR yields were obtained using p-nitroacetophenone as an internal
standard. The product was isolated by column chromatography (10−
50% EtOAc/hexanes) as a white solid (48 mg, mp 125−128 °C) in
3033, 2924, 2853, 1602, 1494, 1456, 1416, 1335, 1324, 1228, 1122,
1099, 942, 908, 761, 739, 698, 643 cm−1. HRMS (DART): m/z [M +
H]+ calcd for C21H18F3N2 355.1422, found 355.1427.
10,11-Dihydro-5H-benzo[b]pyrazino[2,3-f ]azepine (4c). Follow-
ing procedure 1, 2-chloro-3-vinylpyrazine 1c (28 mg, 0.2 mmol) and
2a (66 mg, 0.3 mmol, 1.5 equiv) were added. The product was isolated
by column chromatography (15−25% EtOAc in hexanes) in 90% yield
(35 mg, mp = 70−71 °C) as a pink solid. 1H NMR (500 MHz,
CDCl3): δ 7.97 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.16 (td,
J = 7.7, 1.6 Hz, 1H), 7.14−7.12 (m, 1H), 7.08 (s, 1H), 6.93 (td, J =
7.4, 1.2 Hz, 1H), 6.88 (dd, J = 7.9, 1.1 Hz, 1H), 3.34−3.21 (m, 2H),
3.17−3.07 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 150.6, 142.6,
140.1, 139.7, 133.9, 130.2, 127.3, 121.8, 118.9, 37.5, 32.3. FT-IR: 3266,
3047, 2924, 2851, 1610, 1542, 1495, 1418, 1319, 1238, 1140, 947, 752
cm−1. HRMS (DART): m/z [M + H]+ calcd for C12H12N3 198.1026,
found 198.1031.
1
93% yield. H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 0.9 Hz, 1H),
7.27−7.21 (m, 1H), 7.14 (ddd, J = 9.3, 7.5, 1.6 Hz, 2H), 6.91 (td, J =
7.4, 1.2 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.01 (s, 1H), 3.40−3.33 (m,
2H), 3.17−3.10 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 151.0 (q,
J(C−F) = 1.4 Hz), 141.0, 138.6, 135.6 (q, J(C−F) = 4.2 Hz), 130.5, 129.8,
127.3, 125.2 (q, J(C−F) = 32.7 Hz), 123.7 (q, J(C−F) = 272.4 Hz), 121.4,
121.0 (q, J(C−F)= 3.7 Hz), 118.5, 38.5, 32.5. 19F NMR (564 MHz,
CDCl3): δ −62.39. IR (NaCl, neat): 3300, 3232, 3206, 3139, 3121,
3043, 2962, 2925, 2854, 2359, 2346, 1544, 1438, 1495, 1468, 1442,
1418, 1343, 1238, 1126, 1095, 968, 750, 668 cm−1. HRMS (DART):
m/z [M + H]+ calcd for C14H12F3N2 265.0947, found 265.0953.
General Procedure 2 for the Synthesis of N-Substituted
Pyridobenzazepines. 5-Benzyl-3-(trifluoromethyl)-10,11-dihydro-
5H-benzo[b]pyrido[2,3-f ]azepine (4b). In a 2 dram vial equipped
with a stir bar were added 3-chloro-5-trifluoro-2-vinylpyridine 1a (42
mg, 0.2 mmol), N-benzyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)aniline 2b (92 mg, 0.3 mmol, 1.5 equiv), [Rh(cod)Cl]2 (2.5 mg,
0.01 mmol, 0.05 equiv), Pd-G1-RuPhos (8.2 mg, 0.01 mmol, 0.05
equiv), RuPhos (4.7 mg, 0.01 mmol, 0.05 equiv), and K2CO3 (84 mg,
0.6 mmol, 3.0 equiv). The vial was flushed with argon gas. Then 1,4-
dioxane (0.2 mL, 0.1 M) was added followed by distilled H2O (0.02
mL). The vial was sealed with a Teflon screw cap, and then the seal
was wrapped with Teflon tape. The mixture was placed into a 110 °C
oil bath and heated for 16 h. Upon cooling to room temperature, the
reaction mixture was partitioned between EtOAc (25 mL) and water
(10 mL). The organic layer was kept, and the aqueous layer was
extracted again with EtOAc (25 mL × 3). The organic fractions were
combined, washed with saturated NaCl solution, dried over anhydrous
MgSO4, and concentrated in vacuo. NMR yields were obtained using
p-nitroacetophenone as an internal standard. The product was isolated
by column chromatography (5% EtOAc in hexanes) as a peach crystal
in 81% yield (57 mg, mp = 60−63 °C). Three-component procedure:
In a 2 dram vial equipped with a stir bar were added 1a (42 mg, 0.2
mmol, 1 equiv), 2a (66 mg, 0.3 mmol, 1.5 equiv), [Rh(cod)Cl]2 (2.5
mg, 0.01 mmol, 0.05 equiv), Pd-G1-RuPhos (8.2 mg, 0.01 mmol, 0.05
3-Methylsulfonyl-10,11-dihydro-5H-benzo[b]pyrido[2,3-f ]-
azepine (4d). Following procedure 1, 2-chloro-5-methylsulfonyl-2-
vinylpyridine 1d (43 mg, 0.2 mmol) and 2a (66 mg, 0.3 mmol, 1.5
equiv) were added. The product was isolated by column
chromatography (30% EtOAc in hexanes) in 62% yield (34 mg, mp
1
= 210−213 °C) as a pink solid. H NMR (500 MHz, CDCl3): δ 8.47
(d, J = 1.9 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.22−7.08 (m, 2H), 6.92
(td, J = 7.4, 1.2 Hz, 1H), 6.85 (dd, J = 7.9, 1.1 Hz, 1H), 6.28 (s, 1H),
3.42−3.36 (m, 2H), 3.16−3.12 (m, 2H), 3.12 (s, 3H). 13C NMR (500
MHz, (CD3)2SO): δ 152.4, 140.7, 139.1, 136.8, 135.0, 130.4, 129.8,
127.4, 122.5, 121.7, 118.7, 45.0, 38.8, 32.3. FT-IR: 3363, 2918, 1575,
1530, 1496, 1358, 1439, 1408, 1315, 1140, 910, 952, 753 cm−1. HRMS
(DART): m/z [M + H]+ calcd for C14H15N2O2S 275.0849, found
275.0854.
3-Cyano-10,11-dihydro-5H-benzo[b]pyrido[2,3-f ]azepine (4e).
Following procedure 1, 3-chloro-5-cyano-2-vinylpyridine 1d (33 mg,
0.2 mmol) and 2a (66 mg, 0.3 mmol, 1.5 equiv) were added. The
product was isolated by column chromatography (15% EtOAc in
hexanes) in 45% yield (20 mg, mp = 179−171 °C) as a pink solid. 1H
NMR (500 MHz, CDCl3): δ 8.2 (d, J = 1.7 Hz, 1H), 7.3 (d, J = 1.7 Hz,
1H), 7.2−7.1 (m, 2H), 6.9 (td, J = 7.4, 1.1 Hz, 1H), 6.8 (dd, J = 7.9,
1.0 Hz, 1H), 6.0 (s, 1H), 3.6−3.3 (m, 2H), 3.2−2.8 (m, 2H).13C NMR
(500 MHz, CDCl3): δ 151.6, 141.3, 141.3, 140.5, 138.7, 130.5, 129.8,
129.3, 127.4, 126.2, 121.8, 118.7, 116.8, 107.7, 38.9, 32.3. FT-IR: 3368,
3293, 2020, 2930, 2845, 2233, 1600, 1582, 1532, 1492, 1457, 1410,
1329, 1248, 906, 729 cm−1. HRMS (DART): m/z [M + H]+ calcd for
C14H12N3 222.1026, found 222.1031.
7-Fluoro-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f ]azepine (4f). Following procedure 1, 1a (42 mg, 0.2 mmol) and
2-amino-4-fluorophenylboronic acid pinacol ester 2c (71 mg, 0.3
mmol, 1.5 equiv) were added. The product was isolated by column
chromatography (15% EtOAc in hexanes) in 68% yield (38 mg, mp =
H
DOI: 10.1021/acs.joc.7b00568
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Article
1
130−134 °C) as a white solid. H NMR (500 MHz, CDCl3): δ 8.27
CDCl3): δ 151.5 (q, J(C−F) = 1.4 Hz), 144.9, 137.2, 137.1 (q, J(C−F) =
(d, J = 0.9 Hz, 1H), 7.27 (d, J = 1.3 Hz, 1H), 7.05 (dd, J = 8.4, 6.4 Hz,
1H), 6.59 (td, J = 8.2, 2.5 Hz, 1H), 6.54 (dd, J = 10.1, 2.5 Hz, 1H),
6.23 (s, 1H), 3.38−3.30 (m, 2H), 3.21−2.65 (m, 2H). 13C NMR (500
MHz, CDCl3): δ 162.8, 160.8, 150.9 (apparent d, J(C−F) = 0.9 Hz),
142.0 (d, J(C−F) = 10.0 Hz), 138.2, 135.9 (q, J(C−F) = 4.0 Hz), 131.8 (d,
J(C−F) = 9.4 Hz), 125.3 (q, J(C−F) = 33.0 Hz), 125.2, 125.2, 123.4 (q,
J(C−F) = 272.4 Hz), 121.4 (q, J(C−F) = 3.6 Hz), 107.9 (d, J(C−F) = 20.9
Hz), 105.2 (d, J(C−F) = 25.0 Hz), 38.3, 31.9. 19F NMR (500 MHz,
CDCl3): δ −62.3, −116.2 (q, J = 8.1, 6.9 Hz). FT-IR: 3316, 3228,
3165, 2962, 2913, 2868, 1617, 1559, 1502, 1468, 1422, 1341, 1241,
1162, 1138, 1093, 1002, 928, 892, 850, 804. HRMS (DART): m/z [M
+ H]+ calcd for C14H11F4N2 283.0853, found 283.0866.
4.1 Hz), 134.8, 131.2, 128.9, 125.4 (q, J(C−F) = 33.0 Hz), 123.3 (q,
J(C−F) = 272.4 Hz), 122.1 (q, J(C−F) = 3.5 Hz), 119.4, 118.7, 102.9,
38.0, 32.8. FT-IR: 3341, 3228, 3144, 3059, 2965, 2929, 2865, 2223,
1614, 1538, 1504, 1462, 1426, 1344, 1162, 1129, 1093, 965, 898, 825,
741. HRMS (DART): m/z [M + H]+ calcd for C15H11F3N3 290.0900,
found 290.0906.
5-(4-Methylbenzyl)-3-(trifluoromethyl)-10,11-dihydro-5H-benzo-
[b]pyrido[2,3-f ]azepine (4k). Following procedure 2, 1a (42 mg, 0.2
mmol) and 2h (97 mg, 0.3 mmol, 1.5 equiv) were added. The product
was isolated by column chromatography (5% EtOAc in hexanes) in
61% yield (45 mg, mp = 74−76 °C) as a clear colorless solid. 1H NMR
(500 MHz, CDCl3): δ 8.28 (dd, J = 1.9, 1.0 Hz, 1H), 7.48 (d, J = 1.6
Hz, 1H), 7.29−7.24 (m, 2H), 7.23−7.19 (m, 1H), 7.19−7.14 (m, 2H),
7.06 (m, 1H), 6.82−6.78 (m, 1H), 4.92 (s, 2H), 3.45−3.36 (m, 2H),
3.36−3.26 (m, 2H), 2.28 (s, 3H). 13C NMR (500 MHz, CDCl3): δ
158.8, 155.8 (q, J(C−F) = 1.3 Hz), 148.0, 143.0, 137.5 (q, J(C−F) = 4.1
Hz), 136.6, 129.3, 128.8, 128.6, 126.9, 124.6, 124.0 (q, J(C−F) = 32.5
Hz), 123.6 (q, J(C−F) = 272.4 Hz), 122.7 (q, J(C−F) = 3.5 Hz), 121.5,
114.0, 55.1, 55.0, 37.5, 29.9. 19F NMR (377 MHz, CDCl3): δ −62.30.
FT-IR: 2926, 2855, 1694, 1518, 1494, 1458, 1418, 1332, 1229, 1128,
1100, 946, 804, 754, 650, 621 cm−1. HRMS (DART): m/z [M + H]+
calcd for C22H20F3N2 369.1573, found 369.1575.
8-Chloro-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepine (4g). Following procedure 1, 1a (33 mg, 0.2 mmol)
and 2-amino-5-chlorophenylboronic acid pinacol ester 2d (76 mg, 0.3
mmol, 1.5 equiv) were added. The product was isolated by column
chromatography (15% EtOAc in hexanes) in 51% yield (30 mg, mp =
1
164−165 °C) as a white solid which turns yellow immediately. H
NMR (500 MHz, CDCl3): δ 8.26 (q, J = 0.8 Hz, 1H), 7.24 (d, J = 1.5
Hz, 1H), 7.13−7.06 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 6.07 (s, 1H),
3.41−3.24 (m, 2H), 3.19−2.85 (m, 2H). 13C NMR (500 MHz,
CDCl3): δ 150.53 (q, J(C−F) = 4.1 Hz), 139.6, 138.2, 136.0 (q, J(C−F)
4.1 Hz), 131.3, 130.1, 127.1, 126.1, 125.2 (q, J(C−F) = 32.9 Hz), 123.4
(q, J(C−F) = 272.4 Hz), 121.1 (q, J(C−F) = 3.6 Hz), 119.7, 38.2, 32.3. 19
=
5-(p-Methyoxybenzyl)-3-(trifluoromethyl)-10,11-dihydro-5H-
benzo[b]pyrido[2,3-f ]azepine (4l). Following procedure 2, 1a (42
mg, 0.2 mmol) and 2i (102 mg, 0.3 mmol, 1.5 equiv) were added. The
product was isolated by column chromatography (5% EtOAc in
F
NMR (377 MHz, CDCl3): δ −62.3. FT-IR: 3310, 3235, 3129, 2950,
2929, 2859, 1656, 1607, 1547, 1492 1465, 1419, 1350, 1138, 1099,
968, 890, 817. HRMS (DART): m/z [M + H]+ calcd for
C14H11ClF3N2 299.0563, found 299.0562.
1
hexanes) in 68% yield (52 mg) as a clear colorless oil. H NMR (500
MHz, CDCl3): δ 8.29 (t, J = 2.0, 1.0 Hz, 1H), 7.53−7.46 (m, 1H),
7.29−7.25 (m, 2H), 7.23−7.14 (m, 3H), 7.05 (ddd, J = 7.4, 6.2, 2.4
Hz, 1H), 6.82−6.78 (m, 2H), 4.90 (s, 2H), 3.74 (s, 3H), 3.46−3.37
(m, 2H), 3.37−3.26 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 158.8,
155.8 (q, J(C−F) = 1.4 Hz), 148.0, 143.0, 137.5 (q, J(C−F) = 4.2 Hz),
136.6, 129.3, 128.8, 128.6, 127.0, 124.6, 124.0 (q, J(C−F) = 32.5 Hz),
123.6 (q, J(C−F) = 272.5 Hz), 122.8 (q, J(C−F) = 3.5 Hz), 121.5, 114.0,
55.1, 55.0, 37.5, 29.9. 19F NMR (377 MHz, CDCl3): δ −62.29. FT-IR:
2925, 2853, 1612, 1513, 1494, 1458, 1430, 1417, 1331, 1250, 1171,
1147, 1127, 1100, 1035, 945, 890, 826, 755 cm−1. HRMS (DART): m/
z [M + H]+ calcd for C22H20F3N2O 385.1522, found 385.1527.
5-Benzyl-7-methoxy-3-(trifluoromethyl)-10,11-dihydro-5H-
benzo[b]pyrido[2,3-f ]azepine (4m). Following procedure 2, 1a (42
mg, 0.2 mmol) and 2j (100 mg, 0.3 mmol, 1.5 equiv) were added. The
product was isolated by column chromatography (5% EtOAc in
hexanes) in 90% yield (69 mg, mp = 107−109 °C) as a pale yellow
8-Methyl-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepine (4h). Following procedure 1, 1a (42 mg, 0.2 mmol)
and 2-amino-5-methylphenylboronic acid pinacol ester 2e (71 mg, 0.3
mmol, 1.5 equiv) were added. The product was isolated by column
chromatography (15% EtOAc in hexanes) in 71% yield (40 mg, mp =
1
99−100 °C) as a white solid. H NMR (400 MHz, CDCl3): δ 8.24
(dd, J = 2.0, 0.9 Hz, 1H), 7.22 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 7.6 Hz,
1H), 6.72 (ddd, J = 7.6, 1.7, 0.8 Hz, 1H), 6.63 (t, J = 1.1 Hz, 1H), 6.13
(s, 1H), 3.40−3.33 (m, 2H), 3.10−3.07 (m, 2H), 2.30 (s, 3H). 13C
NMR (500 MHz, CDCl3): δ 150.9 (q, J(C−F) = 1.4 Hz), 140.7, 138.7,
137.1, 135.4 (q, J(C−F) = 4.1 Hz), 130.4, 126.7, 125.1 (q, J(C−F) = 32.7
Hz), 123.5 (q, J(C−F) = 272.3 Hz), 122.2, 120.9 (q, J(C−F) = 3.6 Hz),
119.0, 38.7, 32.1, 20.9. 19F NMR (377 MHz, CDCl3): δ −62.3. FT-IR:
3311, 3132, 2926, 1629, 1547, 1505, 1468, 1420, 1347, 1241, 1162,
1141, 1117, 1096, 983, 902, 857, 798. HRMS (DART): m/z [M + H]+
calcd for C15H14F3N2 279.1104, found 279.1110.
1
solid. H NMR (500 MHz, CDCl3): δ 8.29 (s, 2H), 7.47 (s, 1H),
7.38−7.33 (m, 2H), 7.30−7.24 (m, 2H), 7.22−7.16 (m, 1H), 7.10 (d, J
= 8.3 Hz, 1H), 6.73 (dd, J = 2.5, 0.7 Hz, 1H), 6.59 (dd, J = 8.3, 2.5 Hz,
1H), 4.94 (s, 2H), 3.75 (s, 3H), 3.47−3.30 (m, 2H), 3.30−3.19 (m,
2H). 13C NMR (500 MHz, CDCl3): δ 158.6, 156.3 (q, J(C−F) = 1.6
Hz), 148.7, 143.0, 137.9 (q, J(C−F) = 4.2 Hz), 136.6, 129.5, 128.6,
7-Methoxy-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]-
pyrido[2,3-f ]azepine (4i). Following procedure 1, 1a (42 mg, 0.2
mmol and 2-amino-5-methylphenylboronic acid pinacol ester 2f (71
mg, 0.3 mmol, 1.5 equiv) were added. The product was isolated by
column chromatography (10% EtOAc in hexanes) in 81% yield (48
mg, mp = 159−160 °C) as a beige solid. 1H NMR (500 MHz,
CDCl3): δ 8.25 (dd, J = 1.7, 0.8 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H),
7.01 (d, J = 8.3 Hz, 1H), 6.47 (dd, J = 8.3, 2.5 Hz, 1H), 6.36 (d, J = 2.5
Hz, 1H), 6.15 (s, 1H), 3.77 (s, 3H), 3.35−3.30 (m, 2H), 3.10−3.03
(m, 2H). 13C NMR (126 MHz, CDCl3): δ 158.9, 151.1 (q, J(C−F) = 1.4
128.4, 128.0, 127.5, 124.0 (q, J(C−F) = 32.6 Hz), 123.5 (q, J(C−F)
=
272.6 Hz), 122.9 (q, J(C−F) = 3.6 Hz), 109.4, 107.9, 55.6 55.4, 37.5,
29.2. 19F NMR (500 MHz, CDCl3): δ −62.28. FT-IR: 2923, 2858,
1724, 1610, 1507, 1436, 1327, 1252, 1219, 1166, 1128, 1080, 1018,
965, 840, 740, 699 cm−1. HRMS (DART): m/z [M + H]+ calcd for
C22H20F3N2O 385.1522, found 385.1527.
Hz), 141.8, 138.5, 135.7 (q, J(C−F) = 4.1 Hz), 131.4, 125.1 (q, J(C−F)
=
32.7 Hz), 123.5 (q, J(C−F) = 272.3 Hz), 122.2, 121.0 (q, J(C−F) = 3.6
Hz), 106.6, 104.2, 55.3, 38.8, 31.8. 19F NMR (377 MHz, CDCl3): δ
−62.3. FT-IR: 3367, 3310, 3217, 3123, 2956, 2923, 2850, 1620, 1595,
1556, 1508, 1468, 1423, 1347, 1244, 1165, 1120, 1096, 1044, 922, 905,
847, 798, 738. HRMS (DART): m/z [M + H]+ calcd for
C15H14F3N2O 295.1053, found 295.1063.
5-Benzyl-8-methyl-3-(trifluoromethyl)-10,11-dihydro-5H-benzo-
[b]pyrido[2,3-f ]azepine (4n). Following procedure 2, 1a (42 mg, 0.2
mmol) and 2k (97 mg, 0.3 mmol, 1.5 equiv) were added. The product
was isolated by column chromatography (5% EtOAc in hexanes) in
1
83% yield (61 mg, mp = 74−75 °C) as a clear colorless oil. H NMR
(500 MHz, CDCl3): δ 8.25 (s, 1H), 7.45 (s, 1H), 7.35 (d, J = 7.5 Hz,
2H), 7.30−7.24 (m, 3H), 7.19 (t, J = 7.1 Hz, 1H), 7.09 (d, J = 7.6 Hz,
1H), 6.99 (s, 1H), 6.87 (d, J = 7.6 Hz, 1H), 4.96 (s, 2H), 3.38 (q, 2H),
3.28 (m, 2H), 2.29 (s, 3H). 13C NMR (500 MHz, CDCl3): δ 156.0 (q,
J(C−F) = 1.5 Hz), 148.1, 142.9, 137.5 (q, J(C−F) = 4.2 Hz), 136.75,
136.73, 133.5, 129.1, 128.6, 128.6, 128.1, 127.7, 127.5, 127.2, 125.3,
124.7, 124.0 (q, J(C−F) = 32.5 Hz), 123.6 (q, J(C−F) = 272.7 Hz), 122.7,
122.6 (q, J(C−F) = 3.5 Hz), 122.5, 122.1, 117.8, 111.4, 55.6, 37.7, 29.5,
21.2.19F NMR (400 MHz, CDCl3): δ −62.38. FT-IR: 3043, 2925,
8-Cyano-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepine (4j). Following procedure 1, 1a (42 mg, 0.2 mmol) and
2-amino-5-cyanophenylboronic acid pinacol ester 2g (73 mg, 0.3
mmol, 1.5 equiv) were added. The product was isolated by column
chromatography (10% EtOAc in hexanes) in 58% yield (33 mg, mp =
1
84−86 °C) as a off-white solid. H NMR (400 MHz, CDCl3): δ 8.33
(s, 1H), 7.60−7.29 (m, 3H), 6.90 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H),
3.44−3.30 (m, 2H), 3.19−2.99 (m, 2H). 13C NMR (500 MHz,
I
DOI: 10.1021/acs.joc.7b00568
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2873, 1603, 1508, 1433, 1328, 1243, 1165, 1124, 1101, 1080, 1027,
957, 892, 740, 699 cm−1. HRMS (DART): m/z [M + H]+ calcd for
C22H20F3N2 369.1573, found 369.1578.
2p (74 mg, 0.3 mmol, 1.5 equiv) were added. The product was isolated
by column chromatography (2−5% EtOAc in hexanes) in 68% yield
1
(40 mg, mp = 74−75 °C) as a clear colorless solid. H NMR (500
Methyl 5-Benzyl-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]-
pyrido[2,3-f ]azepine-8-carboxylate (4o). Following procedure 2, 1a
(42 mg, 0.2 mmol) and 2l (110 mg, 0.3 mmol, 1.5 equiv) were added.
The product was isolated by column chromatography (5% EtOAc in
MHz, CDCl3): δ 8.33 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H),
7.23−7.19 (m, 2H), 7.11−7.05 (m, 2H), 3.80 (q, J = 7.0 Hz, 2H), 3.36
(m, 2H), 3.23 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H). 13C NMR (500 MHz,
CDCl3): δ 155.8 (q, J(C−F) = 1.4 Hz), 147.3, 143.9, 137.3 (q, J(C−F)
=
1
hexanes) in 18% yield (15 mg) as clear colorless oil. H NMR (500
4.2), 137.4, 128.7, 123.68 (q, J(C−F) = 272.2 Hz), 126.9, 124.3 (q, J(C−F)
= 32.7 Hz), 124.6, 122.1 (q, J(C−F) = 3.51 Hz), 121.6, 45.2, 37.4, 29.6,
13.5. 19F NMR (500 MHz, CDCl3): δ −62.13. FT-IR: 2964, 2916,
2846, 1609, 1494, 1458, 1424, 1333, 1234, 1146, 1134, 1104, 961, 901,
765 cm−1. HRMS (DART): m/z [M + H]+ calcd for C16H16F3N2
293.1266, found 293.1266.
MHz, CDCl3): δ 8.34 (dd, J = 2.0, 1.0 Hz, 1H), 7.87 (s, 1H), 7.82 (dd,
J = 8.4, 2.1 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.37−7.29 (m, 2H),
7.29−7.23 (m, 2H), 7.23−7.14 (m, 2H), 5.00 (s, 2H), 3.88 (s, 2H),
3.43 (q, J = 4.9, 4.3 Hz, 2H), 3.34 (dd, J = 7.5, 4.3 Hz, 2H). 13C NMR
(500 MHz, CDCl3): δ 166.6, 156.5 (q, J(C−F) = 1.2 Hz), 151.2, 142.6,
138.6 (q, J(C−F) = 3.8 Hz), 136.1, 134.9, 130.9, 129.2, 128.7, 128.5,
127.9, 126.2, 125.4, 124.4 (q, J(C−F) = 33.2 Hz), 123.7 (q, J(C−F) = 3.4
Hz), 123.4 (q, J(C−F) = 272.6 Hz), 120.9, 56.0, 52.0, 36.6, 30.5. 19F
NMR (500 MHz, CDCl3): −62.28. FT-IR: 2961, 2855, 1717, 1609,
1499, 1431, 1337, 1293, 1227, 1128, 945, 911, 777, 741, 701 cm−1.
HRMS (DART): m/z [M + H]+ calcd for C23H20F3N2O2 413.1471,
found 413.1477.
5-Propyl-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f ]azepine (4t). Following procedure 2, 1a (42 mg, 0.2 mmol), 2q
(78 mg, 0.3 mmol, 1.5 equiv) were added. The product was isolated by
column chromatography (2−5% EtOAc in hexanes) in 70% yield (42
1
mg, mp = 55−56 °C) as a clear colorless solid. H NMR (500 MHz,
CDCl3): δ 8.23 (d, J = 0.6 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.14−
7.06 (m, 2H), 7.03−6.92 (m, 2H), 3.60 (t, J = 6.9 Hz, 2H), 3.29−3.22
(m, 2H), 3.16−3.11 (m, 2H), 1.49 (h, J = 7.2 Hz, 2H), 0.81 (t, J = 7.4
Hz, 3H). 13C NMR (500 MHz, CDCl3): δ 155.8 (q, J(C−F) = 1.4 Hz),
147.4, 144.0, 137.4 (q, J(C−F) = 4.2 Hz), 137.3, 128.8, 126.9, 124.6,
124.3 (q, J(C−F) = 32.4 Hz), 123.7 (q, J(C−F) = 272.9 Hz), 122.1 (q,
J(C−F) = 3.5 Hz), 121.6, 52.5, 37.4, 29.6, 20.7, 11.6.19F NMR (500
MHz, CDCl3): δ −62.13. FT-IR: 2970, 2930, 2882, 2855, 1603, 1494,
1416, 1335, 1226, 1124, 1098, 957, 899, 755 cm−1. HRMS (DART):
m/z [M + H]+ calcd for C17H18F3N2 307.1422, found 307.1422.
5-Benzyl-3-cyano-10,11-dihydro-5H-benzo[b]pyrido[2,3-f ]-
azepine (4u). Following procedure 2, 1a (33 mg, 0.2 mmol) and 2b
(92 mg, 0.3 mmol, 1.5 equiv) were added. The product was isolated by
column chromatography (5% EtOAc in hexanes) in 41% yield (26 mg,
5-Benzyl-7-cyano-3-(trifluoromethyl)-10,11-dihydro-5H-benzo-
[b]pyrido[2,3-f ]azepine (4p). Following procedure 2, 1a (42 mg, 0.2
mmol) and 2m (100 mg, 0.3 mmol, 1.5 equiv) were added. The
product was isolated by column chromatography (5% EtOAc in
1
hexanes) in 13% yield (10 mg) as a clear colorless oil. H NMR (500
MHz, CDCl3): δ 8.37 (dd, J = 2.0, 1.0 Hz, 1H), 7.55 (d, J = 1.9 Hz,
1H), 7.46 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 7.32−
7.23 (m, 4H), 7.24−7.16 (m, 2H), 4.98 (s, 2H), 3.43 (dd, J = 8.3, 4.4
Hz, 2H), 3.33−3.22 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 156.6
(d, J(C−F) = 1.5 Hz), 150.7, 142.4, 139.3 (q, J(C−F) = 4.1 Hz), 135.6,
135.5, 133.4, 130.9, 128.8, 127.9, 124.7 (q, J(C−F) = 32.9 Hz), 124.3 (q,
J(C−F) = 3.5 Hz), 123.3 (q, J(C−F) = 272.6 Hz), 121.6, 118.7, 106.9,
56.1, 35.9, 30.5. 19F NMR (500 MHz, CDCl3): δ −62.38. FT-IR: 3037,
2964, 2927, 2861, 2226, 1606, 1497, 1425, 1339, 1331, 1309, 1233,
1128, 1102, 947, 910, 834, 740, 699 cm−1. HRMS (DART): m/z [M +
H]+ calcd for C22H16F3N3 380.1369, found 380.1375.
1
mp = 146−148 °C) as a clear colorless solid. H NMR (500 MHz,
CDCl3): δ 8.26 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.37−
7.33 (m, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.24−7.14 (m, 4H), 7.09−7.04
(m, 1H), 4.94 (s, 2H), 3.43−3.36 (m, 2H), 3.36−3.28 (m, 2H). 13C
NMR (500 MHz, CDCl3): δ 156.4, 147.8, 143.2, 142.9, 136.8, 136.3,
128.8, 128.7, 127.8, 127.6, 127.2, 125.0, 121.7, 117.0, 106.8, 55.8, 38.2,
29.7. FT-IR: 3040, 2934, 2846, 2231, 1580, 1493, 1451, 1410, 1331,
1242, 1152, 1113, 961, 905, 762, 726, 697 cm−1. HRMS (DART): m/z
[M + H]+ calcd for C21H18N3 312.1495, found 312.1501.
N-Benzyl-3,7-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepine (4q). Following procedure 2, 1a (42 mg, 0.2 mmol), 2n
(113 mg, 0.6 mmol, 1.5 equiv), and KOH (50 mg, 0.6 mmol, 3 equiv)
were added (KOH was used in place of K2CO3). The product was
isolated by column chromatography (5% EtOAc in hexanes) in 24%
yield (21 mg) as a clear colorless oil. 1H NMR (400 MHz, CDCl3): δ
8.41 (d, J = 0.9 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H), 7.52 (s, 1H), 7.48
(dd, J = 8.5, 1.9 Hz, 1H), 7.45−7.38 (m, 2H), 7.37−7.30 (m, 3H),
7.29−7.27 (m, 1H), 5.06 (s, 2H), 3.53−3.50 (m, 2H), 3.44−3.41 (m,
2H). 13C NMR (500 MHz, CDCl3): δ 156.2 (d, J(C−F) = 1.4 Hz),
151.0−149.4 (q, 1.2), 142.6, 138.7 (q, J(C−F) = 4.1 Hz), 136.0, 135.8,
128.8, 128.0, 127.8, 126.3 (q, J(C−F) = 3.7 Hz), 125.9 (q, J(C−F) = 32.8
Hz), 124.4 (q, J(C−F) = 272.3 Hz), 124.4 (q, J(C−F) = 32.8 Hz), 124.0
(q, J(C−F) = 3.8 Hz), 124.0 (q, J(C−F) = 271.4 Hz), 123.6 (q, J(C−F) = 3.5
Hz), 121.3, 55.9, 36.4, 30.4. 19F NMR (377 MHz, CDCl3-insert): δ
−62.1, −62.3. FTIR: 3032, 2926, 2865, 1613, 1597, 1435, 1417, 1323,
1229, 1110, 947, 911, 831, 829 735, 699, 701, 635. HRMS (DART):
m/z [M + H]+ calcd for C22H17F6N2 423.1290, found 423.1292.
5-Methyl-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepine (4r). Following procedure 2, 1a (42 mg, 0.2 mmol) and
2o (70 mg, 0.3 mmol, 1.5 equiv) were added. The product was isolated
by column chromatography (2−5% EtOAc in hexanes) in 80% yield
3-Cyano-5-methyl-10,11-dihydro-5H-benzo[b]pyrido[2,3-f ]-
azepine (4v). Following procedure 2, 1a (33 mg, 0.2 mmol), 2o (70
mg, 0.3 mmol, 1.5 equiv) and KOH (50 mg, 0.6 mmol, 3 equiv) were
added (KOH was used in place of K2CO3). The product was isolated
by column chromatography (5% EtOAc in hexanes) in 51% yield (24
1
mg, 122−123 °C) as clear colorless needles. H NMR (500 MHz,
CDCl3): δ 8.30 (d, J = 1.7 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.25−
7.18 (m, 2H), 7.12−7.05 (m, 2H), 3.39−3.33 (m, 5H), 3.24−3.18 (m,
2H). 13C NMR (500 MHz, CDCl3): δ 155.2, 148.0, 143.9, 142.2,
136.3, 128.5, 127.1, 125.7, 124.5, 120.7, 117.2, 107.1, 40.3, 38.6, 29.7.
FT-IR: 2961, 2931, 2238, 1588, 1494, 1458, 1410, 1325, 1252, 1116,
989, 700 cm−1. HRMS (DART): m/z [M + H]+ calcd for C15H14N3
236.1183, found 236.1187.
3-(Trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-10,11-dihydro-
5H-benzo[b]pyrido[2,3- f]azepine (4w). The substrates used were 3-
chloro-5-(trifluoromethyl)-2-vinylpyridine (42 mg, 0.20 mmol, 1
equiv), 2-aminophenylboronic acid (66 mg, 0.3 mmol, 1.5 equiv),
and 1-chloro-4-(trifluoromethyl)benzene (32 μL, 0.24 mmol, 1.2
equiv). The product was isolated using column chromatography (40%
EtOAc/hexanes) to give the titled compound in 52% yield (21 mg, mp
155−158 °C) as a yellow crystalline solid. 1H NMR (400 MHz,
CDCl3): δ 8.73 (dd, J = 2.2, 1.0 Hz, 1H), 7.98 (d, J = 192.1 Hz, 1H),
7.52−7.33 (m, 6H), 6.67−6.54 (m, 2H), 3.29 (t, J = 6.8 Hz, 2H), 3.02
(dd, J = 7.6, 6.0 Hz, 2H). 13C NMR (126 MHz, CDCl3): δ 161.8 (q,
J(C−F) = 1.1 Hz), 150.28 (q, J = 1.1 Hz), 144.4 (q, J(C−F) = 3.9 Hz),
142.4, 139.1, 138.1, 134.7 (q, J(C−F) = 3.5 Hz), 130.6, 129.4, 128.9,
128.0, 126.6 (q, J(C−F) = 3.7 Hz), 125.4 (q, J(C−F) = 33.3 Hz), 124.5 (q,
J(C−F) = 270.7 Hz), 123.0 (q, J(C−F) = 272.6 Hz), 121.0 (q, J(C−F) = 32.8
Hz), 112.4, 35.3, 28.5. 19F NMR (376 MHz, CDCl3): δ −61.51,
1
(44 mg) as a clear colorless oil. H NMR (500 MHz, CDCl3): δ 8.31
(s, 1H), 7.44 (s, 1H), 7.25−7.19 (m, 2H), 7.12−7.04 (m, 2H), 3.39−
3.36 (m, 5H), 3.22 (m, 2H). 13C NMR (500 MHz, CDCl3): δ 154.5
(q, J(C−F) = 1.4 Hz), 148.3, 144.0, 136.6 (q, J(C−F) = 4.2 Hz), 136.2,
128.6, 126.9, 124.4 (q, J(C−F) = 32.4 Hz), 124.2, 123.7 (q, J(C−F)
=
272.8 Hz), 120.4, 120.3 (q, J(C−F) = 3.5 Hz), 40.1, 38.1, 29.9. 19F NMR
(500 MHz, CDCl3): δ −62.14. FT-IR: 2929, 2812, 1603, 1564, 1495,
1457, 1434, 1413, 1336, 1283, 1116, 1099, 944, 889, 758, 634 cm−1.
HRMS (DART): m/z [M + H]+ calcd for C15H14F3N2 279.1109,
found 279.1109.
5-Ethyl-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido-
[2,3-f]azepine (4s). Following procedure 2, 1a (42 mg, 0.2 mmol) and
J
DOI: 10.1021/acs.joc.7b00568
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−62.07. IR (NaCl, neat): 2930, 2859, 1605, 1518, 1410, 1321, 1165,
1138, 1117, 1069, 827, 756 cm-1. HRMS (DART): m/z cacld for
C21H15F6N2 (M+H)+ 409.1139, found 409.1142.
(21) Pd(OAc)2 only worked well with substrates 1a and 2b.
Changing 1a to 1d, for example, afforded no product.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00568.
1H, 13C NMR for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
ORCID
Heather Lam: 0000-0002-0715-7575
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science and Engineering Research
Council (NSERC), Alphora, Inc., and The University of
Toronto for financial support. Special thanks to T. Johnson for
valuable suggestions and help with the manuscript.
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DOI: 10.1021/acs.joc.7b00568
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