Synthesis of a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, using ring-expansion of cyclic ketoximes with DIBALH

Article abstract of DOI:10.1248/cpb.c13-00961

Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These compounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1, 4]oxazine, dibenzodiazepine, and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes with diisobutylaluminum hydride.

Full text of DOI:10.1248/cpb.c13-00961

354
Regular Article
Chem. Pharm. Bull. 62(4) 354–363 (2014)
Vol. 62, No. 4
Synthesis of a Human Urate Transporter-1 Inhibitor, an Arginine
Vasopressin Antagonist, and a 17β-Hydroxysteroid Dehydrogenase Type-3
Inhibitor, Using Ring-Expansion of Cyclic Ketoximes with DIBALH
,a,b
,a
Hidetsura Cho,* Yusuke Iwama,a Kentaro Okano,a and Hidetoshi Tokuyama*
a Graduate School of Pharmaceutical Sciences, Tohoku University; and b Graduate School of Science, Tohoku
University; 6–3 Aramaki, Aoba-ku, Sendai 980–8578, Japan.
Received December 12, 2013; accepted January 24, 2014
Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine
vasopressin antagonist, and a 17β-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These com-
pounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine, dibenzodiazepine,
and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding
bicyclic or tricyclic oximes with diisobutylaluminum hydride.
Key words diisobutylaluminum hydride; ring-expansion rearrangement; cyclic oxime; urate transporter-1
(URAT-1) inhibitor; arginine vasopressin (AVP) antagonist; 17β-hydroxysteroid dehydrogenase type-3 (17β-HSD3)
inhibitor
Aromatic ring-fused nitrogen heterocycles are often found cal candidates for medicines: a human urate transporter-1
in biologically active compounds and functional molecules. (URAT-1) inhibitor 1,6) an arginine vasopressin (AVP) an-
The synthesis of this class of heterocycles is an important tagonist 2,7–9) and a 17β-hydroxysteroid dehydrogenase type-3
research topic from the viewpoint of both synthetic and (17β-HSD3) inhibitor 3 (Fig. 1). We conducted synthetic
medicinal chemistry. Recently, we devised a reductive ring- studies on these molecules.10,11) Herein, the synthesis of com-
expansion reaction of aromatic ring-fused cyclic oximes or pounds 1, 2, and 3 via construction of their basic skeletons
their hydroxylamine derivatives to the corresponding cyclic 4, 5, and 6 using the reductive ring-expansion reaction of
secondary amines using aluminum hydrides such as diiso- the corresponding bicyclic and tricyclic oximes 7, 8, and 9,
butylaluminum hydride (DIBALH)1–4) and AlHCl2.5) The most respectively, is reported (Chart 1).
notable feature of this rearrangement reaction is that reaction
of an E/Z mixture of ketoxime provides the corresponding
Results and Discussion
ring-expanded aromatic secondary amine as the sole com-
Synthesis of URAT-1 Inhibitor 1 Synthesis of URAT-1
pound, which is in sharp contrast to the geometry-dependent inhibitor 1, 2,6-dichloro-4-(2,3-dihydro-1,4-benzoxazin-4-
migration of activated oximes in a typical Beckmann rear- ylcarbonyl)phenol, for the remedy of hyperuricemia and
rangement reaction.
gout, was reported by Hirata et al.6) They synthesized 1 in
To demonstrate the synthetic utility of the DIBALH- several steps through 3,4-dihydro-2H-benzo[b][1,4]oxazine
mediated ring-expansion reaction, we selected three clini- 4 (X=O),12) which was obtained by reduction of 2H-1,4-
Fig. 1. Clinical Candidates: URAT-1 Inhibitor, AVP Antagonist, and 17β-HSD3 Inhibitor
Chart 1. Rearrangement of Bicyclic Oximes 7 and Tricyclic Symmetrical and Pseudo-Symmetrical Oximes 8 and 9
The authors declare no conflict of interest.
© 2014 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: hcho@mail.pharm.tohoku.ac.jp;
tokuyama@mail.pharm.tohoku.ac.jp

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Reagents and conditions: (a) DIBALH, CH2Cl2, 0°C to rt (80%)3) (b) LiAlH4, THF, reflux6) (c) 3,5-dichloro-4-hydroxybenzoyl chloride, EtOAc, rt (29%)
Chart 2. Synthesis of URAT-1 Inhibitor 1 Using 4 Obtained by DIBALH Rearrangement of 7 and LiAlH4 Reduction6) of 10
Reagents and conditions: (a) BH3·THF, THF, reflux, 4h; (b) Boc2O, DMAP, CH3CN, 0°C to rt, 11h, 80% (two steps); (c) t-BuONO, KHMDS, THF, 0°C, 0.5h, 93%; (d)
TFA, CH2Cl2, 0°C to rt, 0.5h; (e) DIBALH (6eq), CH2Cl2, 0°C to rt, 2h; (f) p-nitrobenzoyl chloride, Et3N, CH2Cl2, 0°C to rt, 1h, 80% (three steps); (g) H2, cat. Pd/C,
EtOAc, rt, 2h; (h) 2-methyl-benzoyl chloride, Et3N, CH2Cl2, 0°C to rt, 1h, 85% (two steps).
Chart 3. Rearrangement of 9(10H)-Acridone Oxime 8 and Transformation to Arginine Vasopressin Antagonist 2
benzoxazin-3(4H)-one 10 with lithium aluminum hydride in A nitroso group was introduced by treating 13 with potassium
tetrahydrofuran (THF) at reflux. Alternatively, we prepared hexamethyldisilazide (KHMDS) in THF in the presence of
3,4-dihydro-2H-benzo[b][1,4]oxazine 4 in 80% yield by reduc- 1.2eq of t-BuONO at 0°C for 0.5h to provide oxime 14 in
tion of coumaran-3-one oxime 7 with DIBALH.3) Successive- 93% yield.13) Finally, the Boc group was deprotected to pro-
ly, acylation of the resulting compound 4 with 3,5-dichloro- vide the desired 9(10H)-acridone oxime 8.
4-hydroxybenzoyl chloride afforded the URAT-1 inhibitor 1
On treatment with 6eq of DIBALH, oxime 8 underwent a
(Chart 2).
smooth reductive ring-expansion reaction to yield expected
Synthesis of Arginine Vasopressin Antagonist 2 AVP diazepine derivative 5, which was directly converted to stable
antagonists are useful in the treatment of syndrome of inap- 15 by acylation with p-nitrobenzoyl chloride and Et3N (80%
propriate secretion of antidiuretic hormone (SIADH).7) We overall yield). The o-methylbenzanilide moiety of compound
planned to construct the dibenzodiazepine ring in the AVP an- 2 was then introduced by hydrogenation of the nitro group in
tagonist 2 by reductive ring-expansion reaction of symmetric 15, and subsequent acylation of the resultant aniline 16 with
tricyclic oxime 8 (D=W=H, X=NH) with DIBALH (Chart 1). o-methylbenzoyl chloride and Et3N provided the desired AVP
Synthesis of 2 commenced with preparation of tricyclic antagonist 2 (85% overall yield).
oxime 8 by the condensation reaction of 9(10H)-acridone
Synthesis of 17β-Hydroxysteroid Dehydrogenase Type-3
11 with hydroxylamine hydrochloride in pyridine (Chart 3). Inhibitor 3 17β-HSD3 inhibitor 3, which has a dibenzazo-
However, this conventional reaction did not proceed pos- cine ring, exhibits inhibitory activity against 17β-HSD3 in
sibly due to the low electrophilicity of the carbonyl group. cell-free enzymatic assays from picomolar to low nanomolar
Therefore, we developed a new protocol for the preparation of levels, as well as in cell-based transcriptional reporter assays.
oximes by nitrosation of the benzylic anion and tautomeriza- Therefore, this compound is considered to be useful for the
tion to the oxime form.13) Reduction of 9(10H)-acridone 11 treatment of prostate cancer.10,11)
with BH3·THF in THF afforded compound 12, which was pro-
The synthetic strategy for 17β-HSD3 inhibitor 3 is shown
tected with a Boc group to give 13 in 80% yield (two steps). in Chart 4. The biphenyl moiety would be formed by a tran-

356
Vol. 62, No. 4
Chart 4. Synthetic Strategy for 17β-HSD3 Inhibitor Based on Regiocontrolled Migration of Aryl Moiety
Reagents and conditions: (a) trimethylsilyl acetylene, PdCl2(PPh3)2 (1mol%), CuI (2mol%), Et3N, DMF, rt, 30h; (b) K2CO3, MeOH, 0°C, 10min, 75% (two steps); (c) io-
dobenzene or 3-iodo-1-methylthiobenzene, PdCl2(PPh3)2 (1mol%), CuI (2mol%), Et3N, DMF, rt, 3–7h, 19a: 54%, 19b: 92%; (d) H2 (1atm), PtO2 (10mol%), EtOAc–EtOH–
AcOH, rt, 1.5h, 20a: 89%; (e) H2 (70atm), PtO2 (5mol%), THF, rt, 14h; (f) 2M NaOH aq, THF–MeOH, 0°C to rt, 9–11h; (g) PPMA (P2O5/methanesulfonic acid), 80°C,
0.5h, 22a: 68% (two steps), 22b: 71% (three steps); (h) NH2OH·HCl, pyridine, reflux, 34–48h, 9a: 90%, 9b: 66%.
Chart 5. Preparation of Oximes 9
Table 1. DIBALH-Mediated Ring-Expansion Reactiona)
sition metal-catalyzed cross-coupling reaction at one of the
benzene rings with a halogen substituent such as a bromine
atom. The dibenzazocine skeleton would be constructed by
the reductive ring-expansion reaction of pseudo-symmetrical
dibenzosuberone oxime 9 with DIBALH and acetylation of
the resultant secondary amine 6. A key issue here was the re-
giochemistry of migration during the reductive ring-expansion
reaction of pseudo-symmetrical dibenzosuberone oxime 9.
We observed that the more electron-rich aromatic ring pref-
erentially migrates when the reaction was examined by using
4,4′-disubstituted pseudo-symmetrical benzophenone oximes.3)
Therefore, we predicted that the regiochemistry could be con-
trolled by the differentiation of electron densities between the
two benzene rings by introduction of suitable substituents. We
expected that the bromine atom would decrease the electron
density of the right-hand benzene ring to control regiochem-
Entry
X
Temp. (°C)
Time (h)
Yield (%)b)
23:24c)
1
H
0 to rt
80
12
16
12
12
46d)
73
3.3:1.0
2.0:1.0
8.5:1.0
6.0:1.0
2e)
H
3
SMe
SMe
0 to rt
rt
42f )
4
67
a) Reaction conditions: DIBALH (6eq) was added to the mixture of 9 in CH2Cl2
(0.1M). b) Isolated yields as a mixture of 23 and 24. c) Determined by 1H-NMR. d)
Starting material 9a (28%) was recovered. e) Instead of CH2Cl2, 1,2-dichloroethane
was used as a solvent. f ) Starting material 9b (36%) was recovered.
istry (9a: D=H, W=Br in Chart 4). Furthermore, introduction of 20 and subsequent Friedel–Crafts-type acylation of 21
of a methylthio group, which is easily removed by Raney Ni, using P2O5–MsOH (PPMA) afforded dibenzosuberones 22,16,17)
should enhance desired regioselectivity by increasing electron which was converted to the corresponding oximes 9a and 9b
density of other benzene ring (9b: D=SMe, W=Br).
With these considerations, we prepared dibenzosuberone
by treatment with NH2OH·HCl in pyridine.
The pseudo-symmetrical oximes 9a and 9b were then used
oximes 9a and 9b to examine the regiochemistry during the to examine the regiochemistry of the reductive ring-expansion
ring-expansion reaction (Chart 5). Sonogashira coupling of reaction during the construction of a dibenzazocine ring
methyl 3-bromo-6-iodobenzoate 17 and trimethylsilylacety- (Table 1). Reaction of oxime 9a using 6eq of DIBALH at 0°C
lene followed by basic removal of the trimethylsilyl (TMS) was incomplete even after increasing the reaction temperature
group gave arylacetylene 18. The second Sonogashira cou- to room temperature, giving a mixture of azocines 23a and
pling with iodobenzene or 3-iodo-1-methylthiobenzene14,15) 24a (23a:24a=3.3:1.0) in 46% yield with recovery of 28%
provided 1,2-diarylacetylenes 19. While hydrogenation of 19a of the oxime 23a (Entry 1). When the reaction was carried
smoothly gave ester 20a with catalytic platinum oxide under out at 80°C in 1,2-dichloroethane, oxime 9a was completely
atmospheric pressure, reduction of 19b required high-pressure consumed to afford a mixture of azocines (23a:24a=2.0:1.0)
(70 atm) conditions for the high-yielding process. Hydrolysis in 73% yield (Entry 2). This low regiochemistry prompted us

April 2014
357
Reagents and conditions: (a) Ac2O, DMAP, Et3N, CH2Cl2, rt, 0.5–1h, 25a: 66%, 27a: 19%, 25b: 70%, 27b: 11%; (b) PhB(OH)2, Pd(PPh3)4 (10mol%), K2CO3, THF–H2O,
reflux, 6–22h, 3: 70%, 26: 78%; (c) H2 (1atm), Raney Ni, EtOH, reflux, 3h, 69%.
Chart 6. Regioselective Rearrangement of Asymmetric Oxime and Transformation to 17β-HSD3 Inhibitor 3
to test the reactions of 9b, which has an SMe group instead of
H. To this end, treatment of 9b with DIBALH at 0°C gave a
mixture of azocines with substantially improved regioselectiv-
ity (23b:24b=8.5:1.0), albeit yield (42%) was modest (Entry
3). Finally, we established satisfactory conditions using 6eq of
DIBALH at room temperature to give azocines 23b and 24b
in 67% yield (23b:24b=6.0:1.0) (Entry 4).
Having succeeded in using a regioselective ring-expansion
reaction to form a dibenzoazocine ring, we then proceeded to
complete the synthesis of 17β-HSD3 inhibitor 3 (Chart 6). As
the mixture of 23b and 24b was not easily separable, the mix-
ture was subjected to acetylation conditions using Ac2O and
4-(dimethylamino)pyridine (DMAP)–Et3N. After flash column
chromatography on silica gel, 25a and 27a were obtained
in 66% and 19% isolated yields, respectively. The structure
Fig. 2. ORTEP Drawing of the Molecular Structure of Compound 25a
of compound 25a was confirmed by X-ray crystallographic with Thermal Ellipsoids at 50% Probability Levels
analysis18) (Fig. 2). Suzuki–Miyaura cross coupling of 25b
Hydrogen atoms are omitted for clarity.
with phenylboronic acid furnished 26 in 78% yield. Finally,
desulfurization of 26 under hydrogen atmosphere in the pres-
ence of Raney Ni afforded 5-acetyl-5,6,11,12-tetrahydro-8-
phenyldibenz[b,f]azocine 3 in 69% yield.
Experimental
General Remarks Materials were obtained from com-
mercial suppliers and used without further purification un-
less otherwise mentioned. All reactions were carried out in
oven-dried glassware under a slight positive pressure of argon
Conclusion
Synthesis of three clinical candidates for medicines, the unless otherwise noted. Anhydrous THF and CH2Cl2 were
human urate transporter-1 (URAT-1) inhibitor 1, the arginine purchased from Kanto Chemical Co., Inc. Anhydrous toluene,
vasopressin (AVP) antagonist 2, and the 17β-hydroxysteroid DMF, and MeCN were purchased from Wako Pure Chemi-
dehydrogenase type-3 (17β-HSD3) inhibitor 3, was accom- cal Industries, Ltd. Anhydrous EtOAc, MeOH, 1,2-dichloro-
plished via efficient construction of their 3,4-dihydro-2H- ethane, and EtOH were dried and distilled according to the
benzo[b][1,4]oxazine 4, dibenzodiazepine 5, and dibenzazo- standard protocols. Column chromatography was performed
cine 6 skeletons using the reductive ring-expansion reaction on Silica Gel 60N (Kanto, spherical neutral, 63–210µm) and
of the corresponding bicyclic or tricyclic oximes 7, 8, and 9, flash column chromatography was performed on Silica Gel
respectively. As oximes are a readily available intermediate, 60N (Kanto, spherical neutral, 40–50µm) using the indicated
this ring-expansion strategy should be a powerful tool to con- eluent. Preparative TLC and analytical TLC were performed
struct a broad range of 6-, 7-, and 8-membered benzo-fused on Merck 60F254 glass plates precoated with a 0.25mm thick-
nitrogen heterocyclic rings and should find widespread use in ness of silica gel. All melting points were determined on a
synthetic and medicinal chemistry in the near future.
Yanaco micro melting point apparatus and uncorrected. IR

358
Vol. 62, No. 4
spectra were measured on a SHIMADZU FTIR-8300 spec- DMAP (203mg, 1.66mmol) at 0°C and stirring was continued
trometer or a JASCO FT/IR-4100 spectrometer. NMR spectra for 11h at room temperature. The reaction was diluted with
were recorded on a JEOL-ECA600, a GX500 spectrometer ether. The mixture was washed with saturated aqueous NH4Cl
and JNM-AL400 spectrometer with tetramethylsilane (0ppm) and brine, dried over anhydrous sodium sulfate, filtered, and
or chloroform (7.26ppm) as an internal standard. Mass spectra concentrated under reduced pressure to leave the residue,
were recorded on a JEOL JMS-DX-303 spectrometer, a JMS- which was purified by silica gel column chromatography
AX-500 spectrometer, a JMS-T100GC spectrometer, or a (hexanes–EtOAc=9:1) to afford 13 (226mg, 0.803mmol,
MS-50070BU spectrometer. Optical rotations were measured 80%); mp 97.4–98.9°C, colorless crystals; Rf=0.47 (Silica gel,
on a Horiba SEPA-300 high sensitive polarimeter. Elemental hexanes–EtOAc=9:1); IR (neat) cm−1: 1706, 1476, 1328, 1269,
1
analyses were performed by a Yanaco CHN CORDER MT-5.
1253, 1151, 760; H-NMR (400MHz, CDCl3) δ: 7.63 (d, 2H,
3,5-Dichloro-4-hydroxybenzoyl Chloride A screw top J=8.0Hz), 7.36–7.17 (m, 4H), 7.12 (d, 2H, J=7.2Hz), 3.80 (s,
test tube equipped with
a
magnetic stirring bar was 2H), 1.54 (s, 9H); 13C-NMR (125MHz, CDCl3) δ: 152.5, 138.8,
charged with 3,5-dichloro-4-hydroxybenzoic acid (57.8mg, 133.0, 126.9, 125.9, 125.04, 124.96, 33.8, 28.2, 27.9; HR-MS
0.279mmol) and anhydrous dichloromethane (0.56mL). To the (ESI) Calcd for C14H12NO2 [(M−t-Bu+2H)+] 226.0863, Found:
solution were added oxalyl chloride (36µL, 0.42mmol) and 226.0878.
N,N-dimethylformamide (DMF) (2.0µL, 0.026mmol) at 0°C.
tert-Butyl 9-(Hydroxyimino)acridine-10(9H)-carboxylate
After the reaction mixture was stirred at 0°C for 5min, the (14) A two-necked 30-mL round-bottomed flask equipped
mixture was allowed to warm to room temperature and the with a magnetic stirring bar was charged with tert-butyl
solution was stirred for 1.5h. The mixture was concentrated acridine-10(9H)-carboxylate 13 (100.5mg, 0.36mmol) and
under reduced pressure to afford 3,5-dichloro-4-hydroxyben- anhydrous THF (3.6mL). To the solution was added t-BuONO
zoyl chloride as a yellow solid, which was used to the next (51.0 µL, 0.43mmol) at 0°C, followed by KHMDS (0.47M in
reaction without further purification.
toluene, 0.91mL, 0.43mmol) dropwise at 0°C. After 0.5h, the
2,6-Dichloro-4-(2,3-dihydro-1,4-benzoxazin-4-ylcarbon- reaction was quenched with saturated aqueous NH4Cl, and
yl)phenol (1) A screw top test tube equipped with a mag- the aqueous layer was extracted three times with ether. The
netic stirring bar was charged with benzoxazine 4 (18.8mg, combined organic extracts were washed with brine, dried over
0.139mmol) and anhydrous EtOAc (0.30mL). To the stirred anhydrous sodium sulfate, and filtered. The organic solvents
solution was added the crude acid chloride (0.279mmol) in were removed under reduced pressure to leave the residue,
anhydrous EtOAc (0.26mL) at room temperature. Stirring which was purified by flash silica gel column chromatog-
was continued for 4h and the reaction mixture was quenched raphy (hexanes–EtOAc=4:1) to afford oxime 14 (103.6mg,
with saturated aqueous NaHCO3 and extracted with EtOAc 0.33mmol, 93%) as a colorless solid; Rf=0.35 (hexanes–
three times. The combined organic extracts were washed with EtOAc=4:1); IR (neat) cm−1: 3071, 2974, 2928, 1716, 1598,
1
brine, dried over anhydrous sodium sulfate, filtered, and con- 1463, 1322, 1251, 1159, 955, 923, 755; H-NMR (400MHz,
centrated under reduced pressure to leave the residue, which CDCl3) δ: 8.42 (dd, 1H, J=8.0, 1.2Hz), 8.23 (brs, 1H), 7.79
was purified by preparative TLC (hexanes–EtOAc=3:1) to (d, 1H, J=8.0Hz), 7.78 (d, 1H, J=8.0Hz), 7.72 (dd, 1H, J=8.0,
afford the URAT-1 inhibitor 1 (12.9mg, 0.0398mmol, 29%) 1.2Hz), 7.41 (ddd, 1H, J=8.0, 8.0, 1.2Hz), 7.39 (ddd, 1H,
as a colorless solid; Rf=0.21 (Silica gel, hexanes–EtOAc= J=8.0, 8.0, 1.2Hz), 7.27 (dd, 1H, J=8.0, 8.0Hz), 7.24 (dd, 1H,
3:1); IR (neat) cm−1: 2927, 1618, 1597, 1489, 1399, 1240, J=8.0, 8.0Hz), 1.53 (s, 9H); 13C-NMR (100MHz, CDCl3) δ:
1179, 1059, 755; 1H-NMR (400MHz, acetone-d6) δ: 7.55 152.0, 146.4, 138.5, 137.5, 129.2, 129.0, 128.3, 128.2, 125.47,
(2H, s), 7.25–7.11 (1H, m), 7.00 (1H, ddd, J=8.4, 7.6, 1.6Hz), 125.42, 124.7, 124.6, 124.3, 124.2, 82.9, 28.1; HR-MS (ESI)
6.88 (1H, dd, J=8.4, 1.6Hz), 6.73 (1H, ddd, J=8.4, 7.6, Calcd for C18H19N2O3 (M+H+) 311.1390, Found: 311.1386;
1.6Hz), 4.43–4.33 (2H, m), 4.02–3.91 (2H, m), 2.81 (1H, brs); Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03; Found:
13C-NMR (100MHz, acetone-d6) δ: 166.5, 151.8, 147.3, 129.9, C, 69.79; H, 5.81; N, 8.94.
129.6, 127.0, 126.1, 125.1, 122.4, 120.4, 117.9, 66.8, 44.2; high
9(10H)-Acridone Oxime (8) A 20-mL round-bottomed
resolution (HR)-MS (electrospray ionization (ESI)) Calcd for flask equipped with a magnetic stirring bar was charged with
C15H12Cl2NO3 (M+H+): 324.0189; Found: 324.0173.
tert-Butyl Acridine-10(9H)-carboxylate (13)
carbamate 14 (32.6mg, 0.105mmol) and anhydrous dichloro-
two- methane (0.7mL). To the solution was added trifluoroacetic
A
necked 20-mL round-bottomed flask equipped with a mag- acid (TFA) (0.35mL, 4.7mmol) at 0°C. After the reaction
netic stirring bar was charged with acridone 11 (195mg, mixture was stirred at 0°C for 5min, the mixture was allowed
1.00mmol), and THF (2.5mL). To the solution was added to warm to room temperature and the solution was stirred
BH3·THF (1.08M in THF, 1.3mL, 1.4mmol) at room tempera- for 3h. The reaction mixture was quenched with saturated
ture. The reaction mixture was heated at reflux for 4h. The aqueous NaHCO3 at 0°C and was extracted with EtOAc three
reaction was quenched with brine and 2M aqueous NaOH, times. The combined organic extracts were washed with brine,
and the mixture was extracted with ether three times. The dried over anhydrous sodium sulfate, and filtered. The filtrate
combined organic extracts were washed with saturated aque- was concentrated under reduced pressure to afford the crude
ous NaHCO3, dried over anhydrous magnesium sulfate, and acridone oxime 8, which was subjected to the next reaction
filtered. The filtrate was concentrated under reduced pressure without further purification.
to afford the crude dihydroacridine 12 as a colorless solid,
(5H-Dibenzo[b,e][1,4]diazepin-10(11H)-yl)(4-nitrophenyl)-
which was used to the next reaction without further puri- methanone (15) A 20-mL round-bottomed flask equipped
fication. A 50-mL round-bottomed flask equipped with a with a magnetic stirring bar was charged with oxime 8 and
magnetic stirring bar was charged with 12, Boc2O (766mg, anhydrous dichloromethane (1.0mL). To the stirred solution
3.51mmol), and MeCN (3.3mL). To the solution was added was added DIBALH (1.03M in hexane, 0.60mL, 0.62mmol) at

April 2014
359
0°C. After the reaction mixture was stirred at 0°C for 5min, CDCl3) δ: 7.92 (brs, 1H), 7.60–7.06 (m, 10H), 6.98 (dd, 1H,
the mixture was allowed to warm to room temperature and J=7.6, 7.6Hz), 6.83 (d, 2H, J=8.0Hz), 6.79 (dd, 1H, J=7.6,
the solution was stirred for 2h. The reaction was quenched 7.6Hz), 6.70 (brs, 1H), 6.63–6.45 (m, 2H), 5.80 (brs, 1H), 4.20
with NaF (127mg) and H2O (40µL) at 0°C, and the result- (brs, 1H), 2.36 (s, 3H); 13C-NMR (125MHz, CDCl3) δ: 168.4,
ing mixture was stirred for 30min at the same temperature. 168.1, 141.4, 139.5, 138.5, 136.4, 136.0, 132.0, 131.2, 130.3,
Then the mixture was filtered through a pad of Celite. The 130.1, 129.7, 128.9, 128.5, 127.7, 126.9, 126.6, 125.8, 125.7,
filter cake was washed with ether and dichloromethane, and 123.8, 119.7, 119.4, 118.4, 117.4, 20.0, 19.7; HR-MS (ESI) Calcd
the filtrate was concentrated under reduced pressure to afford for C28H24N3O2 (M+H+) 434.1863, Found: 434.1870.
the crude dibenzodiazepine 5 as yellow solids, which was
Methyl 5-Bromo-2-ethynylbenzoate (18) A two-necked
subjected to the next reaction without further purification. A 200-mL round-bottomed flask equipped with a magnetic stir-
20-mL round-bottomed flask equipped with a magnetic stir- ring bar was charged with aryl iodide 17 (1.733g, 5.083mmol),
ring bar was charged with 5, Et3N (73µL, 0.52mmol), and CuI (20.8mg, 0.109mmol), and DMF (25mL). To the solution
anhydrous dichloromethane (1.0mL). To the solution was were added Et3N (2.1mL, 15.1mmol), PdCl2(PPh3)2 (36.1mg,
added p-nitrobenzoyl chloride (39.3mg, 0.212mmol) at 0°C. 0.0514mmol), and trimethylsilylacetylene (1.1mL, 7.8mmol).
After the reaction mixture was stirred at 0°C for 5min, the The solution was stirred for 30h. The reaction was quenched
mixture was allowed to warm to room temperature and the with water, and the mixture was extracted with EtOAc three
solution was stirred for 1h. The reaction was quenched with times. The combined organic extracts were washed with
saturated aqueous NH4Cl, and the mixture was extracted with water and brine, dried over anhydrous magnesium sulfate,
dichloromethane three times. The combined organic extracts filtered, and concentrated under reduced pressure to leave the
were washed with brine, dried over anhydrous sodium sulfate, residue, which was purified by short silica gel column chro-
filtered, and concentrated under reduced pressure to leave matography (hexanes–EtOAc=9:1) to afford TMS-acetylene
the residue, which was purified by silica gel column chro- (1.706g, 5.49mmol, quant.) as yellow solids; Rf=0.74 (Silica
matography (hexanes–EtOAc=3:1 to 3:2) to afford amide gel, hexanes–EtOAc=3:1). A 100-mL round-bottomed flask
15 (29.1mg, 0.0843mmol, 80% for 3 steps) as a yellow solid; equipped with a magnetic stirring bar was charged with
Rf=0.63 (Silica gel, hexanes–EtOAc=1:1); IR (neat) cm−1: TMS-acetylene and MeOH (10mL). To the solution was added
1
3337, 1634, 1595, 1520, 1504, 1495, 1344, 745, 731; H-NMR K2CO3 (1.4g, 10.1mmol) at 0°C. The solution was stirred for
(400MHz, CDCl3) δ: 8.00 (d, 2H, J=8.4Hz), 7.41 (d, 2H, 10min. The solution was concentrated under reduced pressure.
J=8.4Hz), 7.29 (d, 1H, J=8.0Hz), 7.19 (dd, 1H, J=8.0, 8.0Hz), The reaction mixture was filtered through a pad of Celite. The
7.13–7.00 (m, 1H), 6.95–6.80 (m, 3H), 6.62–6.50 (m, 2H), 6.43 filter cake was washed with ether, and the filtrate was con-
(brs, 1H), 5.81 (brs, 1H), 4.27 (brs, 1H); 13C-NMR (100MHz, centrated under reduced pressure to leave the residue, which
CDCl3) δ: 167.0, 148.1, 142.1, 140.9, 138.6, 130.6, 130.2, 129.2, was purified by silica gel column chromatography (hexanes–
128.8, 128.7, 128.3, 123.5, 123.0, 119.9, 119.8, 118.5, 117.6, ether=9:1) to afford aryl acetylene 18 (909mg, 3.80mmol,
51.9; HR-MS (EI) Calcd for C20H15N3O3 (M+) 345.1113, Found: 75% for 2 steps) as a pale yellow solid; Rf=0.50 (Silica
345.1087.
gel, hexanes–ether=3:1); IR (neat) cm−1: 3256, 3099, 2950,
1
N-(4-(10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepine-10- 2103, 1730, 1430, 1291, 1243, 1073, 689; H-NMR (400MHz,
carbonyl)phenyl)-2-methylbenzamide (2) A Schlenk tube CDCl3) δ: 8.09 (d, 1H, J=2.0Hz), 7.61 (dd, 1H, J=8.0, 2.0Hz),
equipped with a magnetic stirring bar was charged with amide 7.48 (d, 1H, J=8.0Hz), 3.94 (s, 3H), 3.45 (s, 1H); 13C-NMR
15 (13.1mg, 0.038mmol), 10% Pd/C (10.6mg, 0.010mmol) and (100MHz, CDCl3) δ: 165.1, 136.2, 134.8, 133.9, 133.3, 122.6,
EtOAc (0.38mL). To the flask was charged with hydrogen gas 121.6, 83.4, 81.1, 52.5; HR-MS (ESI) Calcd for C10H8BrO2
(1atm). The resulting suspension was vigorously stirred for (M+H+) 238.9702, Found: 238.9697.
2h. The reaction mixture was filtered through a pad of Celite.
The filter cake was washed with EtOAc, and the filtrate was 1-methylthiobenzene
Procedure for the Sandmeyer Reaction to Give 3-Iodo-
300-mL round-bottomed flask
A
concentrated under reduced pressure to leave the crude amine equipped with a magnetic stirring bar was charged with m-
16 as yellow solids, which was subjected to the next reaction (methylthio)aniline (4.00mL, 32.5mmol), crushed ice (24g),
without further purification. A 20-mL round-bottomed flask and MeCN (24mL). To the stirred solution was added concen-
equipped with a magnetic stirring bar was charged with 16, trated H2SO4 (24mL) at 0°C over 30min. To the slurry was
Et3N (26µL, 0.19mmol), and anhydrous dichloromethane added aqueous NaNO2 (4.04g, 58.6mmol) in cold H2O (8mL)
(0.76mL). To the solution was added 2-methylbenzoyl chloride at 0°C dropwise over 30min to maintain the internal tem-
(7.5 µL, 0.057mmol) at 0°C. After the reaction mixture was perature below 5°C. After the mixture was stirred at 0°C for
stirred at 0°C for 5min, the mixture was allowed to warm 30min, the mixture was poured into a solution of KI (18.9g,
to room temperature and the solution was stirred for 1h. The 114mmol) in H2O (24mL) at 0°C. After the resulting mixture
reaction was quenched with saturated aqueous NH4Cl, and the was stirred at 0°C for 5min, the mixture was allowed to warm
mixture was extracted with dichloromethane three times. The to room temperature and the solution was stirred for 1h.
combined organic extracts were washed with saturated aque- The reaction was quenched with H2O, and the mixture was
ous NaHCO3 and brine, dried over anhydrous sodium sulfate, extracted with CHCl3 three times. The combined organic ex-
filtered, and concentrated under reduced pressure to leave the tracts were washed with saturated aqueous NaHCO3, saturated
residue, which was purified by preparative TLC (hexanes– aqueous Na2S2O3, and brine, dried over anhydrous sodium sul-
EtOAc=1:1) to afford amide 2 (14.0mg, 0.0323mmol, 85% fate, and filtered. The filtrate was concentrated under reduced
for 2 steps) as a yellow solid; Rf=0.39 (Silica gel, hexanes– pressure to leave the residue, which was purified by silica gel
EtOAc=1:1); IR (neat) cm−1: 3320, 3229, 3056, 3012, 1660, column chromatography (hexanes) to afford 3-iodo-1-methyl-
1
1623, 1594, 1525, 1493, 1407, 1317, 752; H-NMR (400MHz, thiobenzene (7.71g, 30.8mmol, 95%) as a pale yellow oil. The

360
Vol. 62, No. 4
spectral data of 3-iodo-1-methylthiobenzene was identical with mixture was filtered through a pad of Celite, the filter cake
those reported in ref. 14. was washed with EtOAc. The filtrate was concentrated under
Methyl 5-Bromo-2-[(3-methylthiophenyl)ethynyl]benzo- reduced pressure to leave the residue, which was purified by
ate (19b) two-necked 200-mL round-bottomed flask silica gel column chromatography (hexanes–EtOAc=19:1)
A
equipped with a magnetic stirring bar was charged with aryl to afford ester 20b as a mixture of inseparable compounds
acetylene 18 (718mg, 3.00mmol), 3-iodo-1-methylthiobenzene (855mg, <2.34mmol, <92%) as a yellow solid; Rf=0.25
(906mg, 3.62mmol), and DMF (6.0mL). To the solution were (Silica gel, hexanes–EtOAc=19:1); IR (neat) cm−1: 2949, 2921,
1
added PdCl2(PPh3)2 (21.5mg, 0.0306mmol), CuI (11.4mg, 1725, 1591, 1479, 1434, 1291, 1244, 1078, 967, 788; H-NMR
0.0599mmol), and Et3N (1.3mL, 9.3mmol). The solution was (400MHz, CDCl3) δ: 8.03 (d, 1H, J=2.4Hz), 7.50 (dd, 1H,
stirred for 3h. The reaction was quenched with water, and the J=8.0, 2.4Hz), 7.19 (dd, 1H, J=8.0, 8.0Hz), 7.13–7.06 (m,
mixture was extracted with EtOAc three times. The combined 2H), 7.04 (d, 1H, J=8.0Hz), 6.99–6.92 (m, 1H), 3.89 (s, 3H),
organic extracts were washed with water and brine, dried over 3.26–3.14 (m, 2H), 2.92–2.88 (m, 2H), 2.45 (s, 3H); 13C-NMR
anhydrous sodium sulfate, filtered, and concentrated under (100MHz, CDCl3) δ: 166.4, 142.4, 142.1, 138.2, 134.8, 133.5,
reduced pressure to leave the residue, which was purified by 132.8, 131.1, 128.8, 126.9, 125.4, 124.3, 119.6, 52.2, 37.7,
silica gel column chromatography (hexanes–EtOAc=19:1) to 35.9, 15.8; HR-MS (ESI) Calcd for C16H14BrOS [(M–OMe)+]
afford diaryl acetylene 19b (999mg, 2.77mmol, 92%) as a 332.9943, Found: 332.9915.
pale yellow solid; Rf=0.25 (Silica gel, hexanes–EtOAc=19:1);
3-Bromo-10,11-dihydro-5H-dibenzo[a,d][7]annulen-
IR (neat) cm−1: 2214, 1726, 1561, 1475, 1437, 1286, 1241, 1092, 5-one (22a) A 10-mL round-bottomed flask equipped with
1
1078, 964, 817, 780, 679; H-NMR (400MHz, CDCl3) δ: 8.12 a magnetic stirring bar was charged with ester 20a (38.0mg,
(d, 1H, J=2.0Hz), 7.61 (dd, 1H, J=8.4, 2.0Hz), 7.49 (d, 1H, 0.119mmol), THF (0.6mL), and MeOH (0.6mL). To the solu-
J=8.4Hz), 7.42 (brs, 1H), 7.33 (ddd, 1H, J=6.8, 1.6, 1.6Hz), tion was added 2M aqueous NaOH (1.2mL) at 0°C. After the
7.26 (dd, 1H, J=8.0, 6.8Hz), 7.23 (ddd, 1H, J=6.8, 1.6, 1.6Hz), reaction mixture was stirred at 0°C for 5min, the mixture was
3.96 (s, 3H), 2.50 (s, 3H); 13C-NMR (100MHz, CDCl3) δ: allowed to warm to room temperature and the solution was
165.2, 139.0, 135.2, 134.7, 133.5, 133.2, 129.1, 128.7, 128.3, stirred for 11h. The reaction was quenched with 2M aqueous
126.9, 123.6, 122.5, 121.9, 95.0, 87.6, 52.4, 15.6; HR-MS (ESI) HCl at 0°C, and the mixture was extracted with EtOAc three
Calcd for C17H14BrO2S (M+H+) 360.9892, Found: 360.9890.
times. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, and filtered. The filtrate
Methyl 5-Bromo-2-(Phenylethynyl)benzoate (19a)
A
pale yellow solid; IR (neat) cm−1: 1727, 1492, 1438, 1289, was concentrated under reduced pressure to afford the crude
1
1244, 1077, 968, 825, 758, 690; H-NMR (400MHz, CDCl3) δ: carboxylic acid 21a as a colorless solid, which was subjected
8.12 (d, 1H, J=2.4Hz), 7.61 (dd, 1H, J=8.4, 2.4Hz), 7.59–7.54 to the next reaction without further purification. A screw top
(m, 2H), 7.50 (d, 1H, J=8.4Hz), 7.41–7.32 (m, 3H), 3.97 (s, test tube equipped with a magnetic stirring bar was charged
3H); 13C-NMR (100MHz, CDCl3) δ: 165.3, 135.2, 134.8, 133.5, with carboxylic acid 21a. To the tube was added the PPMA
133.2, 131.7, 128.8, 128.4, 123.0, 122.7, 121.8, 95.5, 87.3, 52.4; solution, which was prepared from P2O5 (161mg, 1.13mmol)
HR-MS (ESI) Calcd for C16H12BrO2 (M+H+) 315.0015, Found: and MsOH (1.0mL) at 80°C for 1h. After the mixture was
315.0014.
Methyl 5-Bromo-2-phenethylbenzoate (20a)
stirred for 0.5h at 80°C, the reaction mixture was poured into
two- ice-water and extracted with CHCl3. The combined extracts
A
necked 10-mL round-bottomed flask equipped with a mag- were washed with brine and dried over anhydrous sodium sul-
netic stirring bar was charged with acetylene 19a (58.1mg, fate, filtered, and concentrated under reduced pressure to leave
0.184mmol), PtO2 (3.9mg, 0.017mmol), EtOAc (0.7mL), EtOH the residue, which was purified by preparative TLC (hexanes–
(0.7mL), and AcOH (0.4mL). To the flask was charged with EtOAc=17:3) to afford ketone 22a (23.3mg, 0.0811mmol,
hydrogen gas (1atm). The resulting suspension was vigor- 68% for 2 steps) as a yellow oil; Rf=0.51 (Silica gel, hexanes–
ously stirred for 1.5h. After the reaction mixture was filtered EtOAc=17:3); IR (neat) cm−1: 3060, 2921, 2856, 1652, 1597,
through a pad of Celite, the filter cake was washed with 1584, 1474, 1289, 841, 751; 1H-NMR (400MHz, CDCl3) δ:
EtOAc. The filtrate was concentrated under reduced pressure 8.14 (d, 1H, J=2.4Hz), 7.98 (dd, 1H, J=8.0, 2.4Hz), 7.53 (dd,
to leave the residue, which was purified by silica gel column 1H, J=8.0, 1.6Hz), 7.45 (ddd, 1H, J=8.0, 8.0, 1.6Hz), 7.33
chromatography (hexanes–EtOAc=19:1) to afford ester 20a (ddd, 1H, J=8.0, 8.0, 1.2Hz), 7.22 (dd, 1H, J=8.0, 1.2Hz), 7.11
(52.2mg, 0.164mmol, 89%) as a yellow solid; Rf=0.35 (Silica (d, 1H, J=8.0Hz), 3.24–3.10 (m, 4H); 13C-NMR (100MHz,
gel, hexanes–EtOAc=19:1); IR (neat) cm−1: 1726, 1434, 1288, CDCl3) δ: 193.9, 141.8, 140.8, 140.1, 138.0, 135.0, 133.3, 132.7,
1
1246, 1081, 967, 700; H-NMR (400MHz, CDCl3) δ: 8.03 (d, 131.1, 130.7, 129.3, 126.8, 120.5, 34.7, 34.4; HR-MS (ESI)
1H, J=2.4Hz), 7.50 (dd, 1H, J=8.4 and 2.4Hz), 7.33–7.24 (m, Calcd for C15H12BrO (M+H+), 287.0066; Found: 287.0059.
2H), 7.24–7.16 (m, 3H), 7.05 (d, 1H, J=8.4Hz), 3.90 (s, 3H),
7-Bromo-2-(Methylthio)-10,11-dihydro-5H-dibenzo[a,d]-
3.28–3.16 (m, 2H), 2.93–2.83 (m, 2H); 13C-NMR (100MHz, [7]annulen-5-one (22b) Yellow solid; IR (neat) cm−1: 2918,
1
CDCl3) δ: 166.6, 142.6, 141.5, 134.8, 133.5, 132.9, 131.1, 128.5, 1622, 1573, 1558, 1261, 1112, 774; H-NMR (400MHz, CDCl3)
128.3, 126.0, 119.5, 52.2, 37.8, 36.2; HR-MS (ESI) Calcd for δ: 8.15 (d, 1H, J=2.4Hz), 8.03 (d, 1H, J=8.0Hz), 7.52 (dd,
C15H12BrO [(M−OMe)+] 287.0066, Found: 287.0063.
1H, J=8.0, 2.4Hz), 7.16 (dd, 1H, J=8.0, 2.0Hz), 7.10 (d, 1H,
Methyl
5-Bromo-2-(3-(Methylthio)phenethyl)benzoate J=8.0Hz), 7.03 (d, 1H, J=2.0Hz), 3.19–3.09 (m, 4H), 2.52 (s,
(20b) A Parr pressure bomb equipped with a magnetic stir- 3H); 13C-NMR (100MHz, CDCl3) δ: 192.1, 145.5, 142.8, 140.6,
ring bar was charged with acetylene 19b (917mg, 2.54mmol), 140.2, 134.9, 133.8, 133.5, 131.8, 130.8, 125.7, 123.4, 120.6,
PtO2 (28.9mg, 0.127mmol), and THF (12.7mL). To the flask 35.3, 34.3, 14.7; HR-MS (ESI) Calcd for C16H14BrOS (M+H+)
was charged with hydrogen gas (70atm). The resulting sus- 332.9943, Found: 332.9921.
pension was vigorously stirred for 14h. After the reaction
3-Bromo-10,11-dihydro-5H-dibenzo[a,d][7]annulen-

April 2014
361
5-one Oxime (9a) A 20-mL round-bottomed flask equipped ganic extracts were washed with brine, dried over anhydrous
with a magnetic stirring bar was charged with ketone 22a sodium sulfate, and filtered. The filtrate was concentrated
(608mg, 2.12mmol) and pyridine (4.2mL). To the solution under reduced pressure to leave the residue, which was puri-
was added hydroxylamine hydrochloride (1.8g, 26mmol). fied by silica gel column chromatography (hexanes–EtOAc=
The solution was stirred at 130°C for 48h. The reaction was 9:1) to afford an inseparable mixture of 23b and 24b (113mg,
quenched with water. The resulting mixture was extracted 0.337mmol, 67%) as a yellow solid; IR (neat) cm−1: 3376 (br),
1
with EtOAc three times. The combined organic extracts were 2919, 2891, 1592, 1484, 1258, 813, 756; H-NMR (400MHz,
washed with brine, dried over anhydrous sodium sulfate, and CDCl3, isomeric mixture (6:1)). Major isomer: δ: 7.22–7.15
filtered. The filtrate was concentrated under reduced pressure (m, 2H), 6.96 (d, 1H, J=2.0Hz), 6.90 (dd, 1H, J=8.0, 2.0Hz),
to leave the residue, which was purified by silica gel column 6.89 (d, 1H, J=7.6Hz), 6.46 (d, 1H, J=8.0Hz), 4.35 (s, 2H),
chromatography (hexanes–EtOAc=17:3) to afford oxime 9a 3.27–3.18 (m, 2H), 3.16–3.08 (m, 2H), 2.37 (s, 3H). Minor iso-
(577mg, 1.91mmol, 90%) as a pale yellow solid; Rf=0.53 mer: δ: 7.02–7.15 (m, 3H), 6.81 (d, 1H, J=8.0Hz), 6.77 (dd, 1H,
(Silica gel, hexanes–EtOAc=3:1); IR (neat) cm−1: 3172, 3059, J=7.6, 2.0Hz), 6.61 (d, 1H, J=2.0Hz), 4.37 (s, 2H), 3.27–3.18
2916, 1426, 1311, 1006, 935, 819, 745; 1H-NMR (400MHz, (m, 2H), 3.16–3.08 (m, 2H), 2.41 (s, 3H); 13C-NMR (100MHz,
CDCl3) δ: 7.92 (brs, 0.55H), 7.82–7.70 (m, 0.9H), 7.62–7.57 CDCl3) δ: 148.5, 145.3, 140.7, 139.3, 137.3, 133.7, 132.5, 132.2,
(m, 0.55H), 7.57–7.51 (m, 0.55H), 7.48–7.09 (m, 5H), 7.05–6.97 132.1, 131.9, 131.8, 131.2, 130.22, 130.19, 129.7, 128.3, 127.7,
(m, 0.45H), 3.24–2.96 (m, 4H); 13C-NMR (100MHz, CDCl3) 127.6, 125.8, 124.6, 122.5, 121.2, 119.9, 119.8, 51.1, 50.8, 35.4,
δ: 157.6, 157.3, 138.5, 138.1, 137.8, 137.4, 136.1, 135.4, 133.8, 34.8, 32.1, 31.6, 17.9, 15.6; HR-MS (ESI) Calcd for C16H17BrNS
133.0, 132.2, 132.0, 132.0, 131.1, 131.0, 130.5, 130.0, 129.6, (M+H+), 334.0260; Found: 334.0249.
129.5, 128.6, 128.4, 128.3, 126.4, 125.8, 119.6, 119.3, 33.3,
33.1, 31.8, 31.5; HR-MS (ESI) Calcd for C15H13BrNO (M+H+) cine (25a) A screw top test tube equipped with a magnetic
302.0175, Found: 302.0176. stirring bar was charged with mixture of 23a and 24a, Et3N
5-Acetyl-8-bromo-5,6,11,12-tetrahydrodibenz[b,f]azo-
7-Bromo-2-methylthio-10,11-dihydro-5H-dibenzo[a,d][7]- (25 µL, 0.18mmol) and anhydrous dichloromethane (0.36mL).
annulen-5-one Oxime (9b) Pale yellow solid; IR (neat) To the solution were added Ac2O (7.0µL, 0.074mmol) and
1
cm−1: 3214, 1588, 1427, 1002, 931, 812; H-NMR (400MHz, DMAP (2.2mg, 0.018mmol) at room temperature. The solu-
acetone-d6) δ: 10.64 (brs, 0.5H), 10.60 (brs, 0.5H), 7.70 (d, tion was stirred for 0.5h. The reaction mixture was quenched
0.5H, J=2.4Hz), 7.56 (d, 0.5H, J=1.6Hz), 7.54–6.80 (m, 5H), with saturated aqueous NH4Cl, and the mixture was extracted
3.20–2.95 (m, 4H), 2.49 (s, 1.5H), 2.46 (s, 1.5H); 13C-NMR with dichloromethane three times. The combined organic ex-
(100MHz, acetone-d6) δ: 140.7, 140.6, 140.0, 139.9, 138.84, tracts were washed with brine, dried over anhydrous sodium
138.77, 138.2, 137.6, 133.3, 132.3, 132.14, 132.09, 132.06, sulfate, and filtered. The filtrate was concentrated under re-
132.01, 131.95, 131.5, 131.3, 130.9, 130.3, 130.3, 128.3, 126.1, duced pressure to leave the residue, which was purified by
124.4, 123.8, 119.6, 119.3, 34.1, 33.8, 32.4, 31.9, 15.1, 15.0; preparative TLC (hexanes–EtOAc=3:1) to afford acetamide
HR-MS (ESI) Calcd for C16H15BrNOS (M+H+) 348.0052, 25a (7.9mg, 0.024mmol, 66%) as colorless plates and acet-
Found: 348.0037.
8-Bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine (23a) and
amide 27a (2.3mg, 0.0070mmol, 19%) as colorless plates.
5-Acetyl-8-bromo-5,6,11,12-tetrahydrodibenz[b,f]azo-
3-Bromo-5,6,11,12-tetrahydrodibenz[b,f]azocine
(24a)
A
cine (25a) mp 146.5–148.3°C, colorless crystals; IR (neat)
screw top test tube equipped with a magnetic stirring bar cm−1: 2944, 1651, 1496, 1386, 1282, 724; H-NMR (400MHz,
was charged with oxime 9a (15.6mg, 0.0516mmol) and anhy- CDCl3) δ: 7.25–7.12 (m, 4H), 7.10–7.00 (m, 2H), 6.96–6.88
drous 1,2-dichloroethane (0.26mL). To the solution was added (m, 1H), 5.75 (d, 1H, J=14.8Hz), 4.02 (d, 1H, J=14.8Hz),
DIBALH (1.03M in hexane, 0.30mL, 0.31mmol) dropwise at 3.26–3.12 (m, 2H), 2.94–2.72 (m, 2H), 1.80 (s, 3H); 13C-NMR
80°C for 0.5h. The solution was stirred for 15h. The reaction (100MHz, CDCl3) δ: 170.2, 140.5, 139.3, 139.0, 137.3, 132.7,
mixture was cooled to 0°C, and diluted with ether. The reaction 131.2, 131.1, 130.8, 128.7, 128.5, 128.0, 119.7, 52.0, 34.6, 30.9,
was quenched with methanol and 2M aqueous NaOH, and the 22.7; HR-MS (ESI) Calcd for C17H17BrNO (M+H+) 330.0488,
mixture was extracted with ether three times. The combined Found: 330.0489.
1
organic extracts were washed with brine, dried over anhydrous
5-Acetyl-3-bromo-5,6,11,12-tetrahydrodibenz[b,f]azo-
sodium sulfate, and filtered. The filtrate was concentrated under cine (27a) mp 140.7–142.2°C, colorless crystals; IR (neat)
reduced pressure to leave the residue, which was purified by cm−1: 3019, 2927, 1660, 1486, 1385, 1295, 761; 1H-NMR
preparative TLC (hexanes–EtOAc=17:3) to afford a mixture (600MHz, CDCl3) δ: 7.31–7.19 (m, 2H), 7.16–7.01 (m, 4H),
of 23a and 24a (10.8mg, 0.0375mmol, 73%) as a yellow solid.
6.91 (d, 1H, J=7.8Hz), 5.76 (d, 1H, J=15.0Hz), 4.07 (d, 1H,
8-Bromo-2-methylthio-5,6,11,12-tetrahydrodibenz- J=15.0Hz), 3.30–3.18 (m, 1H), 3.16–3.07 (m, 1H), 2.93–2.77
[b,f]azocine (23b) and 3-Bromo-9-methylthio-5,6,11,12- (m, 2H), 1.82 (s, 3H); 13C-NMR (100MHz, CDCl3) δ: 169.8,
tetrahydrodibenz[b,f]azocine (24b) A two-necked 30-mL 142.0, 139.9, 138.7, 134.5, 132.6, 131.6, 131.5, 130.2, 129.4,
round-bottomed flask equipped with a magnetic stirring bar 128.0, 126.5, 120.2, 52.5, 34.4, 31.0, 22.9; HR-MS (ESI) Calcd
was charged with oxime 9b (175mg, 0.503mmol) and an- for C17H17BrNO (M+H+) 330.0488, Found: 330.0484.
hydrous dichloromethane (5.0mL). To the stirred solution
5-Acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azo-
was added DIBALH (1.03M in hexane, 3.0mL, 3.09mmol) cine (3) A screw top test tube equipped with a magnetic
dropwise at room temperature in water bath for 10min. The stirring bar was charged with aryl bromide 25a (10.8mg,
solution was stirred for 12h. The reaction mixture was cooled 0.0287mmol), phenylboronic acid (6.7mg, 0.055mmol),
to 0°C and diluted with ether. The reaction was quenched K2CO3 (7.9mg, 0.057mmol), Pd(PPh3)4 (2.2mg, 1.9µmol),
with methanol and 2M aqueous NaOH, and the mixture was THF (0.15mL), and H2O (0.04mL). The reaction mixture
extracted with diethyl ether three times. The combined or- was heated to reflux for 6h. The reaction mixture was di-

362
Vol. 62, No. 4
luted with EtOAc, washed with brine, dried over anhydrous 26 (27.1mg, 0.0726mmol, 78%) as a colorless oil; IR (neat)
1
sodium sulfate, and filtered. The filtrate was concentrated cm−1: 3349, 2888, 1637, 1388, 1017, 762; H-NMR (400MHz,
under reduced pressure to leave the residue, which was puri- CDCl3) δ: 7.51 (d, 2H, J=8.0Hz), 7.43–7.26 (m, 5H), 7.11
fied by preparative TLC (hexanes–acetone=3:1) to afford 3 (d, 1H, J=8.0Hz), 7.04–6.96 (m, 2H), 6.91 (s, 1H), 5.82 (d,
(6.7mg, 0.020mmol, 70%) as a colorless oil; IR (neat) cm−1: 1H, J=14.8Hz), 4.13 (d, 1H, J=14.8Hz), 3.35–3.12 (m, 2H),
3027, 2930, 1658, 1494, 1389, 765; 1H-NMR (400MHz, 2.94–2.80 (m, 2H), 2.40 (s, 3H), 1.81 (s, 3H); 13C-NMR
CDCl3) δ: 7.49 (d, 2H, J=7.2Hz), 7.45–7.27 (m, 5H), 7.21–7.00 (100MHz, CDCl3) δ: 170.3, 140.5, 139.8, 139.2, 139.1, 138.9,
(m, 5H), 5.83 (d, 1H, J=14.8Hz), 4.16 (d, 1H, J=14.8Hz), 137.7, 135.4, 130.0, 128.8, 128.7, 128.6, 128.5, 127.1, 126.9,
3.38–3.15 (m, 2H), 3.00–2.81 (m, 2H), 1.82 (s, 3H); 13C-NMR 126.4, 125.0, 52.7, 34.9, 31.0, 22.8, 15.3; HR-MS (ESI) Calcd
(150MHz, CDCl3) δ: 170.3, 140.5, 139.43, 139.37, 139.1, 135.4, for C24H24NOS (M+H+) 374.1573, Found: 374.1576.
131.2, 130.0, 128.8, 128.7, 128.6, 128.54, 128.46, 127.8, 127.1,
126.9, 126.3, 52.8, 34.8, 31.2, 22.8; HR-MS (ESI) Calcd for cine (3) A Schlenk tube equipped with a magnetic stirring
C23H22NO (M+H+) 328.1696, Found: 328.1699.
bar was charged with sulfide 26 (10.8mg, 0.0289mmol) and
5-Acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azo-
5-Acetyl-8-bromo-5,6,11,12-tetrahydro-2-methylthio- Raney nickel (W-2) in ethanol (0.5mL). To the flask was
dibenz[b,f]azocine (25b) A screw top test tube equipped charged with hydrogen gas (1atm). The reaction mixture was
with a magnetic stirring bar was charged with mixture of 23b heated to reflux for 3h. The reaction mixture was filtered
and 24b, Et3N (33µL, 0.24mmol) and anhydrous dichloro- through a pad of Celite. The filter cake was washed with
methane (0.50mL). To the solution were added Ac2O (10µL, EtOAc, and the filtrate was concentrated under reduced pres-
0.11mmol) and DMAP (1.0mg, 8.2µmol) at room temperature. sure to leave the residue, which was purified by preparative
The solution was stirred for 1h. The reaction was quenched TLC (hexanes–EtOAc=3:1) to afford 3 (6.6mg, 0.020mmol,
with saturated aqueous NH4Cl, and the mixture was extracted 69%).
with dichloromethane three times. The combined organic ex-
tracts were washed with brine, dried over anhydrous sodium
Acknowledgments This work was supported by KAKENHI,
sulfate, and filtered. The filtrate was concentrated under re- a Grant-in-Aid for Scientific Research (C) (23590001), the
duced pressure to leave the residue, which was purified by Cabinet Office, Government of Japan through its “Funding
preparative TLC (hexanes–EtOAc=3:1) to afford acetamide Program for Next Generation World-Leading Researchers,”
25b (12.4mg, 0.033mmol, 70%) and acetamide 27b (2.0mg, Platform for Drug Discovery, Informatics, and Structural
0.0053mmol, 11%).
Life Science from the Ministry of Education, Culture, Sports,
5-Acetyl-8-bromo-5,6,11,12-tetrahydro-2-methylthio- Science and Technology of Japan, a JSPS predoctoral fellow-
dibenz[b,f]azocine (25b) A colorless oil; IR (neat) cm−1: 3002, ship to Y.I., Japan Tobacco Inc. to H.C., and Banyu Life Sci-
1
2921, 1657, 1491, 1386, 1286, 754; H-NMR (400MHz, CDCl3) ence Foundation International.
δ: 7.26–7.20 (m, 2H), 7.03 (dd, 1H, J=8.0, 2.0Hz), 6.97 (d,
1H, J=8.0Hz), 6.91 (d, 1H, J=8.0Hz), 6.89 (d, 1H, J=2.0Hz),
5.73 (d, 1H, J=14.8Hz), 3.99 (d, 1H, J=14.8Hz), 3.24–3.10 (m,
2H), 2.88–2.70 (m, 2H), 2.42 (s, 3H), 1.80 (s, 3H); 13C-NMR
(100MHz, CDCl3) δ: 170.3, 139.4, 139.3, 139.1, 137.3, 137.2,
132.7, 131.1, 130.8, 128.8, 128.4, 125.1, 119.8, 52.0, 34.7, 30.7,
22.7, 15.3; HR-MS (ESI) Calcd for C18H19BrNOS (M+H+)
376.0365, Found: 376.0381.
References and Notes
1) Cho H., Murakami K., Fujisawa A., Niwa M., Nakanishi H., Uchida
I., Heterocycles, 48, 1555–1566 (1998).
2) Cho H., Iwama Y., Sugimoto K., Kwon E., Tokuyama H., Hetero-
cycles, 78, 1183–1190 (2009).
3) Cho H., Iwama Y., Sugimoto K., Mori S., Tokuyama H., J. Org.
Chem., 75, 627–636 (2010).
4) Cho H., Sugimoto K., Iwama Y., Mitsuhashi N., Okano K.,
Tokuyama H., Heterocycles, 82, 1633–1644 (2011).
5) Cho H., Iwama Y., Mitsuhashi N., Sugimoto K., Okano K.,
Tokuyama H., Molecules, 17, 7348–7355 (2012).
5-Acetyl-3-bromo-5,6,11,12-tetrahydro-9-methyl-
thiodibenz[b,f]azocine (27b) A colorless oil; IR (neat) cm−1:
1
2292, 1660, 1587, 1487, 1382, 1295, 754; H-NMR (600MHz,
CDCl3) δ: 7.31–7.25 (m, 1H), 7.22 (d, 1H, J=1.8Hz), 7.03 (d,
1H, J=7.2Hz), 6.99–6.90 (m, 3H), 5.68 (d, 1H, J=15.0Hz),
4.03 (d, 1H, J=15.0Hz), 3.26–3.15 (m, 1H), 3.15–3.05 (m,
1H), 2.91–2.81 (m, 1H), 2.81–2.73 (m, 1H), 2.42 (s, 3H), 1.81
(s, 3H); 13C-NMR (100MHz, CDCl3) δ: 169.8, 142.1, 140.6,
138.5, 138.0, 132.6, 131.7, 131.5, 131.4, 130.8, 127.6, 124.2,
120.3, 52.1, 34.2, 31.3, 22.8, 15.7; HR-MS (ESI) Calcd for
C18H19BrNOS (M+H+), 376.0365; Found: 376.0351.
6) Hirata K., Ogawa N., Sinagawa Y., Kiguchi T., Inoue T., Komeda
Y., Yamashita I., Kamiya Y., Application WO 2007139002, U.S.
2006–809966. CAN 148:33748.
7) Sum F.-W., Dusza J., Santos E. D., Grosu G., Reich M., Du X., Al-
bright J. D., Chan P., Coupet J., Ru X., Mazandarani H., Saunders
T., Bioorg. Med. Chem. Lett., 13, 2195–2198 (2003).
8) Cho H., Murakami K., Nakanishi H., Fujisawa A., Isoshima H.,
Niwa M., Hayakawa K., Hase Y., Uchida I., Watanabe H., Wakitani
K., Aisaka K., J. Med. Chem., 47, 101–109 (2004).
5-Acetyl-5,6,11,12-tetrahydro-2-methylthio-8-phenyl-
dibenz[b,f]azocine (26) A screw top test tube equipped
with a magnetic stirring bar was charged with aryl bromide
9) Ogawa H., Yamashita H., Kondo K., Yamamura Y., Miyamoto H.,
Kan K., Kitano K., Tanaka M., Nakaya K., Nakamura S., Mori T.,
Tominaga M., Yabuuchi Y., J. Med. Chem., 39, 3547–3555 (1996).
25b (35.2mg, 0.0935mmol), phenylboronic acid (23.2mg, 10) Fink B. E., Gavai A. V., Tokarski J. S., Goyal B., Misra R., Xiao
H.-Y., Kimball S. D., Han W.-C., Norris D., Spires T. E., You D.,
Gottardis M. M., Lorenzi M. V., Vite G. D., Bioorg. Med. Chem.
Lett., 16, 1532–1536 (2006).
0.190mmol), K2CO3 (65.5mg, 0.474mmol), Pd(PPh3)4 (11mg,
9.5 µmol), THF (0.4mL), and H2O (0.1mL). The mixture
was heated to reflux for 22h. The reaction mixture was di-
luted with EtOAc, washed with brine, dried over anhydrous
11) Cho H., Iwama Y., Okano K., Tokuyama H., Synlett, 24, 813–816
(2013).
sodium sulfate, and filtered. The filtrate was concentrated
12) Torraca K. E., Kuwabe S.-I., Buchwald S. L., J. Am. Chem. Soc.,
under reduced pressure to leave the residue, which was pu-
rified by preparative TLC (hexanes–EtOAc=3:1) to afford
122, 12907–12908 (2000).

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363
13) Iwama Y., Noro T., Okano K., Cho H., Tokuyama H., Heterocycles, 18) Crystal data for 25a C17H16BrNO: MW=330.22, triclinic, a=
88, 1433–1444 (2014).
14) Mongin O., Papamicaël C., Hoyler N., Gossauer A., J. Org. Chem.,
63, 5568–5580 (1998).
15) We prepared 3-iodo-1-methylthiobenzene from m-(methylthio)-
aniline by Sandmeyer reaction. This procedure is described in the
experimental.
16) Eaton P. E., Carlson G. R., Lee J. T., J. Org. Chem., 38, 4071–4073
(1973).
8.647(4)Å, b=8.985(4)Å, c=9.396(5)Å, α=90.802(5)°, β=96.809(6)°,
γ=102.040(6)°, V=708.4(6) Å3, T=173(2)K, Space group P-1, Z=2.
The final residuals were R=0.0663 and wR2=0.1682. Crystallo-
graphic data of 25a have been deposited with the Cambridge Crys-
tallographic Data Centre (CCDC) as supplementary publication no.
CCDC 903314. Copies of the data can be obtained free of charge
from the CCDC via http://beta-www.ccdc.cam.ac.uk/pages/Home.
aspx
17) Cho H., Matsuki S., Heterocycles, 43, 127–131 (1996).