A traceless solid-phase synthesis of 1,4-diazepan-2-ones

Article abstract of DOI:10.1246/cl.2008.820

A novel synthesis of 1,4-diazepan-2-ones using a traceless solid-phase approach is described, in which many kinds of 1,4-diazepan-2-one have been efficiently obtained in high purity. The strategy is based on intramolecular alkylation of tertiary amines, followed by elimination of the desired tertiary amines from the generated quarternary ammonium salts. Copyright

Full text of DOI:10.1246/cl.2008.820

820
Chemistry Letters Vol.37, No.8 (2008)
A Traceless Solid-phase Synthesis of 1,4-Diazepan-2-ones
Kunio Sarutaꢀ and Tsuyoshi Ogiku
Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Corporation,
3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505
(Received May 12, 2008; CL-080486; E-mail: saruta.kunio@ma.mt-pharma.co.jp)
A novel synthesis of 1,4-diazepan-2-ones using a traceless
reactions would remain on the solid support.4,5 For instance,
while the last debenzylation step might be accompanied by an
SN2 reaction at the ꢀ-position of the carbonyl group, the by-
products generated from such an undesirable reaction would
remain bound to the solid support and not reduce the purity of
the products. In addition, all of the assumed unreacted intermedi-
ates would not be detached from the solid support at the end of
the reaction scheme.
solid-phase approach is described, in which many kinds of 1,4-
diazepan-2-one have been efficiently obtained in high purity.
The strategy is based on intramolecular alkylation of tertiary
amines, followed by elimination of the desired tertiary amines
from the generated quarternary ammonium salts.
Compounds having a 1,4-diazepan-2-one (1) skeleton have
been known to show intriguing biological activities, e.g., antag-
onism on muscarinic receptors, inhibition of platelet aggrega-
tion, antibacterial activity, inhibition of HIV protease, etc.1
Therefore, this skeleton is very attractive as a template of
chemical libraries to generate new bioactive compounds in
high-throughput screenings. Compounds 1 (Chart 1) have been
synthesized using conventional solution-phase methods,2 al-
though these methods are not applicable or are inappropriate
for multistep syntheses of libraries, owing to the purification
required in each step. On the other hand, efficient traceless
syntheses of tertiary amines on polymer supports suitable for
library syntheses have been reported.3 However, no library syn-
thesis of tertiary amines having the 1,4-diazepan-2-one skeleton
has been reported. In relation to our research to find new drug
candidates from chemical libraries, we now report an efficient
traceless solid-phase synthesis of 1,4-diazepan-2-one derivatives
via elimination of tertiary amines from quarternary ammonium
salts on a polymer support.
The synthesis began with the Mitsunobu reaction on 4-hy-
droxymethyl polystyrene 2 with N-monosubstituted 2-nitroben-
zenesulfonamides 3 (Scheme 2).6,7 Next, N,N-disubstituted
R1
OH
N
Ns
R1
a
N
H
+
Ns
2
3
4
R1
N
H
O
c or d
b
+
R2
5
6
O
H
R3
N
R1
R2
e
+
N
H
7
8
R2
R1
R3
O
f or g
N
N
R1
N
H
+
R2
Cl
HO
10
R4
N
R4
R3
O
9
1
R2
O
Chart 1.
Cl
In many cases of multi-step solid-phase syntheses, products
obtained by cleavage of the resin in the final step are often mix-
tures of the desired compounds, along with many impurities gen-
erated by incomplete reactions on the polymer support in the
previous steps. In our strategy depicted in Scheme 1, we expect-
ed that the debenzylation of quarternary ammonium salts by an
SN2 reaction could afford products in high purity without time-
consuming purification steps such as column chromatography.
By-products generated from incomplete and/or undesired
N
N
h
R1
R3 R4
11
R1
N
R1
R4
N
R2
R2
i or j
R4
N
N
R3
R3
O
O
12
1
X
Scheme 2. (a) 3, PPh3, DEAD, THF, rt, 16 h; (b) HOCH2-
CH2SH, DBU, DMF, rt, 1 h; (c) 6, ClCH2CH2Cl, 40 ꢁC, 72 h;
(d) 6, ClCH2CH2Cl, 80 ꢁC, 96 h; (e) NaBH(OAc)3, 8, CH2Cl2,
rt, 48 h; (f) DIC, 10, DMF, rt, 20 h; (g) PyBrop, 10, i-Pr2NEt,
rt, 20 h; (h) CsI, dioxane, water, 95 ꢁC, 3 h; (i) HOCH2CH2SH,
2 M NaOH aq, EtOH, 70 ꢁC, 3 h; (j) HSCH2CO2H, 2 M NaOH
aq, EtOH, 70 ꢁC, 3 h.
Het
N
R
N
R
Het
N
Nucleophile
R
Scheme 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.8 (2008)
Table 1. Syntheses of 1,4-diazepan-2-one derivatives 1
821
Entry
1
R1
R2
R3
R4
5 ! 7
9 ! 11
12 ! 1
Yielda/% (purityb/%)
drc
1
2
1a
1b
1c
1d
1e
1f
(4-Br)PhCH2CH2
(4-Br)PhCH2
Et
Et
Et
Et
Et
Me
H
(4-F)PhCH2CH2
(4-F)PhCH2CH2
(4-F)PhCH2CH2
(4-F)PhCH2CH2
(4-F)PhCH2CH2
(4-F)PhCH2CH2
(4-F)PhCH2CH2
(4-CF3O)Ph
H
H
c
c
c
c
d
c
c
c
c
c
c
c
f
f
f
f
f
f
f
g
f
f
f
f
i
44 (97)
45 (98)
33 (97)
18 (95)
25 (98)
48 (91)
0
—
—
i
3
PhCH2
H
i
—
4
(4-MeO)PhCH2
Ph
H
i
—
5
H
i
—
6
(4-Br)PhCH2CH2
(4-Br)PhCH2CH2
(4-Br)PhCH2CH2
(4-Br)PhCH2CH2
(4-Br)PhCH2CH2
(4-Br)PhCH2CH2
(4-Br)PhCH2CH2
H
i
—
7
1g
1h
1i
H
i
—
8
Et
Et
Et
Et
Et
H
i
27 (97)
51 (95)
16 (92)
32 (97)
23 (93)
—
9
(4-NMe2)PhCH2
H
H
i
jd
—
10
11
12
1j
H
—
1k
1l
(4-F)PhCH2CH2
(4-F)PhCH2CH2
Me
Ph
i
99:1
95:5
i
b
aIsolated overall yields (7 steps) based on 2. HPLC was carried out using a reverse phase column [ODS, eluent: CH3CN/20 mM phosphate
buffer (pH 6.5)]. Purity was determined by summation of integrated HPLC peak areas at 210 nm. cHPLC was carried out using a column with
a chiral stationary phase (Chiralpak IA, eluent: hexane/i-PrOH) because a reverse phase column (ODS) could not achieve separation of dia-
d
stereomers. Ratio of the diastereomers was determined by summation of integrated HPLC peak areas at 210 nm. Condition j gave a slightly
higher purity of 92% than condition i (purity of 89%).
089,937, 2004. c) M. S. Butler, A. D. Buss, Biochem. Pharmacol.
2006, 71, 919. d) C. N. Hodge, C. H. Fernandez, WO Patent
08,977, 1994.
2-nitrobenzenesulfonamides 4 provided the secondary amines 5
by deprotection of the 2-nitrobenzenesulfonyl (Ns) group. Next,
by the Michael addition, 5 were transformed into ꢁ-amino ke-
tones 7, which were then converted to the corresponding dia-
mines 9 by reductive amination. Diamines 9 were transformed
into the key intermediates 11 by acylation with ꢀ-haloacetic
acids 10. Intramolecular cyclization and the quaternization of
the resin-bound tertiary nitrogen were carried out in the presence
of CsI in dioxane–H2O at 95 ꢁC. The products 12 were treated
with thiols under conditions reported in the literature8 to provide
the desired compound 1 in high purity without column chroma-
tography purification.
To demonstrate the usefulness of this approach, several 1,4-
diazepan-2-one derivatives were synthesized and characterized.9
Representative results of these syntheses are shown in Table 1.
Alkyl and aryl groups could be introduced at R1–R4 with high
purities and moderate total yields, while compounds with func-
tional groups such as basic nitrogen could also be obtained
(Entry 9). It is worth noting that introduction of the benzyl
groups at R1 (Entries 2–4) was also possible, but the yields were
relatively low (Entries 3 and 4) under these conditions because
nucleophilic attack during the last step might have occurred at
R1 instead of the resin-bound benzyl group.10 Introduction of
substituents at R4 gave mixtures of diastereomers. Unexpected-
ly, the major/minor diastereomer ratio exceeded 90:10 because
epimerization might have occurred under the final cleavage
conditions which were basic at 70 ꢁC. Lack of substituents at
R3 and R4 (Entry 10) was allowed, but the compound without
substituents at R2 (Entry 7) could not be prepared owing to the
probable instability of the intermediate.
2
3
a) O. E. Fancher, S. Hayao, W. G. Strycker, J. Med. Chem. 1964,
7, 154. b) I. S. Weitz, M. Pellegrini, D. F. Mierke, M. Chorev, J.
Org. Chem. 1997, 62, 2527. c) Y. Han, D. F. Mierke, M. Chorev,
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Morphy, J. Am. Chem. Soc. 1997, 119, 3288. c) F. E. K. Kroll,
R. Morphy, D. Rees, D. Gani, Tetrahedron Lett. 1997, 38,
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D. C. Rees, J. Comb. Chem. 2000, 2, 508. e) P. Heinonen,
H. Lonnberg, Tetrahedron Lett. 1997, 38, 8569. f) X. Ouyang,
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4
5
6
Utilizing this strategy, we have already reported an efficient
traceless solid-phase synthesis of 1,4-diazabicyclo[3,3,1]nonane
derivatives: K. Saruta, T. Ogiku, Chem. Lett. 2007, 36, 1430.
Simple synthetic examples of tertiary amines based on debenzyl-
ation of resin-bound quarternary ammonium salts were reported
in Ref. 3n.
T. Fukuyama, C.-K. Jow, M. Cheng, Tetrahedron Lett. 1995, 36,
6373.
4-Hydroxymethyl polystyrene was from Polymer Laboratories.
T. Kametani, K. Kigasawa, M. Hiiragi, N. Wagatsuma, K.
Wakisaka, Tetrahedron Lett. 1969, 10, 635.
In conclusion, a novel traceless solid-phase synthesis of
1,4-diazepan-2-one derivatives based on 4-hydroxymethyl
polystyrene has been developed. Using this approach, we are
currently constructing novel and diverse chemical libraries
for high-throughput screenings. Biological activity of the syn-
thesized compounds will be reported in due course.
7
8
9
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
10 Although 2-hydroxyethyl benzyl sulphides might be detached
from solid supports under this cleavage condition, such impuri-
ties can be excluded by simple solid-phase extraction based on
cation exchange.
References and Notes
1
a) A. M. Madera, R. S. Stabler, R. J. Weikert, WO Patent
090,082, 2001. b) Y. Ochiai, T. Ishiyama, N. Kanaya, WO Patent
Published on the web (Advance View) June 28, 2008; doi:10.1246/cl.2008.820