Synthesis of Substituted 2,3-Benzodiazepines

Article abstract of DOI:10.1021/acs.joc.6b01935

A new, four-step synthetic route for substituted 2,3-benzodiazepines 1, starting from aldehyde 4, was developed with excellent overall yields. This route included the 1,2-addition of various aromatic Grignard reagents to 4, PCC oxidation, and aerobic Wacker-type oxidation of the olefinic group of 6, followed by condensation of the resulting 1,5-dicarbonyl 7 with N₂H₄. Isoquinolones 9 were obtained when an aldehyde group was used instead of a ketone. The key structures were confirmed by X-ray single-crystal diffraction analysis.

Full text of DOI:10.1021/acs.joc.6b01935

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Article
Synthesis of Substituted 2,3-Benzodiazepines
Chieh-Kai Chan, Yu-Lin Tsai, Yi-Ling Chan, and Meng-Yang Chang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Oct 2016
Downloaded from http://pubs.acs.org on October 7, 2016
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Synthesis of Substituted 2,3-Benzodiazepines
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Chieh-Kai Chan, Yu-Lin Tsai, Yi-Ling Chan and Meng-Yang Chang*
*mychang@kmu.edu.tw
Department of Medicinal and Applied Chemistry, and General Research Centers of R&D office, Kaohsiung Medical
University, Kaohsiung 807, Taiwan
ABSTRACT
A new, four-step synthetic route for substituted 2,3-benzodiazepines 1, starting from aldehyde 4, was
developed with excellent overall yields. This route was carried out by the 1,2-addition of 4 with various
aromatic Grignard reagents, PCC-oxidation, and aerobic Wacker-type oxidation of the olefinic group of
6, followed by condensation of the resulting 1,5-dicarbonyl 7 with N2H4. Isoquinolones 9 were obtained
when an aldehyde group was used instead of a ketone. The key structures were confirmed by X-ray
single crystal diffraction analysis.
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INTRODUCTION
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The benzodiazepine moiety is considered a prominent skeleton in medicinal chemistry, and many
biologically active compounds, such as those with anti-inflammatory, anticonvulsant, antianxiety,
antidepressive, sedative, psychoactive and hypnotic activities, possess this important core.1 Among them,
substituted 2,3-benzodiazepines 1 act as tranquilizing agents and constitute the partial molecules of
meaningful scaffolds known as noncompetitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic
acid (AMPA) receptor antagonists, which exert anticonvulsant and neuroprotective activities.2 Further,
tofisopam, which is the most activated derivative, was found to be a highly active nonsedative,
anxiolytic in humans.3 Other representative 2,3-benzodiazepines, such as girisopam and nerisopam, are
biologically active (Figure 1). Some synthetic routes for the synthesis of the 2,3-benzodiazepine
skeleton, such as the four-step formation starting from arylethanols or arylacetones,4 base-mediated
reaction of arynes with β-diketones5 and acid-promoted transformation from 2-benzopyrylium salts6
have been reported. Herein, a facile synthetic route starting from commercially available materials with
higher isolated yields is reported.
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Figure 1. Bioactive 2,3-benzodiazepines
RESULTS AND DISCUSSION
Recently, we developed a series of synthetic routes toward benzofused compounds, such as
1-azahomoisotwistanes,7 benzodioxepanes,8 benzo[g]indazoles,9 benzo[g]chrysenes,10 2-naphthols,11
isochromenes12 and isoquinolines,13 by using commercially available isovanillin (2a) as a starting
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material. All of the compounds were derived from the versatile 2-allylbenzaldehyde (4), which was
easily prepared via a three-step synthesis with moderate overall yields by a reaction procedure of
O-allylation and Claisen rearrangement followed by O-alkylation. We established the synthetic
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procedures
for
substituted
benzazepines,
including
dihydro-1-benzazepines14
and
tetrahydro-3-benzazepines via the facile, efficient and high-yields synthetic routes.15 Based on these
results, the synthesis of dinitrogen-containing, heterocyclic 2,3-benzodiazepines 1, skeletons from
2-allylbenzaldehyde 2 was our goal (Scheme1).
Allylbenzenes are well-known molecules with naturally occurring scaffolds that are mainly isolated
from plants.16 Among them, generalized allylbenzenes, such as 2-propenylbenzenes and
1-propenylbenzenes, are widely used in the pharmaceutical, materials chemistry, fragrance, and
cosmetic industries and are also important intermediates for the construction of complicated compounds
in organic chemistry.17
Scheme 1. Synthesis of benzofused nitrogen-containing compounds
On the basis of our successful experiments, including Grignard addition of aldehydes,
PCC-oxidation of secondary alcohols and aerobic Wacker-type oxidation of the resulting terminal
olefins,11 we believed that it may be possible to develop a synthetic route for the 1,5-dicarbonyl skeleton
7, which can condense with N2H4 to afford 2,3-benzodiazepines. As shown in Table 1, an efficient
five-step synthetic route was employed to build 6 from isovanillin (2a) and 2-hydroxybenzaldehyde (2b)
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via (i) O-allylation with allyl or trans-crotyl bromide (R = H or Me), (ii) Claisen rearrangement with
decalin, (iii) O-alkylation or O-benzylation of 3 with alkyl or benzyl bromide, (iv) Grignard 1,2-addition
with arylmagnesium bromide (R2 = 4-OMeC6H4, 4-FC6H4, 4-MeC6H4, 2-MeC6H4 and C6H5) and (v)
oxidation with pyridinium chlorochromate (PCC).
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Table 1. Five-step synthesis of 6a, b
6a (90%)
6b (83%)
6c (85%)
6d (86%)
6e (88%)
6f (86%)
6k (86%)
6g (87%)
6l (84%)
6h (84%)
6m (81%)
6i (89%)
6n (88%)
6j (87%)
6o (83%)
6p (85%)
6q (83%)
6r (82%)
6s (89%)
6t (87%)
6u (85%)
6v (83%)
6w (81%)
6x (90%)
6y (86%)
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OMe
MeO
O
OMe
6z (84%)
6aa (78%)
11
a
b
1
The reactions were conducted on a 1.0 mmol scale with 2. The isolated products 6a-6aa were >95% pure as determined by H
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NMR analysis.
Next, for the aerobic Wacker reaction of 6 with a terminal olefin moiety, 6a was selected as the
model substrate in a PdII/CuII system catalyzed oxidation. Then, the condensation reaction of in situ
generated 7 with N2H4 took place. As shown in Table 2, after screening different Wacker-type oxidative
conditions and our previous work,11,18 we still believed that the PdCl2/CuCl2 system-mediated
Wacker-type oxidation by O2 was better than other oxidants such as CAN, DDQ, IBX, Oxone, t-BuO2H
and TBHP, which all gave lower yields (entries 1-6). When molecular oxygen was used as the oxidant,
the isolated yield increased to 91% (entry 7). No apparent yield was isolated when the amounts of PdCl2
and CuCl2 were increased (entries 8-10). Changing the Pd(II) catalyst from PdCl2 to Pd(OAc)2, PdBr2,
PdCl2(MeCN)2, PdCl2(PPh3)2 or Pd2(dba)3 gave a similar yield of the desired 1,5-dicarbonyl 7a as
shown in entries 11-15. Without molecular oxygen, 7a was only isolated in a 15% yield, with 6a
recovered in a yield of 80% (entry 16).
Table 2. Reaction conditions of 6aa,b
entry PdII (mol %)
PdCl2 (5.8)
CuCl2 (eq.)oxidants (eq.) yield (%)b
1.5 CAN (1.0)
20c
1
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PdCl2 (5.8)
PdCl2 (5.8)
PdCl2 (5.8)
PdCl2 (5.8)
PdCl2 (5.8)
PdCl2 (5.8)
PdCl2 (11.6)
PdCl2 (5.8)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
1.5
1.5
1.5
1.5
1.5
1.5
DDQ (1.0)
18c
15c
16c
19c
14c
91d
85d
83d
84d
85d
86d
85d
83d
83d
15e
IBX (1.0)
Oxone (1.0)
t-BuO2H (1.0)
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TBHP (1.0)
O2
O2
O2
O2
O2
O2
O2
O2
O2
air
10 PdCl2 (11.6)
11 Pd(OAc)2 (5.8)
12 PdBr2 (5.8)
13 PdCl2(ACN)2 (5.8)
14 PdCl2(PPh3)2 (5.8)
15 Pd2(dba)3 (5.8)
16 PdCl2 (5.8)
a The reactions were conducted on a 1.0 mmol scale with 6a. b 7a was >95% pure as determined by H NMR analysis. c Unknown
1
d
products were obtained (entry1, 5%; entry 2, 6%; entry 3, 6%; entry 4, 5%; entry 5, 7%; entry 6, 5%). Trace amounts (< 5%) of
unknown products were obtained. e The starting material 6a was recovered in 80% yield.
The above results show that 7a was isolated in high yield (Table 2, entry 7). An efficient synthetic
route for substituted 2,3-benzodiazepines 1 from 6 was created. Based on the results, 6a was selected as
the model substrate to test the feasibility of a one-pot method with N2H4. Accordingly, the desired
product 1a was obtained in good yield, and the overall two-step yield was 87% (Scheme 2).
Scheme 2. One-pot synthetic route for 1a from 6a
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Based on the optimal conditions (Scheme 2), we further examined the substrate scope and
generality of the reaction. The electron-donating group (R2 = 4-OMe) and various aryl substituents on 6,
including an electron-withdrawing group (R2 = 4-F) and electron-neutral groups (R2 = 4-Me, 2-Me or H),
were all also suitable for the synthesis of 1b-1e. Changing the R1 substituents of 6 to isopropyl, n-butyl,
cyclopentyl and benzyl groups was well tolerated, providing the desired 1f-1y products. Accordingly, 1z
(X = OMe, R = Me) and 1aa (X = H, R = H) were also synthesized in this transformation. Consequently,
6a-6aa were synthesized in this successive procedure, which included a Wacker-type oxidation and
condensation with N2H4 to synthesize 2,3-benzodiazepines 1a-1aa in high yields ranging from 79% to
90%. All of the compound structures and corresponding isolated yields for 1a-1aa are shown in Table 3.
The structures of 1a, 1c, 1p and 7y were determined by single-crystal X-ray crystallography.19
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Table 3. Synthesis of 1a
OMe
OMe
OMe
MeO
MeO
MeO
N
N
N
N
N
N
F
MeO
1a (87%)
1b (88%)
1c (83%)
1d (86%)
1e (90%)
O
O
O
MeO
MeO
MeO
N
N
N
N
N
N
MeO
1f (89%)
O
F
1g (82%)
O
1h (81%)
1m (82%)
1i (86%)
1n (86%)
1j (88%)
O
MeO
MeO
MeO
N
N
N
N
N
N
F
MeO
1k (89%)
1l (85%)
1o (88%)
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O
O
O
MeO
MeO
MeO
N
N
N
N
N
N
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MeO
F
1p (90%)
1q (85%)
1r (84%)
1s (84%)
1t (85%)
O
O
O
MeO
MeO
MeO
N
N
N
N
N
N
MeO
F
1u (89%)
1v (83%)
1w (81%)
1x (85%)
1y (84%)
OMe
OMe
MeO
N
N
N
N
MeO
MeO
1z (85%)
1aa (79%)
a
Optimal reaction conditions: (i) compound 6 (1.0 mmol), PdCl2 (10 mg, 5.8 mol %), CuCl2 (200 mg, 1.5 mmol), O2 (bubbled),
dioxane (10 mL), rt, 10 h, (ii) N2H4 (2 mL), rt, 10 min. b The isolated products 1a-1aa were >95% pure as determined by H NMR
1
analysis.
Isoquinolone is an important molecular framework in alkaloidal natural products, and compounds
that contain this skeleton show distinct bioactivities.20 Due to their chemical stability, isoquinolones are
frequently used as building blocks.21 Among them, functionalized isoquinolin-1(2H)-ones appear in
numerous natural products and drugs.22 Although a number of methods for the synthesis of
isoquinolin-1(2H)-ones and their derivatives are available, the development of efficient approaches for
the synthesis of the isoquinolin-1(2H)-one skeleton is of interest.23 Starting material 6 when changed to
4, which has an H atom instead of the Ar substituent group (ketonealdehyde), and a Wacker-type
oxidation afforded compound 8. Then, 8 reacted with N2H4 under optimized conditions. Intriguingly, the
desired 2,3-benzodiazepine was not observed, but the substituted isoquinolones 9a-9d were isolated in
good yields (Scheme 3). The structure of 9a was confirmed by single-crystal X-ray crystallography (see
Supporting Information).19
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Scheme 3. Synthesis of 1 and 9
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The possible mechanism for the synthesis of 9a is shown in Scheme 4. First, the pathway
intermediate I should form via the condensation of 4a with N2H4. With an intramolecular aldol-type
condensation of I, IV was formed from the hydrated reaction of II and dehydration of III (path a). In
another route (path b), the deprotonative elimination of hydroxyl anion from III to install the alkene is
likely to compete with the cleavage of the C-N bond leading to formation of an enol I-1, which will
reverse to I by tautomerization. Then, in situ hydration generated IV to achieve V. Finally, the
oxygen-catalyzed oxidation of V was conducted to formed 9a.
Scheme 4. Possible mechanism
The differential behavior of 7 and 8 with N2H4 was discussed in Scheme 5. For the construction of
2,3-benzodiazepines 1, we think that N2H4 first preferred to treat with C5 position of 7 via
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intermolecular condensation (carbonyl reactivity: C5 > C1). Subsequently, the formal (5+2) annulation
was achieved by intramolecular condensation between primary amine and benzylic ketone (eq. 1).
Compared with the formation of isoquinolin-1(2H)-ones 9, the formyl group (C1) of aldehydes 8
favored to react with N2H4 than C5 carbonyl position by intermolecular condensation. In the following
intramolecular process, the formal (5+1) annulation of tertiary amine with ketone was conducted due to
the tendency of the ring closure (six-membered > seven-membered), as shown in equation 2. Therefore,
N2H4 played as a key condensation role for the construction of bicycles 1 and 9 via the intermolecular
and intramolecular routes.
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Scheme 5. Differential behavior of 7 and 8 with N2H4
On the basis of our successful experiments for the synthesis of substituted quinoxalines,24 we
changed the di-nitrogen source from N2H4 (H2N-NH2) to 1,2-diaminobenzene (H2N-C-C-NH2). 8a was
transformed into benzimidazo[2,1-a]isoquinoline 10 in high yield (Scheme 6).
Scheme 6. Synthesis of 10
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In summary, we have presented a facile synthetic route for the synthesis of substituted
2,3-benzodiazepines via Grignard addition, PCC-oxidation, aerobic Wacker-type oxidation and the
condensation with N2H4 in high yields. Changing the functional group from allylketone to allylaldehyde,
one-pot procedure of Wacker-type oxidation/N2H4 or 1,2-diaminobenzene condensation provided the
functionalized isoquinolin-1(2H)-ones and benzimidazo[2,1-a]isoquinoline in good to excellent yields
under the optimal conditions. This protocol started from simple starting materials and reagents, provided
a new synthetic route toward the skeleton of 2,3-benzodiazepines. The structural frameworks of key
products were confirmed by X-Ray single crystal diffraction analysis. Further investigation regarding
synthetic applications of 2-allylbenzaldehyde and bioactive applications of and 2,3-benzodiazepines will
be conducted and published in due course.
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EXPERIMENT SECTION
General
All other reagents and solvents were obtained from commercial sources and used without further
purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic
stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration
in vacuo. Purity was determined by NMR and melting point. Melting points were determined with a
SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian spectrometer operating at
400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the
coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a
mass spectrometer microTOF-Q by ESI using a hybrid ion-trap. X-ray crystal structures were obtained
with an diffractometer (CAD4, Kappa CCD).
General synthetic procedure for synthesis of 6a-6aa is as follows
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A solution of a Grignard reagent (1.0 M in THF, 1.5 mL, 1.5 mmol) was added to a stirred solution
of skeleton 4 (1.0 mmol) in THF (10 mL) at ice bath. The reaction mixture was stirred at rt for 5 h.
Water (5 mL) was added to the reaction mixture and the mixture was filtered through a short plug of
Celite. The filtrate was concentrated under reduced pressure. The residue was extracted with EtOAc (3 x
50 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford
different crude product under reduced pressure. Without further purification, a solution of the resulting
secondary alcohol 5 in DCM (10 mL) was added to a mixture of pyridinium chlorochromate (430 mg,
2.0 mmol) and Celite (500 mg) in DCM (20 mL). After being stirred at rt for 3 h, the mixture was
filtered through a short silica gel column. The filtrate was dried, filtered, and evaporated to yield crude
compound. Purification on silica gel (hexanes/EtOAc = 6/1~3/1) afforded 6a-6aa.
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(2-Allyl-3,4-dimethoxyphenyl)(4-methoxyphenyl)methanone (6a).13a
Yield = 90% (281 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.8 Hz, 2H), 6.98 (d,
J = 8.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.4 Hz, 1H), 5.89-5.79 (m, 1H), 4.86-4.79 (m, 2H),
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3.82 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.51 (dt, J = 1.2, 6.0 Hz, 2H); C NMR (100 MHz, CDCl3): δ
195.8, 163.1, 154.0, 147.3, 136.9, 133.3, 132.2 (2x), 132.0, 130.7, 125.1, 115.0, 113.2 (2x), 108.7, 60.4,
55.4, 55.1, 30.4; HRMS (ESI, M++Na) calcd for C19H20O4Na 335.1259, found 335.1252.
(2-Allyl-3,4-dimethoxyphenyl)(4-fluorophenyl)methanone (6b).13a
Yield = 83% (249 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.81-7.77 (m, 2H), 7.13-7.07 (m,
2H), 7.04 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.93-5.83 (m, 1H), 4.90-4.84 (m, 2H), 3.92 (s,
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3H), 3.85 (s, 3H), 3.58 (dt, J = 1.6, 6.0 Hz, 2H); C NMR (100 MHz, CDCl3): δ 195.9, 165.5 (d, J =
253.2 Hz), 154.7, 147.8, 137.1, 134.7 (d, J = 3.1 Hz,), 134.1, 132.8 (d, J = 9.1 Hz, 2x), 131.6, 125.9,
115.4, 115.3 (d, J = 21.9 Hz, 2x), 108.9, 60.9, 55.7, 30.5; HRMS (ESI, M++H) calcd for C18H18FO3
301.1240, found 301.1244.
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(2-Allyl-3,4-dimethoxyphenyl)(p-tolyl)methanone (6c).
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Yield = 85% (252 mg); Colorless solid; mp = 59-60 C (recrystallized from hexanes and EtOAc); H
NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H),
6.79 (d, J = 8.4 Hz, 1H), 5.94-5.84 (m, 1H), 4.91-4.85 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.58 (dt, J =
1.6, 6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.2, 154.5, 147.7, 143.6, 137.2, 135.8,
134.0, 132.2, 130.4 (2x), 128.9 (2x), 125.9, 115.3, 108.9, 60.8, 55.7, 30.6, 21.6; HRMS (ESI, M++H)
calcd for C19H21O3 297.1491, found 297.1493.
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(2-Allyl-3,4-dimethoxyphenyl)(o-tolyl)methanone (6d).13a
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Yield = 86% (255 mg); Colorless gum; H NMR (400 MHz, CDCl3): δ 7.37-7.15 (m, 4H), 7.06 (d, J =
8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.05-5.95 (m, 1H), 5.00-4.94 (m, 2H), 3.89 (s, 3H), 3.85 (s, 3H),
3.77 (dt, J = 1.6, 6.4 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 199.3, 155.4, 147.7, 139.7,
137.6, 137.3, 135.1, 132.0, 131.0, 130.5, 129.8, 128.4, 125.1, 115.1, 108.7, 60.8, 55.6, 30.3, 20.3;
HRMS (ESI, M++H) calcd for C19H21O3 297.1491, found 297.1496.
(2-Allyl-3,4-dimethoxyphenyl)(phenyl)methanone (6e).13a
Yield = 88% (248 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.78-7.75 (m, 2H), 7.57-7.52 (m,
1H), 7.44-7.40 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.95-5.86 (m, 1H), 4.92-4.89
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(m, 1H), 4.88-4.86 (m, 1H), 3.91 (s, 3H), 3.85 (s, 3H), 3.60 (dt, J = 1.6, 6.4 Hz, 2H); C NMR (100
MHz, CDCl3): δ 197.4, 154.6, 147.7, 138.4, 137.1, 134.2, 132.6, 131.7, 130.1 (2x), 128.1 (2x), 126.2,
115.3, 108.8, 60.8, 55.7, 30.5; HRMS (ESI, M++Na) calcd for C18H18O3Na 305.1154, found 305.1146.
(2-Allyl-3-isopropoxy-4-methoxyphenyl)(4-methoxyphenyl)methanone (6f).
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Yield = 86% (293 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.8 Hz, 2H), 6.98 (d, J
= 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 1H), 5.84-5.74 (m, 1H), 4.83-4.78 (m, 2H),
4.58-4.51 (m, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.59 (dt, J = 1.6, 6.4 Hz, 2H), 1.29 (d, J = 6.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3): δ 196.3, 163.2, 154.2, 145.1, 136.6, 133.8, 132.9, 132.4 (2x), 131.1, 124.8,
115.2, 113.3 (2x), 108.6, 74.7, 55.5, 55.3, 30.8, 22.5 (2x); HRMS (ESI, M++Na) calcd for C21H24O4Na
363.1572, found 363.1566.
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(2-Allyl-3-isopropoxy-4-methoxyphenyl)(4-fluorophenyl)methanone (6g).
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Yield = 87% (285 mg); Colorless solid; mp = 46-47 C (recrystallized from hexanes and EtOAc); H
NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.07-7.02 (m, 2H), 6.96
(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.83-5.73 (m, 1H), 4.81-4.76 (m, 2H), 4.57-4.51 (m, 1H),
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3.83 (s, 3H), 3.61 (dt, J = 1.6, 6.0 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H); C NMR (100 MHz, CDCl3): δ
195.9, 165.3 (d, J = 252.5 Hz), 154.6, 145.2, 136.6, 134.6 (d, J = 3.0 Hz), 134.2, 132.5 (d, J = 9.1 Hz,
2x), 131.5, 125.2, 115.3, 115.1 (d, J = 21.2 Hz, 2x), 108.6, 74.7, 55.4, 30.5, 22.4 (2x); HRMS (ESI,
M++Na) calcd for C20H21FO3Na 351.1372, found 351.1366.
(2-Allyl-3-isopropoxy-4-methoxyphenyl)(p-tolyl)methanone (6h).
Yield = 84% (272 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 2H), 7.22 (d, J
= 8.0 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.86-5.76 (m, 1H), 4.85-4.80 (m, 2H),
4.58-4.52 (m, 1H), 3.88 (s, 3H), 3.62 (dt, J = 1.6, 6.4 Hz, 2H), 2.41 (s, 3H), 1.31 (d, J = 6.4 Hz, 6H); 13C
NMR (100 MHz, CDCl3): δ 197.4, 154.5, 145.2, 143.4, 136.8, 135.9, 134.3, 132.3, 130.3 (2x), 128.9
(2x), 125.4, 115.4, 108.6, 74.9, 55.6, 30.8, 22.6 (2x), 21.6; HRMS (ESI, M++H) calcd for C21H25O3Na
325.1804, found 325.1809.
(2-Allyl-3-isopropoxy-4-methoxyphenyl)(o-tolyl)methanone (6i).
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Yield = 89% (289 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.37-7.32 (m, 1H), 7.28-7.23 (m,
2H), 7.19-7.15 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.96-5.86 (m, 1H), 4.95-4.90
(m, 2H), 4.58-4.52 (m, 1H), 3.86 (s, 3H), 3.79 (dt, J = 1.6, 6.4 Hz, 2H), 2.39 (s, 3H), 1.31 (d, J = 6.0 Hz,
6H); 13C NMR (100 MHz, CDCl3): δ 199.5, 155.4, 145.3, 139.7, 137.8, 137.0, 135.5, 132.3, 131.1,
130.5, 129.9, 127.8, 125.1, 115.2, 108.5, 74.8, 55.5, 30.5, 22.5 (2x), 20.4; HRMS (ESI, M++Na) calcd
for C21H24O3Na 347.1623, found 347.1617.
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(2-Allyl-3-isopropoxy-4-methoxyphenyl)(phenyl)methanone (6j).
Yield = 87% (270 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.77-7.74 (m, 2H), 7.57-7.53 (m,
1H), 7.45-7.41 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.87-5.77 (m, 1H), 4.86-4.83
(m, 1H), 4.82-4.80 (m, 1H), 4.59-4.53 (m, 1H), 3.88 (s, 3H), 3.64 (dt, J = 1.6, 6.4 Hz, 2H), 1.31 (d, J =
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6.0 Hz, 6H); C NMR (100 MHz, CDCl3): δ 197.7, 154.8, 145.3, 138.5, 136.8, 134.6, 132.6, 130.5,
130.2 (2x), 128.2 (2x), 125.8, 115.4, 108.6, 74.9, 55.6, 30.7, 22.6 (2x); HRMS (ESI, M++Na) calcd for
C20H22O3Na 333.1467, found 333.1460.
(2-Allyl-3-butoxy-4-methoxyphenyl)(4-methoxyphenyl)methanone (6k).
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Yield = 86% (305 mg); Colorless solid; mp = 59-60 C (recrystallized from hexanes and EtOAc); H
NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H),
6.77 (d, J = 8.4 Hz, 1H), 5.91-5.81 (m, 1H), 4.86-4.82 (m, 2H), 3.96 (t, J = 7.2 Hz, 2H), 3.87 (s, 3H),
3.83 (s, 3H), 3.56 (d, J = 1.6, 6.0 Hz, 2H), 1.81-1.74 (m, 2H), 1.55-1.46 (m, 2H), 0.97 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 196.2, 163.3, 154.3, 146.8, 137.1, 133.6, 132.5 (2x), 132.3, 131.1, 125.2,
115.1, 113.3 (2x), 108.8, 72.9, 55.6, 55.3, 32.3, 30.6, 19.1, 13.8; HRMS (ESI, M++Na) calcd for
C22H26O4Na 377.1729, found 377.1722.
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(2-Allyl-3-butoxy-4-methoxyphenyl)(4-fluorophenyl)methanone (6l).
Yield = 84% (287 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.8 Hz, 1H), 7.76 (d, J
= 8.8 Hz, 1H), 7.10-7.04 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.91-5.81 (m, 1H),
4.85-4.80 (m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.58 (dt, J = 1.6, 6.0 Hz, 2H), 1.80-1.73 (m,
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2H), 1.55-1.46 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 195.8, 165.4 (d, J =
253.2 Hz), 154.7, 146.9, 137.0, 134.7 (d, J = 3.0 Hz), 134.1, 132.6 (d, J = 9.1 Hz, 2x), 131.4, 125.7,
115.2 (d, J = 22.0 Hz, 2x), 115.2, 108.8, 72.9, 55.6, 32.3, 30.4, 19.1, 13.8; HRMS (ESI, M++Na) calcd
for C21H23FO3Na 365.1529, found 365.1525.
(2-Allyl-3-butoxy-4-methoxyphenyl)(p-tolyl)methanone (6m).
Yield = 81% (274 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 2H), 7.22 (d, J
= 8.0 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.93-5.83 (m, 1H), 4.89-4.83 (m, 2H),
3.97 (t, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.59 (dt, J = 1.6, 6.4 Hz, 2H), 2.41 (s, 3H), 1.82-1.75 (m, 2H),
1.57-1.47 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 197.3, 154.6, 146.9, 143.5,
137.2, 135.8, 134.1, 132.1, 130.4 (2x), 128.9 (2x), 125.7, 115.2, 108.8, 73.0, 55.7, 32.3, 30.6, 21.6, 19.2,
13.9; HRMS (ESI, M++H) calcd for C22H27O3 339.1960, found 339.1965.
(2-Allyl-3-butoxy-4-methoxyphenyl)(o-tolyl)methanone (6n).
Yield = 88% (342 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.37-7.33 (m, 1H), 7.27-7.23 (m,
2H), 7.20-7.16 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.03-5.93 (m, 1H), 4.98-4.92
(m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 3.88 (s, 3H), 3.77 (dt, J = 1.6, 6.0 Hz, 2H), 2.38 (s, 3H), 1.83-1.76 (m,
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2H), 1.57-1.48 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 199.5, 155.5, 147.0,
139.8, 137.7, 137.4, 135.3, 132.1, 131.1, 130.5, 129.9, 128.3, 125.2, 115.1, 108.7, 73.1, 55.6, 32.3, 30.4,
20.4, 19.2, 13.9; HRMS (ESI, M++Na) calcd for C22H26O3Na 361.1780, found 361.1775.
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(2-Allyl-3-butoxy-4-methoxyphenyl)(phenyl)methanone (6o).
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1H), 7.42-7.39 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.94-5.84 (m, 1H), 4.90-4.84
(m, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.63 (dt, J = 1.6, 6.4 Hz, 2H), 1.82-1.75 (m, 2H),
1.57-1.47 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 197.4, 154.7, 146.9, 138.4,
137.1, 134.2, 132.5, 131.6, 130.1 (2x), 128.1 (2x), 126.0, 115.1, 108.7, 72.9, 55.6, 32.3, 30.5, 19.1, 13.8;
HRMS (ESI, M++Na) calcd for C21H24O3Na 347.1623, found 347.1619.
(2-Allyl-3-(cyclopentyloxy)-4-methoxyphenyl)(4-methoxyphenyl)methanone (6p).
Yield = 85% (311 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.8 Hz, 2H), 6.98 (d, J
= 8.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 5.85-5.75 (m, 1H), 4.91-4.86 (m, 1H),
4.83-4.77 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.56 (dt, J = 1.6, 6.0 Hz, 2H), 1.93-1.71 (m, 6H), 1.61-1.57
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(m, 2H); C NMR (100 MHz, CDCl3): δ 196.4 163.3, 154.1, 145.5, 136.7, 133.8, 132.4 (2x), 132.4,
131.1, 124.7, 115.2, 113.3 (2x), 108.8, 84.6, 55.5, 55.4, 32.8 (2x), 30.7, 23.6 (2x); HRMS (ESI, M++H)
calcd for C23H27O4 367.1909, found 367.1904.
(2-Allyl-3-(cyclopentyloxy)-4-methoxyphenyl)(4-fluorophenyl)methanone (6q).
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Yield = 83% (294 mg); Colorless solid; mp = 70-71 C (recrystallized from hexanes and EtOAc); H
NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.11-7.05 (m, 2H), 6.97
(d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.85-5.75 (m, 1H), 4.91-4.82 (m, 1H), 4.82-4.77 (m, 2H),
3.88 (s, 3H), 3.59 (dt, J = 1.6, 6.0 Hz, 2H), 1.93-1.70 (m, 6H), 1.62-1.57 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 196.1, 165.4 (d, J = 253.2 Hz), 154.5, 145.7, 136.7, 134.7 (d, J = 3.0 Hz), 134.2, 132.7 (d, J =
9.1 Hz, 2x), 131.6, 125.2, 115.3, 115.2 (d, J = 21.2 Hz, 2x), 108.8, 84.7, 55.6, 32.8 (2x), 30.6, 23.6 (2x);
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HRMS (ESI, M++Na) calcd for C22H23FO3Na 377.1529, found 377.1523.
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(2-Allyl-3-(cyclopentyloxy)-4-methoxyphenyl)(p-tolyl)methanone (6r).
Yield = 82% (287 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 2H), 7.21 (d, J
= 8.0 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.87-5.77 (m, 1H), 4.91-4.87 (m, 1H),
4.85-4.80 (m, 2H), 3.87 (s, 3H), 3.60 (dt, J = 1.6, 6.0 Hz, 2H), 2.40 (s, 3H), 1.94-1.72 (m, 6H), 1.62-1.56
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(m, 2H); C NMR (100 MHz, CDCl3): δ 197.3, 154.3, 145.5, 143.4, 136.7, 135.8, 134.1, 132.1, 130.3
(2x), 128.8 (2x), 125.2, 115.2, 108.7, 84.6, 55.5, 32.8 (2x), 30.6, 23.6 (2x), 21.5; HRMS (ESI, M++H)
calcd for C23H27O3 351.1960, found 351.1965.
(2-Allyl-3-(cyclopentyloxy)-4-methoxyphenyl)(o-tolyl)methanone (6s).
Yield = 89% (312 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.37-7.33 (m, 1H), 7.28-7.23 (m,
2H), 7.19-7.15 (m, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.96-5.86 (m, 1H), 4.94-4.85
(m, 3H), 3.87 (s, 3H), 3.76 (dt, J = 1.6, 6.4 Hz, 2H), 2.39 (s, 3H), 1.94-1.81 (m, 4H), 1.79-1.72 (m, 2H),
1.64-1.58 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 199.6, 155.3, 145.7, 139.7, 137.8, 137.0, 135.3,
132.3, 131.1, 130.5, 129.9, 127.7, 125.1, 115.2, 108.7, 84.7, 55.6, 32.8 (2x), 30.4, 23.6 (2x), 20.4;
HRMS (ESI, M++Na) calcd for C23H26O3Na 373.1780, found 373.1773.
(2-Allyl-3-(cyclopentyloxy)-4-methoxyphenyl)(phenyl)methanone (6t).
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Yield = 87% (292 mg); Colorless oil; H NMR (400 MHz, CDCl3): δ 7.76-7.73 (m, 2H), 7.54-7.49 (m,
1H), 7.41-7.37 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 5.88-5.78 (m, 1H), 4.91-4.88
(m, 1H), 4.85-4.80 (m, 2H), 3.86 (s, 3H), 3.62 (dt, J = 1.6, 6.4 Hz, 2H), 1.94-1.70 (m, 6H), 1.64-1.53 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 197.5, 154.4, 145.5, 138.4, 136.7, 134.2, 132.5, 131.7, 130.0 (2x),
128.0 (2x), 125.5, 115.2, 108.7, 84.5, 55.5, 32.7 (2x), 30.5, 23.5 (2x); HRMS (ESI, M++Na) calcd for
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C22H24O3Na 359.1623, found 359.1619.
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(2-Allyl-3-(benzyloxy)-4-methoxyphenyl)(4-methoxyphenyl)methanone (6u).
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Yield = 85% (330 mg); Colorless solid; mp = 65-66 C (recrystallized from hexanes and EtOAc); H
NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 7.2 Hz, 2H), 7.42-7.38 (m, 2H),
7.36-7.32 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.93-5.83
(m, 1H), 5.07 (s, 2H), 4.88-4.83 (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.57 (d, J = 6.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ 196.1, 163.3, 154.3, 146.2, 137.6, 136.9, 133.8, 132.4 (2x), 132.4, 131.0, 128.2
(2x), 127.9 (2x), 127.8, 125.4, 115.3, 113.4 (2x), 109.0, 74.5, 55.6, 55.3, 30.8; HRMS (ESI, M++Na)
calcd for C25H24O4Na 411.1572, found 411.1567.
(2-Allyl-3-(benzyloxy)-4-methoxyphenyl)(4-fluorophenyl)methanone (6v).
Yield = 83% (312 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.81-7.76 (m, 2H), 7.50 (d, J = 8.8
Hz, 2H), 7.42-7.32 (m, 3H), 7.13-7.09 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H),
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5.90-5.80 (m, 1H), 5.05 (s, 2H), 4.88-4.80 (m, 2H), 3.94 (s, 3H), 3.57 (dt, J = 1.6, 6.0 Hz, 2H); C
NMR (100 MHz, CDCl3): δ 195.8, 165.5 (d, J = 253.2 Hz), 154.8, 146.4, 137.6, 136.9, 134.7 (d, J = 3.1
Hz), 134.4, 132.7 (d, J = 9.1 Hz, 2x), 131.6, 128.4 (2x), 128.0 (2x), 127.9, 126.0, 115.4 (d, J = 22.0 Hz,
2x), 115.2, 109.0, 74.7, 55.7, 30.7; HRMS (ESI, M++H) calcd for C24H22FO3 377.1553, found 377.1558.
(2-Allyl-3-(benzyloxy)-4-methoxyphenyl)(p-tolyl)methanone (6w).
Yield = 81% (301 mg); Colorless oil; 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 2H), 7.54 (d, J
= 8.4 Hz, 2H), 7.43-7.39 (m, 2H), 7.37-7.33 (m, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H),
6.85 (d, J = 8.4 Hz, 1H), 5.97-5.88 (m, 1H), 5.09 (s, 2H), 4.93-4.87 (m, 2H), 3.93 (s, 3H), 3.64 (dt, J =
1.6, 6.4 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.4, 154.9, 146.7, 143.9, 138.0, 137.4,
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136.1, 134.5, 132.5, 130.6 (2x), 129.2 (2x), 128.6 (2x), 128.3 (2x), 128.2, 126.4, 115.7, 109.3, 74.9, 56.0,
31.1, 21.9; HRMS (ESI, M++H) calcd for C25H25O3 373.1804, found 373.1812.
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(2-Allyl-3-(benzyloxy)-4-methoxyphenyl)(o-tolyl)methanone (6x).
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Yield = 90% (335 mg); Colorless gum; H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 7.2 Hz, 2H),
7.43-7.33 (m, 4H), 7.29-7.25 (m, 2H), 7.21-7.18 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz,
1H), 6.03-5.94 (m, 1H), 5.05 (s, 2H), 4.97-4.92 (m, 2H), 3.93 (s, 3H), 3.77 (d, J = 6.0 Hz, 2H), 2.41 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 199.3, 155.5, 146.5, 139.7, 137.7, 137.6, 137.3, 135.4, 132.2,
131.1, 130.5, 129.8, 128.5, 128.3 (2x), 127.9 (2x), 127.9, 125.2, 115.2, 108.8, 74.7, 55.7, 30.5, 20.4;
HRMS (ESI, M++Na) calcd for C25H24O3 395.1623, found 395.1616.
(2-Allyl-3-(benzyloxy)-4-methoxyphenyl)(phenyl)methanone (6y).
Yield = 86% (308 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.77-7.74 (m, 2H), 7.58-7.32 (m,
8H), 7.11 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.92-5.82 (m, 1H), 5.05 (s, 2H), 4.88-4.81 (m,
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2H), 3.94 (s, 3H), 3.58 (dt, J = 1.6, 6.4 Hz, 2H); C NMR (100 MHz, CDCl3): δ 197.5, 154.8, 146.4,
138.4, 137.7, 137.1, 134.5, 132.7, 130.2 (2x), 128.4 (2x), 128.2 (2x), 128.0 (2x), 127.9 (2x), 126.4,
115.4, 108.9, 74.7, 55.8, 30.8; HRMS (ESI, M++Na) calcd for C24H22O3Na 381.1467, found 381.1460.
(2-(But-3-en-2-yl)-3,4-dimethoxyphenyl)(4-methoxyphenyl)methanone (6z).13a
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Yield = 84% (274 mg); Colorless gum; H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.8 Hz, 2H),
6.93-6.89 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 6.14 (ddd, J = 6.4, 10.8, 17.2 Hz, 1H), 4.90-4.85 (m, 2H),
3.90 (s, 3H), 3.87 (s, 6H), 3.69-3.62 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
197.1, 163.6, 154.1, 148.0, 152.5, 138.2, 132.9, 132.6 (2x), 131.2, 123.7, 113.5 (2x), 113.4, 109.5, 60.6,
55.7, 55.5, 38.7, 19.6; HRMS (ESI, M++H) calcd for C20H23O4 327.1596, found 327.1600.
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(2-Allyl-3-methoxyphenyl)(4-methoxyphenyl)methanone (6aa).
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Yield = 78% (220 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.8 Hz, 2H), 7.24 (t,
J = 7.6 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H), 5.91-5.81
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(m, 1H), 4.86-4.80 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.39 (d, J = 6.4 Hz, 2H); C NMR (100 MHz,
CDCl3): δ 196.8, 163.7, 157.8, 140.8, 136.4, 132.6 (2x), 130.5, 126.7, 126.6, 119.9, 115.0, 113.5 (2x),
111.7, 55.7, 55.4, 31.0; HRMS (ESI, M++H) calcd for C18H19O3 283.1334, found 283.1337.
General synthetic procedure for synthesis of 1a-1aa and 9a-9d is as follows
A representative synthetic procedure of skeleton 1 or 9 is as follows: PdCl2 (10 mg, 5.8 mol %) and
CuCl2 (200 mg, 1.5 mmol) were added to a solution of skeleton 6 or 4 (1.0 mmol) in dioxane (10 mL) at
rt. Then oxygen was bubbled into the mixture for 2 h, and stirred at rt for 4 h. N2H4 (2 mL) was added to
a reaction mixture at rt. The reaction mixturewas stirred at rt for 10 min. The residue was diluted with
water (2 mL) and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered, and evaporated to afford crude product. Purification on silica gel
(hexanes/EtOAc = 5/1~3/1) afforded skeleton 1a-1aa and 9a-9d.
6,7-Dimethoxy-1-(4-methoxyphenyl)-4-methyl-5H-benzo[d][1,2]diazepine (1a).
Yield = 87% (282 mg); Colorless solid; mp = 196-197 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H),
6.86 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.90 (d, J = 12.0 Hz, 1H), 3.89 (s, 3H), 3.91 (s, 3H), 2.73 (d, J =
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12.0 Hz, 1H), 2.13 (s, 3H); C NMR (100 MHz, CDCl3): δ 160.9, 157.8, 155.6, 154.5, 144.0, 133.6,
131.5, 130.9 (2x), 126.5, 124.0, 113.4 (2x), 110.4, 61.3, 55.7, 55.2, 30.6, 23.3; HRMS (ESI, M++H)
calcd for C19H21N2O3 325.1552, found 325.1546. Single-crystal X-ray diagram: crystal of 1a was grown
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by slow diffusion of EtOAc into a solution of 1a in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P 21/n, a = 8.1616(6) Å, b = 8.6757(7) Å, c =
22.6247(19) Å, V = 1601.9(2) Å3, Z = 4, dcalcd = 1.345 g/cm3, F(000) = 688, 2θ range 1.80-26.47o, R
indices (all data) R1 = 0.0418, wR2 = 0.1152.
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1-(4-Fluorophenyl)-6,7-dimethoxy-4-methyl-5H-benzo[d][1,2]diazepine (1b).
Yield = 88% (275 mg); Colorless solid; mp = 150-151 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.8 Hz, 2H), 7.07 (t, J = 8.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H),
6.89 (d, J = 8.4 Hz, 1H), 3.95 (d, J = 12.0 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 2.73 (d, J = 12.0 Hz, 1H),
2.16 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.9 (d, J = 248.7 Hz), 157.6, 156.0, 154.9, 144.3, 135.1
(d, J = 3.0 Hz), 133.7, 131.5 (d, J = 8.3 Hz, 2x), 126.4, 123.9, 115.1 (d, J = 22.0 Hz, 2x), 110.7, 61.4,
55.8, 30.7, 23.4; HRMS (ESI, M++H) calcd for C18H18FN2O2 313.1352, found 313.1347.
6,7-Dimethoxy-4-methyl-1-p-tolyl-5H-benzo[d][1,2]diazepine (1c).
Yield = 83% (256 mg); Colorless solid; mp = 155-156 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H),
6.86 (d, J = 8.8 Hz, 1H), 3.91 (d, J = 12.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.73 (d, J = 12.0 Hz, 1H),
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2.37 (s, 3H), 2.14 (s, 3H); C NMR (100 MHz, CDCl3): δ 158.2, 155.5, 154.5, 144.0, 139.7, 136.2,
133.6, 129.4 (2x), 128.7 (2x), 126.4, 124.1, 110.4, 61.3, 55.7, 30.6, 23.3, 21.2; HRMS (ESI, M++H)
calcd for C19H21N2O2 309.1603, found 309.1596. Single-crystal X-ray diagram: crystal of 1c was grown
by slow diffusion of EtOAc into a solution of 1c in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P 21/c, a = 7.1877(5) Å, b = 25.1688(16) Å, c
= 9.8090(6) Å, V = 1664.46(19) Å3, Z = 4, dcalcd = 1.231 g/cm3, F(000) = 656, 2θ range 1.62-26.41o, R
indices (all data) R1 = 0.0649, wR2 = 0.1299.
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6,7-Dimethoxy-4-methyl-1-o-tolyl-5H-benzo[d][1,2]diazepine (1d).
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Yield = 86% (265 mg); Colorless gum; H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.2 Hz, 1H),
7.32-7.22 (m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.01 (d, J
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= 12.0 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 2.80 (d, J = 12.0 Hz, 1H), 2.20 (s, 3H), 2.04 (s, 3H); C
NMR (100 MHz, CDCl3): δ 159.8, 155.4, 154.7, 144.2, 139.3, 137.0, 132.6, 130.5, 130.4, 129.1, 125.9,
125.7, 125.6, 110.9, 61.5, 55.8, 30.6, 23.6, 20.2; HRMS (ESI, M++H) calcd for C19H21N2O2 309.1603,
found 309.1599.
6,7-Dimethoxy-4-methyl-1-phenyl-5H-benzo[d][1,2]diazepine (1e).
Yield = 90% (265 mg); Colorless solid; mp = 131-132 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 2H), 7.37-7.32 (m, 3H), 6.98 (d, J = 8.4 Hz, 1H), 6.85
(d, J = 8.4 Hz, 1H), 3.91 (d, J = 12.0 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 2.71 (d, J = 12.0 Hz, 1H), 2.13
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(s, 3H); C NMR (100 MHz, CDCl3): δ 158.3, 155.4, 154.5, 143.9, 138.9, 133.5, 129.5, 129.4 (2x),
127.9 (2x), 126.3, 123.9, 110.5, 61.2, 55.6, 30.5, 23.2; HRMS (ESI, M++H) calcd for C18H19N2O2
295.1447, found 295.1441.
6-Isopropoxy-7-methoxy-1-(4-methoxyphenyl)-4-methyl-5H-benzo[d][1,2]diazepine (1f).
Yield = 89% (313 mg); Colorless solid; mp = 158-159 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H),
6.85 (d, J = 8.4 Hz, 1H), 4.54-4.48 (m, 1H), 3.95 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.74 (d,
J = 12.0 Hz, 1H), 2.12 (s, 3H), 1.42 (d, J =6.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 160.9, 158.1, 156.1, 154.8, 141.9, 134.7, 131.7, 131.0 (2x), 126.1, 124.1, 113.4 (2x), 110.3,
75.4, 55.7, 55.3, 31.2, 23.4, 22.9, 22.1; HRMS (ESI, M++H) calcd for C21H25N2O3 353.1865, found
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1-(4-Fluorophenyl)-6-isopropoxy-7-methoxy-4-methyl-5H-benzo[d][1,2]diazepine (1g).
Yield = 82% (279 mg); Colorless solid; mp = 189-190 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.09-7.03 (m, 2H), 6.96
(d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.55-4.49 (m, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H),
2.72 (d, J = 12.0 Hz, 1H), 2.13 (s, 3H), 1.43 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 163.8 (d, J = 247.9 Hz), 157.6, 156.0, 155.0, 142.0, 135.3 (d, J = 3.0 Hz), 134.7, 131.4
(d, J = 8.4 Hz, 2x), 125.9, 123.8, 115.0 (d, J = 21.2 Hz, 2x), 110.4, 75.4, 55.7, 31.2, 23.4, 22.9, 22.1;
HRMS (ESI, M++H) calcd for C20H22FN2O2 341.1665, found 341.1660.
6-Isopropoxy-7-methoxy-4-methyl-1-p-tolyl-5H-benzo[d][1,2]diazepine (1h).
Yield = 81% (272 mg); Colorless solid; mp = 115-116 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H),
6.85 (d, J = 8.4 Hz, 1H), 4.54-4.48 (m, 1H), 3.95 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H), 2.74 (d, J = 12.0 Hz,
1H), 2.38 (s, 3H), 2.13 (s, 3H), 1.43 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 158.6, 156.1, 154.8, 141.9, 139.8, 136.3, 134.7, 129.5 (2x), 128.8 (2x), 126.1, 124.1, 110.3,
75.4, 55.7, 31.2, 23.4, 22.9, 22.1, 21.3; HRMS (ESI, M++H) calcd for C21H25N2O2 337.1916, found
337.1909.
6-Isopropoxy-7-methoxy-4-methyl-1-o-tolyl-5H-benzo[d][1,2]diazepine (1i).
Yield = 86% (289 mg); Colorless solid; mp = 135-136 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.2 Hz, 1H), 7.30-7.22 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.77
(d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 4.58-4.52 (m, 1H), 4.03 (d, J = 12.0 Hz, 1H), 3.84 (s, 3H),
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2.79 (d, J = 12.0 Hz, 1H), 2.16 (s, 3H), 1.99 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 159.9, 155.5, 154.8, 141.8, 139.5, 136.8, 133.8, 130.5, 130.2, 128.9,
125.8, 125.5, 125.2, 110.7, 75.0, 55.7, 31.0, 23.6, 22.8, 22.0, 20.0; HRMS (ESI, M++H) calcd for
C21H25N2O2 337.1916, found 337.1911.
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6-Isopropoxy-7-methoxy-4-methyl-1-phenyl-5H-benzo[d][1,2]diazepine (1j).
Yield = 88% (284 mg); Colorless solid; mp = 133-134 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 2H), 7.39-7.37 (m, 3H), 6.98 (d, J = 8.8 Hz, 1H), 6.85
(d, J = 8.8 Hz, 1H), 4.55-4.48 (m, 1H), 3.96 (d, J = 12.0 Hz, 1H), 3.87 (s, 3H), 2.73 (d, J = 12.0 Hz, 1H),
2.13 (s, 3H), 1.42 (d, J = 6.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 158.6,
155.9, 154.8, 141.8, 139.1, 134.7, 129.6, 129.5 (2x), 128.0 (2x), 126.0, 123.9, 110.3, 75.3, 55.7, 31.1,
23.4, 22.8, 22.1; HRMS (ESI, M++H) calcd for C20H23N2O2 323.1760, found 323.1755.
6-Butoxy-7-methoxy-1-(4-methoxyphenyl)-4-methyl-5H-benzo[d][1,2]diazepine (1k).
Yield = 89% (326 mg); Colorless solid; mp = 166-167 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H),
6.86 (d, J = 8.4 Hz, 1H), 4.07-3.98 (m, 2H), 3.92 (d, J = 11.6 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 2.74 (d,
J = 11.6 Hz, 1H), 2.14 (s, 3H), 1.87-1.79 (m, 2H), 1.61-1.52 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 160.9, 157.9, 155.7, 154.7, 143.4, 133.9, 131.7, 131.0 (2x), 126.3, 124.1, 113.4
(2x), 110.4, 73.7, 55.7, 55.3, 32.3, 30.8, 23.3, 19.2, 13.9; HRMS (ESI, M++H) calcd for C22H27N2O3
367.2022, found 367.2017.
6-Butoxy-1-(4-fluorophenyl)-7-methoxy-4-methyl-5H-benzo[d][1,2]diazepine (1l).
Yield = 85% (301 mg); Colorless solid; mp = 142-143 oC (recrystallized from hexanes and EtOAc); 1H
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NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.08-7.02 (m, 2H), 6.97
(d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.08-3.98 (m, 2H), 3.94 (d, J = 12.0 Hz, 1H), 3.89 (s, 3H),
2.71 (d, J = 12.0 Hz, 1H), 2.14 (s, 3H), 1.87-1.79 (m, 2H), 1.61-1.52 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 163.8 (d, J = 247.9 Hz), 157.4, 155.7, 154.9, 143.5, 135.2 (d, J = 3.0
Hz), 133.9, 131.4 (d, J = 8.3 Hz, 2x), 126.1, 123.8, 115.0 (d, J = 21.2 Hz, 2x), 110.6, 73.7, 55.7, 32.3,
30.8, 23.4, 19.2, 13.9; HRMS (ESI, M++H) calcd for C21H24FN2O2 355.1822, found 355.1818.
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6-Butoxy-7-methoxy-4-methyl-1-p-tolyl-5H-benzo[d][1,2]diazepine (1m).
Yield = 82% (287 mg); Colorless gum; 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 2H), 7.20 (d,
J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.09-3.98 (m, 2H), 3.94 (d, J = 12.0
Hz, 1H), 3.90 (s, 3H), 2.75 (d, J = 12.0 Hz, 1H), 2.39 (s, 3H), 2.16 (s, 3H), 1.88-1.80 (m, 2H), 1.63-1.51
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(m, 2H), 1.02 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 158.6, 156.0, 154.8, 143.4, 139.9,
136.3, 133.9, 129.6 (2x), 128.8 (2x), 126.4, 124.2, 110.5, 73.8, 55.8, 32.4, 30.9, 23.4, 21.3, 19.3, 13.9;
HRMS (ESI, M++H) calcd for C22H27N2O2 351.2073, found 351.2066.
6-Butoxy-7-methoxy-4-methyl-1-o-tolyl-5H-benzo[d][1,2]diazepine (1n).
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Yield = 86% (301 mg); Colorless gum; H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 7.2 Hz, 1H),
7.31-7.22 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.06-4.01
(m, 2H), 4.01 (d, J = 12.0 Hz, 1H), 3.86 (s, 3H), 2.80 (d, J = 12.0 Hz, 1H), 2.19 (s, 3H), 2.02 (s, 3H),
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1.88-1.80 (m, 2H), 1.63-1.53 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 159.8,
155.2, 154.7, 143.4, 139.5, 136.9, 132.9, 130.5, 130.4, 129.0, 125.9, 125.6, 125.4, 110.8, 73.8, 55.7, 32.3,
30.7, 23.6, 20.1, 19.2, 13.9; HRMS (ESI, M++H) calcd for C22H27N2O2 351.2073, found 351.2065.
6-Butoxy-7-methoxy-4-methyl-1-phenyl-5H-benzo[d][1,2]diazepine (1o).
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Yield = 88% (296 mg); Colorless solid; mp = 89-90 C (recrystallized from hexanes and EtOAc); H
NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.0 Hz, 2H), 7.39-7.33 (m, 3H), 6.98 (d, J = 8.8 Hz, 1H), 6.85
(d, J = 8.8 Hz, 1H), 4.08-3.98 (m, 2H), 3.94 (d, J = 12.0 Hz, 1H), 3.87 (s, 3H), 2.72 (d, J = 12.0 Hz, 1H),
2.14 (s, 3H), 1.87-1.79 (m, 2H), 1.59-1.53 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 158.4, 155.5, 154.7, 143.3, 139.0, 133.8, 129.5, 129.5 (2x), 127.9 (2x), 126.2, 123.9, 110.4,
73.6, 55.6, 32.2, 30.7, 23.3, 19.1, 13.8; HRMS (ESI, M++H) calcd for C21H25N2O2 337.1916, found
337.1908.
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6-(Cyclopentyloxy)-7-methoxy-1-(4-methoxyphenyl)-4-methyl-5H-benzo[d][1,2]diazepine (1p).
Yield = 90% (340 mg); Colorless solid; mp = 156-157 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.59 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 9.2 Hz, 2H),
6.83 (d, J = 8.4 Hz, 1H), 4.87-4.83 (m, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 2.72 (d,
J = 11.6 Hz, 1H), 2.09 (s, 3H), 2.04-1.60 (m, 8H); 13C NMR (100 MHz, CDCl3): δ 160.8, 157.9, 155.8,
154.6, 142.0, 134.4, 131.6, 130.9 (2x), 125.8, 123.9, 113.3 (2x), 110.3, 85.0, 55.6, 55.1, 33.2, 32.1, 30.9,
23.6, 23.4, 23.2; HRMS (ESI, M++H) calcd for C23H27N2O3 379.2022, found 379.2018. Single-crystal
X-ray diagram: crystal of 1p was grown by slow diffusion of EtOAc into a solution of 1p in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the triclinic crystal system, space group P -1, a =
8.4384(6) Å, b = 11.0458(8) Å, c = 12.1243(8) Å, V = 1041.25(13) Å3, Z = 2, dcalcd = 1.207 g/cm3, F(000)
= 404, 2θ range 1.82-26.51o, R indices (all data) R1 = 0.0071, wR2 = 0.1461.
6-(Cyclopentyloxy)-1-(4-fluorophenyl)-7-methoxy-4-methyl-5H-benzo[d][1,2]diazepine (1q).
Yield = 85% (311 mg); Colorless solid; mp = 153-154 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.09-7.03 (m, 2H), 6.95
(d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.90-4.86 (m, 1H), 3.92 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H),
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3.72 (d, J = 12.0 Hz, 1H), 2.12 (s, 3H), 2.07-2.01 (m, 1H), 1.97-1.77 (m, 4H), 1.73-1.61 (m, 3H); C
NMR (100 MHz, CDCl3): δ 163.8 (d, J = 248.6 Hz), 157.5, 155.9, 154.8, 142.3, 135.2 (d, J = 3.0 Hz),
134.5, 131.4 (d, J = 8.4 Hz, 2x), 125.7, 123.8, 115.0 (d, J = 21.2 Hz, 2x), 110.6, 85.2, 55.7, 33.4, 32.2,
31.1, 23.7, 23.5, 23.3; HRMS (ESI, M++H) calcd for C22H24FN2O2 367.1822, found 367.1817.
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6-(Cyclopentyloxy)-7-methoxy-4-methyl-1-p-tolyl-5H-benzo[d][1,2]diazepine (1r).
Yield = 84% (304 mg); Colorless solid; mp = 156-157 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.4 Hz, 1H),
6.84 (d, J = 8.4 Hz, 1H), 4.89-4.85 (m, 1H), 3.90 (d, J = 11.6 Hz, 1H), 3.87 (s, 3H), 2.73 (d, J = 11.6 Hz,
1H), 2.37 (s, 3H), 2.11 (s, 3H), 2.07-2.01 (m, 1H), 1.96-1.77 (m, 4H), 1.70-1.61 (m, 3H); 13C NMR (100
MHz, CDCl3): δ 158.5, 155.8, 154.6, 142.1, 139.7, 136.3, 134.5, 129.5 (2x), 128.7 (2x), 125.9, 124.0,
110.4, 85.1, 55.6, 33.3, 32.1, 31.0, 23.6, 23.5, 23.3, 21.2; HRMS (ESI, M++H) calcd for C23H27N2O2
363.2073, found 363.2068.
6-(Cyclopentyloxy)-7-methoxy-4-methyl-1-o-tolyl-5H-benzo[d][1,2]diazepine (1s).
Yield = 84% (304 mg); Colorless solid; mp = 104-105 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.2 Hz, 1H), 7.31-7.22 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 6.78
(d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.92-4.89 (m, 1H), 3.98 (d, J = 12.0 Hz, 1H), 3.85 (s, 3H),
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(100 MHz, CDCl3): δ 159.9, 155.4, 154.6, 142.1, 139.5, 136.9, 133.7, 130.5, 130.3, 128.9, 125.9, 125.6,
125.1, 110.8, 84.9, 55.7, 33.3, 32.1, 30.9, 23.7, 23.6, 23.6, 20.1; HRMS (ESI, M++H) calcd for
C23H27N2O2 363.2073, found 363.2067.
6-(Cyclopentyloxy)-7-methoxy-4-methyl-1-phenyl-5H-benzo[d][1,2]diazepine (1t).
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NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 2H), 7.43-7.36 (m, 3H), 6.99 (d, J = 8.8 Hz, 1H), 6.86
(d, J = 8.8 Hz, 1H), 4.90-4.86 (m, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.89 (s, 3H), 2.74 (d, J = 11.6 Hz, 1H),
2.13 (s, 3H), 2.07-2.02 (m, 1H), 1.97-1.78 (m, 4H), 1.71-1.62 (m, 3H); 13C NMR (100 MHz, CDCl3): δ
158.7, 156.0, 154.8, 142.2, 139.1, 134.6, 129.65, 129.62 (2x), 128.0 (2x), 126.0, 124.1, 110.5, 85.2, 55.7,
33.4, 32.2, 31.1, 23.7, 23.5, 23.4; HRMS (ESI, M++H) calcd for C22H25N2O2 349.1916, found 349.1910.
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6-(Benzyloxy)-7-methoxy-1-(4-methoxyphenyl)-4-methyl-5H-benzo[d][1,2]diazepine (1u).
Yield = 89% (356 mg); Colorless solid; mp = 152-153 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41-7.31 (m, 3H), 7.05
(d, J = 8.8 Hz, 1H), 6.93-6.90 (m, 3H), 5.12 (d, J = 11.2 Hz, 1H), 5.08 (d, J = 11.2 Hz, 1H), 3.92 (s, 3H),
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CDCl3): δ 160.8, 157.8, 155.6, 154.5, 142.6, 137.1, 134.1, 131.5, 130.9 (2x), 128.3 (2x), 128.0, 127.9
(2x), 126.5, 124.0, 113.3 (2x), 110.4, 75.3, 55.7, 55.1, 30.7, 23.2; HRMS (ESI, M++H) calcd for
C25H25N2O3 401.1865, found 401.1858.
6-(Benzyloxy)-1-(4-fluorophenyl)-7-methoxy-4-methyl-5H-benzo[d][1,2]diazepine (1v).
Yield = 83% (322 mg); Colorless solid; mp = 198-199 oC (recrystallized from hexanes and EtOAc); 1H
NMR (400 MHz, CDCl3): δ 7.66-7.62 (m, 2H), 7.49-7.47 (m, 2H), 7.42-7.35 (m, 3H), 7.10-7.06 (m, 2H),
7.02 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.13 (d, J = 11.2 Hz, 1H), 5.09 (d, J = 11.2 Hz, 1H),
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CDCl3): δ 163.8 (d, J = 248.6 Hz), 157.4, 155.8, 154.8, 142.8, 137.1, 135.2 (d, J = 3.0 Hz), 134.2, 131.4
(d, J = 8.3 Hz, 2x), 128.4 (2x), 128.15, 128.05 (2x), 126.4, 123.8, 115.0 (d, J = 22.0 Hz, 2x), 110.6, 75.4,
55.8, 30.8, 23.3; HRMS (ESI, M++H) calcd for C24H22FN2O2 389.1665, found 389.1658.
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