Synthesis of cis-4,5-diarylazepanes

Article abstract of DOI:10.1055/s-0030-1260974

Substituted cis-4,5-diarylazepanes are synthesized in modest overall yields starting from 5,5-diarylazepan-4-ones by areduction, mesylation, rearrangement, and hydrogenation reaction sequence. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260974

LETTER
1875
Synthesis of cis-4,5-Diarylazepanes
S
ynthesis of cis-4,5-D
i
e
a
rylazepan
n
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Fax +886(7)3125339; E-mail: mychang@kmu.edu.tw
Received 17 April 2011
The synthesis of substituted 5,5-diarylazepan-4-ones 2
started with tetrasubstituted exo-olefins 1 via ring expan-
sion with MCPBA and BF3⋅OEt2. Skeleton 1 was easily
yielded from commercially available piperidine-4-car-
boxylic acid ethyl ester via sulfonylation with sulfonyl
chloride, Grignard addition with arylmagnesium bromide,
and dehydration. Skeleton 2 was chosen as the starting
material for synthesizing substituted cis-4,5-diaryl-
azepanes, as shown in Scheme 1.8
Abstract: Substituted cis-4,5-diarylazepanes are synthesized in
modest overall yields starting from 5,5-diarylazepan-4-ones by a
reduction, mesylation, rearrangement, and hydrogenation reaction
sequence.
Key words: cis-4,5-diarylazepanes, boron trifluoride etherate, het-
erocycles, 1,2-sigmatropic shift, spiro compounds
The seven-membered azepane ring is a prevalent scaffold
that serves as a crucial building block for numerous syn-
theses of useful compounds, and it has been previously re-
viewed.1 Depending on the substitution pattern and
functionalization, different derived substitutents in the
structural skeleton of azepane have been shown to be ef-
fective biologically active compounds, such as benz-
azepine or phenazepane analogues.2,3 Consequently, a
significant effort has been directed toward the develop-
ment of new methods for the synthesis of substituted
azepanes.4 In addition, the chiral azepane system can be a
synthetically useful ligand in the asymmetric reactions.5
Due to the particular pharmaceutical interest concerning
specific substitution pattern of the great number of
azepanes and their derivatives, new methods for their
preparation are needed. The adopted synthetic strategies
of substituted azepanes are summarized in Figure 1.5–7 In
this paper, we intend to report the 1,2-sigmatropic shift
methodology for the synthesis of substituted cis-4,5-di-
arylazepanes from known 5,5-diarylazepan-4-ones.
Ar1
Ar2
Ar1
O
Ar2
1) MCPBA, CH2Cl2
2) BF3⋅OEt2, CH2Cl2
N
N
R
R
1
2
Ar1, Ar2 = Ph, 4-FPh, 4-MeOPh
R = Ms (SO2Me), Bs (SO2Ph), Ts (SO2Tol)
Scheme 1 Synthesis of starting material 2
Initially, the azepanol 3c was prepared by reduction of
model substrate 2c (Ar1 = Ar2 = Ph; R = Ts) with sodium
borohydride in methanol at room temperature for 2–3
hours in 89% yield. As shown in Table 1, treatment of
azepanol 3c with MsCl (3.0 equiv) and Et3N (alkylamine)
in DCE (10 mL) generated a mixture of mesylate 4c and
olefin 1c. After adjusting the reaction temperature, time
and equivalents of Et3N, two products (4c/1c = 7:1 to 2:1)
were isolated from the reaction mixture (Table 1, entries
1–4). Under the reflux temperature and prolonged time (5
h or 30 h), compound 1c was yielded as the major product
(Table 1, entries 5 and 6). This showed that higher tem-
perature prompted the in situ rearrangement to occur and
controlled the yield ratios of major product 1c. To in-
crease the yield ratio of compound 4c, other bases with
different basicity were examined in the next step. Mesyla-
tion of azepanol 3c with 5 equivalents of DBU (amidine)
gave 1c as the major product (4c/1c = 1:6) at room tem-
perature (Table 1, entry 7). When pyridine or imidazole
(aromatic amine) was chosen as the base or solvent (for
pyridine) at room temperature, the major product 4c was
isolated in good yields along with a trace amount of rear-
ranged product 1c (Table 1, entries 8–10).
R2
R1
R2
R2
R1
aza-[3.3] Claisen
rearrangement
Beckmann
rearrangement
R1
O
(ref. 7)
(ref. 6)
N
N
R
N
conjugate
addition
(ref. 5)
OH
our work
R1
O
R2
R1
R2
CO2Et
N
R
BocN
Ar
Figure 1 Synthetic strategies toward substituted azepane
With the above results, compounds 4a,b and 4d–h were
also isolated in 82–92% yields under the conditions in en-
try 10 (Table 1). By treating the mesylate 3c with different
bases (alkyl amine, amidine, aromatic amine), we ob-
served that there was an interesting selectivity for the dis-
SYNLETT 2011, No. 13, pp 1875–1880
Advanced online publication: 25.07.2011
DOI: 10.1055/s-0030-1260974; Art ID: W09411ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

1876
M.-Y. Chang, N.-C. Lee
LETTER
Table 1 Reaction of Alcohol 3c with MsCla
gen in the presence of a catalytic amount of 10% palladi-
um on activated carbon at room temperature for 10 hours.
After completing the above procedures, the vicinal cis-
4,5-diarylazapane 6 was synthesized from the geminal
5,5-diarylazapan-4-one 2 in a modest total yield via re-
duction, mesylation, the 1,2-sigmatropic shift, and the hy-
drogenation reaction. Our typical experimental procedure
suggested a general and efficient alternative for the prep-
aration of symmetrical and unsymmetrical cis-4,5-diaryl-
azepanes with the different electron-withdrawing and
electron-donating aryl groups. Comparing the two kinds
of products (e.g., Ar1 = Ar2 = Ph, R = Ts), we found that
six-membered piperidine 1c with a geminal diaryl exo-
olefin was the major product generated from the treatment
of alcohol 3c with Et3N under the basic conditions
(Scheme 2). Under the Lewis acid promoted reaction, me-
sylate 4c was easily converted into seven-membered
azapane 5c with vicinal diaryl endo-olefin.
Ph
Ph
Ph
Ph
HO
MsO
Ph
Ph
MsCl (3.0 equiv)
+
(CH2Cl)2 (10 mL)
conditions
N
N
N
Ts
Ts
Ts
1c
3c
4c
Entry Base
Temp
Time Yield of Yield of
(h)
4c (%)b 1c (%)b
1
2
3
4
5
6
7
8
9
Et3N (3.0 equiv)
ice bath
r.t.
5
72
62
47
50
15
trace
10
86
81
90
10
Et3N (3.0 equiv)
Et3N (3.0 equiv)
Et3N (5.0 equiv)
Et3N (5.0 equiv)
Et3N (5.0 equiv)
DBU (5.0 equiv)
pyridine (5.0 equiv)
5
15
r.t.
30
30
5
31
r.t.
24
reflux
reflux
reflux
r.t.
69
30
5
82
The possible explanation for the interesting transforma-
tions from compound 4c to 5c was that the BF3·OEt2-
mediated demesylation of compound 4c was controlled by
the lone nitrogen pair on the azepane skeleton. The initial
event may be the formation of intermediate I. Next, inter-
mediate II was formed by an intramolecular ring closure
of intermediate I and followed by the aryl group 1,2-shift
of intermediate II. Then, compound 5c was obtained by
the proton abstraction of intermediate II under thermody-
namic control. In another pathway, intermediate III
would be first generated by the mesylation of compound
3c. Furthermore, compound 1c was easily formed by the
migration of the alkyl group under the base-induced con-
ditions via intermediate IV with a more stable diphenyl
carbocation.
63
5
trace
trace
trace
imidazole (5.0 equiv) r.t.
r.t.
5
10 pyridine (6 mL)
5
a The reactions were run on a 0.5 mmol scale with 3c.
b The products were >95% pure as determined by 1H NMR analysis.
tribution of product yields between the piperidine and the
azapane frameworks.
As shown in Table 2, the 1,2-sigmatropic rearrangement
of skeleton 4 (R = Ms, Bs, Ts; Ar = Ph, 4-FC6H4, 4-
MeOC6H4) with BF3·OEt2 (2.0 equiv) gave skeleton 5 as
the major product at reflux for 40 hours.9 The 1,2-sigma-
tropic shift procedure was monitored using TLC until the
reaction was complete. Eight olefins, 5a–h, were obtained
in 55–89% yields. The structural frameworks of com-
pounds 5b and 5e were determined using single-crystal X-
ray analysis.10 Furthermore, cis-4,5-diarylazepanes 6a–h
were achieved by hydrogenation of skeleton 5 with hydro-
It was also found that spiropieridine 7a or 7b was obtained
in low yields (34% and 26%) via the reaction of ketone 2a
or 2b with Et3N (5 equiv) in CH2Cl2 for 25 hours under re-
flux conditions.11 Among the product mixtures, starting
materials 2a and 2b were recovered in nearly 56% and
66% yields. As shown in Scheme 3, the ring system with
the five-membered dioxa spiropiperidine skeleton was
Ph
Ph
Ph
Ph
MsO
HO
Ph
Ph
Ph
Ph
BF3⋅OEt2
MsCl, Et3N
a
b
by acidic
CH2Cl2,
reflux, 40 h
(CHCl)2,
reflux, 30 h
N
••
conditions
N
N
N
Ts
(pathway b)
Ts
Ts
Ts
4c
I
III
3c
acid-promoted
phenyl shift
base-promoted
alkyl shift (pathway a)
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
H
Ph
N
N
N
N
Ts
Ts
1c
Ts
5c
Ts
phenyl
carbocation II
diphenyl
carbocation IV
Scheme 2 Possible rearrangement mechanism
Synlett 2011, No. 13, 1875–1880 © Thieme Stuttgart · New York

LETTER
Synthesis of cis-4,5-Diarylazepanes
1877
found in the presence of CH2Cl2. The possible mechanism chloromethyl quaternary ammonium chloride under high-
is as follows: the initial event was regarded as the forma- pressure conditions in a sealed tube. Thus, skeleton 7 was
tion of intermediate A with an oxonium ion with chloro- afforded by water addition followed by the intramolecular
methyl motif;12 intermediate B with diphenyl carbocation ring closure.
was generated via the rearrangement. The intermediate A
should be generated from reaction of ketone 2 with the
Table 2 Synthesis of Substituted cis-4,5-Diarylazepanes 6a
Ar1
MsO
Ar1
Ar2
Ar1
Ar2
Ar2
BF3⋅OEt2
H2, Pd/C
CH2Cl2
(55–89%)
EtOAc
(90–95%)
N
N
N
R
R
R
4
5
6
Entry
Product 5
Yield of 5 (%)a
Product 6
Yield of 6 (%)a
1
89
92
N
N
Ms
Ms
5a
6a
2
78
95
N
N
Bs
Bs
5b
6b
3
75
93
N
N
Ts
Ts
5c
6c
F
F
F
F
4
70
90
N
N
Ms
Ms
5d
6d
MeO
OMe
MeO
OMe
5
63
92
N
N
Ms
Ms
5e
6e
Synlett 2011, No. 13, 1875–1880 © Thieme Stuttgart · New York

1878
M.-Y. Chang, N.-C. Lee
LETTER
Table 2 Synthesis of Substituted cis-4,5-Diarylazepanes 6a (continued)
Ar1
MsO
Ar1
Ar2
Ar1
Ar2
Ar2
BF3⋅OEt2
H2, Pd/C
CH2Cl2
(55–89%)
EtOAc
(90–95%)
N
N
N
R
R
R
4
5
6
Entry
Product 5
Yield of 5 (%)a
Product 6
Yield of 6 (%)a
F
F
6
59
93
90
92
N
N
Ms
Ms
5f
6f
OMe
OMe
7
55
N
N
Ms
Ms
5g
F
6g
F
OMe
OMe
8
67
N
N
Ms
Ms
5h
6h
a The isolated products were >95% pure as judged by 1H NMR analysis.
To increase the yield of skeleton 7, reaction of ketone 2a Attempts to establish the tetracyclic skeleton 8 via the tri-
with diiodomethane or dibromomethane and Et3N was fluoroacetic acid mediated ring closure of skeleton 514
further examined. But the desired spiro product 7a was failed, perhaps due to insufficient reactivity. In order to
isolated in low yield (15% or 10%). The structural frame- construct the phenanthrene system, photolysis of skeleton
work of compound 7b was established by single-crystal 5 was further examined in different solvents (e.g., metha-
X-ray analysis (Figure 2).10 This study showed that the nol, benzene, ethyl acetate, tetrahydrofuran) and wave-
present synthetic approach could construct the spiro [4.5]- lengths (e.g., l = 3600, 3060, 2540 nm).15 When ethyl
ring system from an azepanone skeleton.13
acetate and l = 3060 nm were chosen as the solvent and
Cl
Cl
NEt3
Cl
Cl
Ph
O
Ph
Ph
O
O
O
Ph
Ph
Ph
Ph
O
Ph
H2O
Et3N
CH2Cl2
N
R
N
R
N
R
N
R
sealed
tube
2a, R = Ms
2b, R = Ts
A
B
7a, R = Ms (34%)
7b, R = Ts (26%) X-ray
Scheme 3 Reaction of ketone 2 with Et3N in CH2Cl2
Synlett 2011, No. 13, 1875–1880 © Thieme Stuttgart · New York

LETTER
Synthesis of cis-4,5-Diarylazepanes
1879
tion, mesylation, rearrangement, and hydrogenation. The
tetracyclic azacyclohepta[l]phenanthrene skeleton was
synthesized. We are currently studying the scope of this
process as well as additional applications of the method-
ology to the synthesis of diarylazocane and its related de-
rivatives.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors would like to thank the National Science Council of the
Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3). The project is also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q100004).
Figure 2 X-ray structure of compound 7b
wavelength, respectively, under the irradiation condi-
tions, we found that a single tetracyclic azacyclohep-
ta[l]phenanthrene skeleton 8 was isolated in good yield, as
shown in Scheme 4.16 The structural framework of com-
pound 8b was constructed using single-crystal X-ray anal-
ysis (Figure 3).10
References and Notes
(1) For reviews on the synthesis of azepane, see: (a) Yet, L.
Chem. Rev. 2000, 100, 2963. (b) Kantorowski, E. J.; Kurth,
M. J. Tetrahedron 2000, 56, 4317. (c) Maier, M. E. Angew.
Chem. Int. Ed. 2000, 39, 2073.
(2) For syntheses of benzazepine, see: (a) Qing, L.; Sasikumar,
T. K.; Bunett, D. A.; Su, J.; Tang, H.; Ye, Y.; Mazzola, R. D.
J.; Zhu, Z.; McKittrick, B. A.; Greenlee, W. J.; Fawzi, A.;
Smith, M.; Zhang, H.; Lachowicz, J. E. Bioorg. Med. Chem.
Lett. 2010, 20, 836. (b) Zhang, J.; Chen, X.; Yu, L.; Zhen,
X.; Zhang, A. Bioorg. Med. Chem. 2008, 16, 9425.
(c) Shimada, I.; Maeno, K.; Kondoh, Y.; Kaku, H.;
Sugasawa, K.; Kimura, Y.; Hatanaka, K.-i.; Naitou, Y.;
Wanibuchi, F.; Sakamoto, S.; Tsukamoto, S.-i. Bioorg. Med.
Chem. 2008, 16, 3309. (d) Bailey, J. M.; Scott, J. S.; Basilla,
J. B.; Bolton, V. J.; Boyfield, I.; Evans, D. G.; Fleury, E.;
Heightman, T. D.; Jarvie, E. M.; Lawless, K.; Matthews,
K. L.; MaKay, F.; Mok, H.; Muir, A.; Orlek, B. S.; Sanger,
G. J.; Stemp, G.; Stevens, A. J.; Thompson, M.; Ward, J.;
Vaidya, K.; Westaway, S. M. Bioorg. Med. Chem. Lett.
2009, 19, 6452.
photolysis
EtOAc, 80 h
N
R
N
R
5a, R = Ms
5b, R = Bs
8a, R = Ms (88%)
8b, R = Bs (76%) X-ray
Scheme 4 Synthesis of tetracyclic skeleton 8
(3) For syntheses of phenazepine, see: (a) Diamond, J.; Bruce,
W. F.; Tyson, F. T. J. Med. Chem. 1964, 7, 57.
(b) Scheiner, J. J.; Richards, D. J. Curr. Ther. Res. Clin. Exp.
1974, 16, 928.
(4) (a) Jacobi, P. A.; Lee, K. A. J. Am. Chem. Soc. 2000, 122,
4295. (b) Boeckman, R. K.; Clark, T. J.; Shook, B. C. Org.
Lett. 2002, 4, 2109. (c) Smith, A. B. III; Cho, Y. S.; Pettit,
G. R.; Hirschmann, R. Tetrahedron 2003, 59, 6991.
(d) Painter, G. F.; Eldridge, P. J.; Falshaw, A. Bioorg. Med.
Chem. 2004, 12, 225. (e) Li, H.; Bleriot, Y.; Mallet, J. M.;
Rodriguez-Garcia, E.; Vogel, P.; Zhang, Y.; Sinay, P.
Tetrahedron: Asymmetry 2005, 16, 313. (f) Wipf, P.;
Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225. (g)Li, H.;
Bleriot, Y.; Chantereau, C.; Mallet, J.-M.; Sollogoub, M.;
Zhang, Y.; Rodriguez-Garcia, E.; Vogel, P.; Jimenez-
Barbero, J.; Sinay, P. Org. Biomol. Chem. 2004, 2, 1492.
(5) Lee, S. J.; Beak, P. J. Am. Chem. Soc. 2006, 128, 2178.
(6) Lyga, J. W. J. Heterocycl. Chem. 1996, 33, 1631.
(7) Lindstrom, U. M.; Somfai, P. J. Am. Chem. Soc. 1997, 119,
8385.
Figure 3 X-ray structure of compound 8b
(8) (a) Chang, M.-Y.; Kung, Y.-H.; Ma, C.-C. Tetrahedron Lett.
2007, 48, 199. (b) Chang, M.-Y.; Kung, Y.-H.; Wu, T.-C.
Tetrahedron 2007, 63, 3098.
In summary, we presented an easy and straightforward
synthesis of unsymmetrically cis-4,5-diarylazepanes by
the treatment of 5,5-diarylazepan-4-ones with the reduc-
(9) Representative Procedure for Skeleton 5
BF3·OEt2 (1.0 mmol) was added to a stirring solution of the
Synlett 2011, No. 13, 1875–1880 © Thieme Stuttgart · New York

1880
M.-Y. Chang, N.-C. Lee
LETTER
skeleton 4 (0.5 mmol) in CH2Cl2 (10 mL) at r.t. The reaction
mixture was stirred at reflux for 40 h. The total procedure
was monitored by TLC until the reaction was completed.
A sat. NaHCO3 solution (1 mL) was added to the reaction
mixture, and the solvent was concentrated under reduced
pressure. The residue was extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexane–
EtOAc = 8:1 to 4:1) afforded skeleton 5.
(12) (a) Mas, M.; Sola, J.; Solans, X.; Aguilo, M. Inorg. Chim.
Acta 1987, 133, 217. (b) Almarzoqi, B.; George, A. V.;
Isaacs, N. S. Tetrahedron 1986, 42, 601. (c) Rudine, A. B.;
Walter, M. G.; Wamser, C. C. J. Org. Chem. 2010, 75,
4292. (d) Munavalli, S.; Poziomek, E. J.; Landis, W. G.
Heterocycles 1986, 24, 7.
(13) For a review on the synthesis of spiropiperidine, see: Dake,
G. Tetrahedron 2006, 62, 3467.
(14) For a MnO2/TFA-mediated reaction, see: (a) Wang, K.; Hu,
Y.; Li, Z.; Wu, M.; Liu, Z.; Su, B.; Yu, A.; Liu, Y.; Wang,
Q. Synthesis 2010, 1083. For a MCPBA/TFA-mediated
reaction, see: (b) Wang, K.; Hu, Y.; Wu, M.; Li, Z.; Liu, Z.;
Su, B.; Yu, A.; Liu, Y.; Wang, Q. Tetrahedron 2010, 66,
9135. For a VOF3/TFA-mediated reaction, see:
(c) Niphakis, M. J.; Georg, G. I. Org. Lett. 2011, 13, 196; and
references cited therein.
(10) CCDC 810260 (5b), 810167 (5e), 805710 (7b), and 817429
(8b) contain the supplementary crystallographic data for this
paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
(11) Representative Procedure for Skeleton 7
(15) (a) Zhang, X.; Jiang, X.; Zhang, K.; Mao, L.; Luo, J.; Chi,
C.; Chan, H. S. O.; Wu, J. J. Org. Chem. 2010, 75, 8069.
(b) Jiao, C.; Huang, K. W.; Chi, C.; Wu, J. J. Org. Chem.
2011, 76, 661.
(16) Representative Procedure for Skeleton 8
Skeleton 5 (0.13 mmol) was dissolved in EtOAc (10 mL;
free of oxygen) and was irradiated under a nitrogen
atmosphere with a lamp (l = 3060 Å), using a Pyrex glass
filter at r.t. for 80 h. The solvent was evaporated to afford
crude product. Purification on silica gel (hexane–
EtOAc = 4:1 to 2:1) afforded skeleton 8.
Et3N (500 mg, 5.0 mmol), skeleton 2 (1.0 mmol), and
CH2Cl2 (6 mL) were added to a sealed tube at r.t. The
reaction mixture was stirred at reflux temperature for 25 h
and then cooled to r.t. CH2Cl2 (10 mL) was added to the
reaction mixture, and then HCl solution (1 N, 10 mL) was
also added to the reaction mixture. The reaction mixture was
extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were washed with brine, dried, filtered, and eva-
porated to afford crude product. Purification on silica gel
(hexane–EtOAc = 4:1 to 2:1) afforded skeleton 7.
Synlett 2011, No. 13, 1875–1880 © Thieme Stuttgart · New York