Construction of Dibenzazocine Skeleton by Regiocontrolled Ring-Expansion Reaction of Cyclic Oxime with DIBAL-H: Facile Synthesis of 17β-Hydroxy- steroid Dehydrogenase Type 3 Inhibitor

Article abstract of DOI:10.1055/s-0032-1318489

Synthetic studies on a 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) inhibitor are described. The unsymmetrical dibenzazocine skeleton was constructed by a regiocontrolled ring-expansion reaction of a cyclic oxime with DIBAL-H. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318489

LETTER
▌813
lCettoernstruction of Dibenzazocine Skeleton by Regiocontrolled Ring-Expansion
Reaction of Cyclic Oxime with DIBAL-H: Facile Synthesis of 17β-Hydroxy-
steroid Dehydrogenase Type 3 Inhibitor
17β-Hydroxysteroid Dehydrogenase Type 3 Inhibitor
Hidetsura Cho,*a,b Yusuke Iwama,b Kentaro Okano,b Hidetoshi Tokuyama*b
a
Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, 980-8578 Sendai, Japan
b
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, 980-8578 Sendai, Japan
Fax +81(22)7956877; E-mail: hcho@mail.pharm.tohoku.ac.jp; E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Received: 30.01.2013; Accepted after revision: 28.02.2013
R1
R1
R2
Abstract: Synthetic studies on a 17β-hydroxysteroid dehydroge-
nase type 3 (17β-HSD3) inhibitor are described. The unsymmetrical
dibenzazocine skeleton was constructed by a regiocontrolled ring-
expansion reaction of a cyclic oxime with DIBAL-H.
DIBAL-H
N
CH2Cl2
0 °C to r.t.
H
NOH
R2
Key words: reduction, ring expansion, rearrangement, hetero-
cycles, regioselectivity
2a R1 = OMe, R2 = H
2b R1 = H, R2 = CF3
(E/Z = ca. 1:1)
(E/Z = ca. 1:1)
3a R1 = OMe, R2 = H; 90%
3b R1 = H, R2 = CF3; 65%
Scheme 1 Regioselective rearrangement of benzophenone oxime
with DIBAL-H
Since 17β-hydroxysteroid dehydrogenase type 3 (17β-
HSD3) is an enzyme involved in testosterone biosynthe-
sis, inhibitors of 17β-HSD3 could be new medicines for
the treatment of prostate cancer. Recently, Fink reported
that several dibenzazocines inhibit 17β-HSD3 at picomo-
lar concentrations in both cell-free enzymatic and cell-
based transcriptional reporter assays (Figure 1).1 While
they synthesized a series of benzazocines by an oxidative
cleavage at the 2,3-position of 2,3-fused indoles accord-
ing to the known protocol,2 the starting indanones and
arylhydrazines are not always available, and a general
synthetic methodology for dibenzazocines is still needed.
selective reductive ring-expansion reaction of a pseudo-
symmetrical dibenzosuberone oxime 5 with fine-tuned
electron density of two aromatic rings by the Br group,
with or without a removable substituent X. Then, N-acyl-
ation and introduction of a phenyl group by cross-
coupling reaction would provide 1 (Scheme 2).
X
X
1
Br
N
H
HON
Br
4
5
Scheme 2 Synthetic strategy for 17β-HSD3 inhibitor 1, including a
regiocontrolled ring expansion mediated by DIBAL-H
17β-HSD3 inhibitor 1
Ph
N
Me
O
IC50 = 0.02 nM (enzyme)
IC50 = 4.0 nM (cellular)
Herein we report a concise synthesis of 17β-HSD3 inhib-
itor 1 featuring a unique regiocontrolled reductive ring-
expansion reaction governed by a slight difference in elec-
tron density between the two benzene rings.
Figure 1 17β-HSD3 inhibitor for the treatment of prostate cancer
Recently, we established new synthetic methodologies for
cyclic arylamines, including a tetrahydrobenzazocine, by
a reductive ring-expansion reaction of cyclic oximes and
hydroxylamines using aluminum hydrides such as
DIBAL-H3 and AlHCl2.4 When we applied the reaction to
pseudosymmetrical benzophenone oximes, it was found
that the more electron-rich aromatic ring has a stronger
migratory aptitude (Scheme 1).3c Thus, treatment of
oximes 2a and 2b with DIBAL-H exclusively provided
the N-arylbenzylamines 3a and 3b as a single isomer.
Preparation of dibenzosuberone oximes 5a and 5b for the
key reaction was performed as shown in Scheme 3. Sono-
gashira coupling of methyl 5-bromo-2-iodobenzoate and
trimethylsilylacetylene followed by basic removal of the
TMS group gave arylacetylene 6. The second Sonogashira
coupling, with the corresponding iodobenzene or 3-iodo-
1-methylthiobenzene,5,6 provided 1,2-diarylacetylenes 7.
While hydrogenation of 7a smoothly gave ester 8a with
catalytic platinum oxide under atmospheric pressure; in
the case of 7b high pressure (68.95 bar) was necessary for
the high-yielding process. Hydrolysis of 8 and subsequent
Friedel–Crafts acylation gave dibenzosuberones 10 using
P2O5–MsOH,7 which were converted into the correspond-
ing oximes 5 by treatment with NH2OH·HCl in pyridine.
Taking advantage of the electron-density-controlled mi-
gration, we planned a synthesis of 17β-HSD3 inhibitor 1.
A dibenzoazocine ring would be constructed by regio-
SYNLETT 2013, 24, 0813–0816
We next focused on the reductive ring-expansion reaction
for the regiocontrolled construction of the dibenzazocine
Advanced online publication: 11.03.2013
DOI: 10.1055/s-0032-1318489; Art ID: ST-2013-U0100-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

814
H. Cho et al.
LETTER
Table 1 DIBAL-H-Mediated Ring-Expansion Reactiona
ArI
TMS
PdCl2(PPh3)2
(1 mol%)
CuI (2 mol%)
Et3N, DMF, r.t.
1)
PdCl2(PPh3)2
(1 mol%)
CuI (2 mol%)
Et3N
X
I
Br
N
H
DMF, r.t.
Br
2) K2CO3, MeOH
0 °C
MeO2C
Br
MeO2C
X
4a X = H
4b X = SMe
DIBAL-H
(6 equiv)
6
75% (2 steps)
Ar = Ph or
3-MeSC6H4
+
H2 (1 atm)
CH2Cl2
X
PtO2
(10 mol%)
EtOAc–EtOH
AcOH, r.t.
(X = H)
HON
Br
5a X = H
5b X = SMe
Br
X
N
H
X
11a X = H
11b X = SMe
or
MeO2C
H2 (68.95 bar)
PtO2
(5 mol%)
THF, r.t.
MeO2C
Br
Br
Entry
X
Temp
Time (h) Yield (%)b 4/11c
7a X = H; 54%
7b X = SMe; 92%
8a X = H; 89%
8b X = SMe; quant
(X = SMe)
1
H
0 °C to r.t.
80 °C
12
16
12
12
46d
73
3.3:1.0
2.0:1.0
8.5:1.0
6.0:1.0
2e
3
H
X
P2O5
MsOH
NaOH (aq)
SMe
SMe
0 °C to r.t.
r.t.
42f
67
THF–MeOH
0 °C to r.t.
80 °C
HO2C
4
Br
9a X = H
9b X = SMe
a Reaction conditions: DIBAL-H (6 equiv) was added to the mixture
of 5 in CH2Cl2 (0.1 M).
b Isolated yields as a mixture of 4 and 11.
c Determined by 1H NMR analysis.
X
X
NH2OH⋅HCl
d Starting material 5a (28%) was recovered.
e Instead of CH2Cl2, DCE was used as a solvent.
f Starting material 5b (36%) was recovered.
pyridine
reflux
O
HON
Br
Br
10a X = H; 68% (2 steps)
10b X = SMe; 71% (3 steps)
5a X = H; 90%
5b X = SMe; 66%
(E/Z = ca. 1:1)
(E/Z = ca. 1:1)
Scheme 3 Preparation of oxime 5
X
X
+
ring (Table 1). First, we treated oxime 5a with six equiv-
alents of DIBAL-H at 0 °C,3 which resulted in incomple-
tion of the reaction even at room temperature, and a
mixture of azocines 4a and 11a (4a/11a = 3.3:1.0) was
obtained in 46% yield with recovery of the starting oxime
5a (28%) (Table 1, entry 1). At 80 °C in 1,2-dichloroeth-
ane, oxime 5a was completely consumed to provide a
mixture of azocines (4a/11a = 2.0:1.0) in 73% yield (Ta-
ble 1, entry 2). These results suggested that we should add
a removable electron-donating group (X) on the other
benzene ring. We selected a methylthio group as substitu-
ent X and examined the ring-expansion reaction. Thus,
treatment of 5b with DIBAL-H at 0 °C also gave a mix-
ture of azocines with better regioselectivity
(4b/11b = 8.5:1.0), although in lower yield (42%, Table
1, entry 3). Finally, we found that the use of six equiva-
lents of DIBAL-H at room temperature gave azocines in
satisfactory yield and selectivity (67% yield,
4b/11b = 6.0:1.0, Table 1, entry 4).8
Br
Br
N
H
N
H
4a X = H
4b X = SMe
11a X = H
11b X = SMe
mixture of 4 and 11
Ac2O, DMAP
Et3N, CH2Cl2, r.t.
X
X
+
Br
Br
N
N
O
O
Me
Me
12a X = H; 66%
12b X = SMe; 70%
13a X = H; 19%
13b X = SMe; 11%
X
PhB(OH)2
Pd(PPh3)4
(10 mol%)
K2CO3
Ph
N
O
THF–H2O
reflux
Me
1 X = H; 70%
14 X = SMe; 78%
Raney Ni, EtOH
reflux, 69%
With the desired azocines 4 in hand as a mixture of regio-
isomers, we then converted them into 17β-HSD3 inhibitor
1 (Scheme 4). After acetylation of azocines 4 and 11, we
separated each regioisomer. The structure of compound
12a9 was confirmed by X-ray crystallographic analysis
(Figure 2).10 Subjection of 12a under the Suzuki–Miyaura
coupling conditions provided 5-acetyl-5,6,11,12-tetra-
Scheme 4 Synthesis of 17β-HSD3 inhibitor 1
hydro-8-phenyldibenz[b,f]azocine (1) in 70% yield. De-
sulfurization of 14, which was prepared from 12b11 in the
same route with Raney Ni, gave 1 in good yield.12
Synlett 2013, 24, 813–816
© Georg Thieme Verlag Stuttgart · New York

LETTER
17β-Hydroxysteroid Dehydrogenase Type 3 Inhibitor
815
mmol) in cold H2O (8 mL) at 0 °C dropwise over 30 min to
maintain an internal temperature below 5 °C. After the
mixture was stirred at 0 °C for 30 min, the mixture was
poured into a solution of KI (18.9 g, 114 mmol) in H2O (24
mL) at 0 °C. The resulting mixture was stirred at 0 °C for 5
min, and then the mixture was allowed to warm to r.t. and the
solution was stirred for 1 h, after which time TLC (hexanes–
EtOAc, 3:1) indicated complete consumption of the starting
aniline. The reaction was quenched with H2O, and the
mixture was extracted with CHCl3 three times. The
combined organic extracts were washed with sat. aq
NaHCO3, sat. aq Na2S2O3, and brine, dried over anhyd
Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography (hexanes) to afford 3-iodo-1-
methylthiobenzene (7.71 g, 30.8 mmol, 95%) as a pale
yellow oil. The spectral data of 3-iodo-1-methylthiobenzene
was identical with those reported in ref. 5a.
(7) (a) Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem.
1973, 38, 4071. (b) Cho, H.; Matsuki, S. Heterocycles 1996,
43, 127.
Figure 2 ORTEP drawing of the molecular structure of compound
12a with thermal ellipsoids at 50% probability levels
(8) Procedure for the DIBAL-H-Mediated Reductive Ring-
Expansion Reaction of 5b
In conclusion, we achieved a concise synthesis of 17β-
HSD3 inhibitor 1 with a dibenzazocine skeleton. The syn-
thesis features the regiocontrolled reductive ring-expan-
sion reaction of cyclic ketoxime.
A two-necked 30 mL round-bottomed flask equipped with a
magnetic stirring bar was charged with oxime 5b (175 mg,
0.503 mmol) and dry CH2Cl2 (5.0 mL). To the solution was
added DIBAL-H (1.03 M in hexane, 3.0 mL, 3.09 mmol)
dropwise at r.t. in a water bath for 10 min. The solution was
stirred for 12 h, after which time TLC (hexanes–EtOAc, 3:1)
indicated complete consumption of 5b. The reaction mixture
was cooled to 0 °C, and diluted with Et2O. The reaction was
then quenched with MeOH and 2 M aq NaOH, and the
mixture was extracted with Et2O three times. The combined
organic extracts were washed with brine, dried over anhyd
Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography (hexanes–EtOAc, 9:1) to afford an
inseparable mixture of 4b and 11b (113 mg, 0.337 mmol,
67%) as a yellow solid.
Acknowledgment
This work was financially supported by the KAKENHI, Grant-in-
Aid for Scientific Research (C) (23590001), the Funding Program
for Next Generation World-Leading Researchers (LS008), Tohoku
University G-COE program ‘IREMC’, a JSPS predoctoral fellow-
ship to Y.I., Banyu Life Science Foundation International, and
Japan Tobacco Inc. to H.C.
References and Notes
Analytical Data
IR (neat): 3376 (br), 2919, 2891, 1592, 1484, 1258, 813, 756
cm–1. 1H NMR [400 MHz, CDCl3, isomeric mixture (6:1)]: δ
(major isomer) = 7.22–7.15 (m, 2 H), 6.96 (d, 1 H, J = 2.0
Hz), 6.90 (dd, 1 H, J = 8.0, 2.0 Hz), 6.89 (d, 1 H, J = 7.6 Hz),
6.46 (d, 1 H, J = 8.0 Hz), 4.35 (s, 2 H), 3.27–3.18 (m, 2 H),
3.16–3.08 (m, 2 H), 2.37 (s, 3 H); δ (minor isomer) = 7.02–
7.15 (m, 3 H), 6.81 (d, 1 H, J = 8.0 Hz), 6.77 (dd, 1 H,
J = 7.6, 2.0 Hz), 6.61 (d, 1 H, J = 2.0 Hz), 4.37 (s, 2 H),
(1) 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. 2006, 16, 1532.
(2) Okamoto, T.; Kobayashi, S.; Yamamoto, H. DE 1952019,
1970.
(3) (a) Cho, H.; Murakami, K.; Fujisawa, A.; Niwa, M.;
Nakanishi, H.; Uchida, I. Heterocycles 1998, 48, 1555.
(b) Cho, H.; Iwama, Y.; Sugimoto, K.; Kwon, E.;
Tokuyama, H. Heterocycles 2009, 78, 1183. (c) Cho, H.;
Iwama, Y.; Sugimoto, K.; Mori, S.; Tokuyama, H. J. Org.
Chem. 2010, 75, 627. (d) Cho, H.; Sugimoto, K.; Iwama, Y.;
Mitsuhashi, N.; Okano, K.; Tokuyama, H. Heterocycles
2011, 82, 1633.
3.27–3.18 (m, 2 H), 3.16–3.08 (m, 2 H), 2.41 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): δ = 148.5, 145.3, 140.7, 139.3,
137.3, 133.7, 132.5, 132.2, 132.1, 131.9, 131.8, 131.2,
130.22, 130.19, 129.7, 128.3, 127.7, 127.6, 125.8, 124.6,
122.5, 121.2, 119.9, 119.8, 51.1, 50.8, 35.4, 34.8, 32.1, 31.6,
17.9, 15.6. HRMS (ESI+): m/z calcd for C16H17BrNS [M +
H+]: 334.0260; found: 334.0249.
(4) Cho, H.; Iwama, Y.; Mitsuhashi, N.; Sugimoto, K.; Okano,
K.; Tokuyama, H. Molecules 2012, 17, 7348.
(9) 5-Acetyl-5,6,11,12-tetrahydro-8-bromo-dibenz[b,f]-
azocine (12a)
(5) (a) Mongin, O.; Papamicaël, C.; Hoyler, N.; Gossauer, A.
J. Org. Chem. 1998, 63, 5568. (b) We prepared 3-iodo-1-
methylthiobenzene from 3-(methylthio)aniline by
Sandmeyer reaction. This procedure is described in ref. 6.
(6) Procedure for the Sandmeyer Reaction for the Synthesis
of 3-Iodo-1-methylthiobenzene
Colorless plates. IR (neat): 2944, 1651, 1496, 1386, 1282,
724 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.25–7.12 (m, 4
H), 7.10–7.00 (m, 2 H), 6.96–6.88 (m, 1 H), 5.75 (d, 1 H,
J = 14.8 Hz), 4.02 (d, 1 H, J = 14.8 Hz), 3.26–3.12 (m, 2 H),
2.94–2.72 (m, 2 H), 1.80 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 170.2, 140.5, 139.3, 139.0, 137.3, 132.7, 131.2,
131.1, 130.8, 128.7, 128.5, 128.0, 119.7, 52.0, 34.6, 30.9,
22.7. HRMS (ESI+): m/z calcd for C17H17BrNO [M + H+]:
330.0488; found: 330.0489.
A 300 mL round-bottomed flask equipped with a magnetic
stirring bar was charged with 3-(methylthio)aniline (4.00
mL, 32.5 mmol), crushed ice (24 g), and MeCN (24 mL). To
the stirred solution was added concd H2SO4 (24 mL) at 0 °C
over 30 min. To the slurry was added aq NaNO2 (4.04 g, 58.6
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 813–816

816
H. Cho et al.
LETTER
(10) Crystal Data for 12a
1 H, J = 14.8 Hz), 3.99 (d, 1 H, J = 14.8 Hz), 3.24–3.10 (m,
C17H16BrNO; MW = 330.22, triclinic, a = 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 P1, Z = 2. The final residuals
were R = 0.0663 and wR2 = 0.1682. Crystallographic data of
12a have been deposited with the Cambridge
Crystallographic 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.
2 H), 2.88–2.70 (m, 2 H), 2.42 (s, 3 H), 1.80 (s, 3 H). 13
C
NMR (100 MHz, 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. HRMS (ESI+): m/z calcd
for C18H19BrNOS [M + H+]: 376.0365; found: 376.0381.
(12) 5-Acetyl-5,6,11,12-tetrahydro-8-phenyldibenz[b,f]azocine (1)
Colorless oil. IR (neat): 3027, 2930, 1658, 1494, 1389, 765
cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.49 (d, 2 H, J = 7.2
Hz), 7.45–7.27 (m, 5 H), 7.21–7.00 (m, 5 H), 5.83 (d, 1 H,
J = 14.8 Hz), 4.16 (d, 1 H, J = 14.8 Hz), 3.38–3.15 (m, 2 H),
3.00–2.81 (m, 2 H), 1.82 (s, 3 H). 13C NMR (150 MHz,
CDCl3): δ = 170.3, 140.5, 139.43, 139.37, 139.1, 135.4,
131.2, 129.9, 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. HRMS (ESI+):
m/z calcd for C23H22NO [M + H+]: 328.1696; found:
328.1699.
(11) 5-Acetyl-5,6,11,12-tetrahydro-8-bromo-2-methylthio-
dibenz[b,f]azocine (12b)
Colorless oil. IR (neat): 3002, 2921, 1657, 1491, 1386, 1286,
754 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.26–7.20 (m, 2
H), 7.03 (dd, 1 H, J = 8.0, 2.0 Hz), 6.97 (dd, 1 H, J = 8.0 Hz),
6.91 (d, 1 H, J = 8.0 Hz), 6.89 (d, 1 H, J = 2.0 Hz), 5.73 (d,
Synlett 2013, 24, 813–816
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