Synthesis of a highly functionalised azepine via a new TBSOTf-mediated cyclisation of a terminal formamide

Article abstract of DOI:10.1055/s-2007-967942

The synthesis of a highly functionalised azepine which can be further derivatised by common chemical transformations is described herein. The present synthesis comprises high-yielding reaction steps and features a new method for the synthesis of azepines via TBSOTf-mediated cyclisation of terminal formamides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967942

LETTER
497
Synthesis of a Highly Functionalised Azepine via a New TBSOTf-Mediated
Cyclisation of a Terminal Formamide
N
ew TBSOTf
t
-Media
e
ted
A
zepin
f
e
S
ynthe
a
sis n Heuser*
Lilly Forschung GmbH, a Division of Eli Lilly Research Laboratories, Essener Bogen 7, 22419 Hamburg, Germany
Fax +49(40)52724601; E-mail: heuser_stefan@lilly.com
Received 21 December 2006
Aubé et al. developed a photochemical rearrangement em-
ploying oxaziridine derivatives8 (Scheme 1). The lactams,
which are obtained in both cases, are then reduced with,
for example, lithium aluminium hydride.
Abstract: The synthesis of a highly functionalised azepine which
can be further derivatised by common chemical transformations is
described herein. The present synthesis comprises high-yielding re-
action steps and features a new method for the synthesis of azepines
via TBSOTf-mediated cyclisation of terminal formamides.
1. Beckmann rearrangement
2. LAH
1. hν
2. LAH
Key words: azepines, enamines, cyclisation, condensation, hetero-
cycles
HN
N
O
NH
HO
Azepines are widely found in natural products that often
show interesting biological profiles. Representative
examples are brasilibactin A,1 nocardimicins,2 A-5030833
and bengamide,4 which show cytotoxic, M3 receptor
binding inhibitory, bacterial translocase I inhibitory or
methionine aminopeptidase inhibitory activities, respec-
tively. Furthermore, the azepine moiety is an important
pharmacophore in a number of drug candidates being in-
vestigated in pharmaceutical industry (Figure 1). Equally
noteworthy is its application as a b-turn mimetic in pepti-
domimetic drug development approaches.5
Scheme 1 Classic azepine syntheses
Very recently, Houpis et al.9 and Diederich et al.10 inde-
pendently developed elegant methodologies based on
ring-closing metathesis.
In the course of our ongoing efforts to explore new chem-
ical space, we became interested in the syntheses of 6,6-
dimethyl-5-oxo-4,5,6,7-tetrahydroazepine-1,3-dicarbox-
ylic acid 1-tert-butyl ester 3-ethyl ester (1, Scheme 2). To
the best of our knowledge, such highly substituted azepine
ring systems are little described in the literature. If the
methods mentioned above would furnish the desired
compound at all, tedious, multistep syntheses would be re-
quired. We therefore planned to accomplish the synthesis
via an intramolecular enamine formation as the key step
by cyclisation of formamide 3.
Despite its importance, there is only a limited number of
syntheses that conveniently form the azepine ring.6
Among the most frequently used methodologies is the
Beckmann rearrangement of oxime derivatives,7 and
HO
N
HO
PG1
O
O
O
N
O
N
NH
meptazinol
OH
non-opiod analgesic
O
O
OEt
O
bazedoxifene
OEt
estrogen receptor modulator
2
1
N
Cl–
N+
O
H
O
PG2
O
N
N +
O
EtO
O
O
Ph
PG1
N
3
HO
Scheme 2 Retrosynthetic analysis
Cl
eptazocine
setastine
opiod analgesic
antiallergic
mixed opioid agonist/antagonist
We started our synthesis by oxidising commercially avail-
able benzyl-protected 1,4-butanediol 4 with Dess–Martin
periodinane.11 The desired aldehyde was obtained in
quantitative yield and was directly used for the following
nucleophilic addition of isobutyronitrile12 to give 5 in
67% yield (Scheme 3). Protection of the secondary
Figure 1 Azepine-containing pharmaceutical compounds
SYNLETT 2007, No. 3, pp 0497–0499
Advanced online publication: 07.02.2007
DOI: 10.1055/s-2007-967942; Art ID: G33406ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
2.
2
0
0
7

498
S. Heuser
LETTER
TIPS
TIPS
O
O
OH
N
a, b
c, d
e
O
O
O
O
NH2
NH
OH
Bn
Bn
Bn
Bn
O
5
6
7
4
TIPS
O
O
HO
O
O
TIPS
j, k
l
NH
i
Boc
N
NH
N
f–h
Boc
O
O
O
O
O
O
O
O
8
9
10
1
Scheme 3 Reagents and conditions: (a) 1.1 equiv Dess–Martin periodinane, r.t., 90 min, CH2Cl2, quant.; (b) 1 equiv isobutyronitrile, 1 equiv
LDA, –78 °C to r.t., 2 h, THF, 67%; (c) 1.1 equiv NaH, 0 °C, 30 min, then 1.3 equiv TIPSCl, 50 °C, 16 h, THF, quant.; (d) 3 equiv DIBAL-H,
–30 °C to –20 °C, 30 min, then 6 equiv NaBH4, toluene, quant.; (e) ethylformate, reflux, 16 h, quant.; (f) H2 (1 bar), 10% Pd/C, r.t., 1 h, EtOAc,
90%; (g) 0.02 equiv RuCl3·H2O, 3 equiv NaIO4, r.t., 2 h, CCl4, MeCN, H2O, 88%; (h) 1.1 equiv EtI, 1.5 equiv K2CO3, r.t., 2.5 d, acetone, quant.;
(i) 7 equiv TBSOTf, 15 equiv Et3N, r.t., 5 d, CH2Cl2, 51%; (j) 5 equiv (Boc)2O, 1.2 equiv Et3N, 1.2 equiv DMAP, r.t., 16 h, THF, not isolated;
(k) 2 equiv TBAF, r.t., 20 h, THF, 45% (2 steps); (l) 1.2 equiv Dess–Martin periodinane, r.t., 2 h, CH2Cl2, 92%.
alcohol succeeded in quantitative yield using triisopropyl- was the cyclisation of formamide 8 using TBSOTf in
silyl chloride (TIPSCl) at 50 °C. The reduction of the dichloromethane. This protocol promises to be superior to
nitrile to a primary amine was first attempted using LAH, traditional condensation methods with regard to yield, re-
but unfortunately under these reaction conditions the action conditions and functional group tolerance. Thereby
TIPS group was cleaved off. Here a combination of it offers a new methodology for the synthesis of azepines
DIBAL-H and NaBH4 was much milder and the desired having an electron-withdrawing group in the 3-position,
amine 6 was obtained quantitatively without any depro- which previously were not easily accessible via known
tection of the alcohol.13 Formylation of the amino group methods. This protocol should in general be applicable to
and hydrogenolytic cleavage of the benzyl ether afforded the synthesis of cyclic enamines with other ring sizes,
the free primary alcohol in 90% yield. Its oxidation to the which is going to be the subject of further investigations.
corresponding carboxylic acid was achieved using
RuCl3·H2O and NaIO414 which was followed by immedi-
References and Notes
ate esterification with ethyl iodide and potassium carbon-
(1) Tsuda, M.; Yamakawa, M.; Oka, S.; Tanaka, Y.; Hoshino,
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A.; Holmes, A. B. Tetrahedron 1991, 47, 9131.
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A.; Scopes, D. I. C. Tetrahedron 1991, 47, 4195.
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C. Tetrahedron Lett. 1990, 31, 2763.
(8) Aubé, J.; Wang, Y.; Hammond, M.; Tanol, M.; Takusagawa,
F.; Velde, D. V. J. Am. Chem. Soc. 1990, 112, 4879.
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Synthesis 2006, 1437.
(10) Brass, S.; Gerber, H.-D.; Dörr, S.; Diederich, W. E.
Tetrahedron 2006, 62, 1777.
ate. For the cyclisation of 8 we tried several procedures
with limited literature precedence. Thus, in our first at-
tempts we used phosphorylchloride to form the enamine
functionality via an intramolecular condensation,15 but
under varying conditions only decomposition occurred.
The same was found using sodium ethanolate or potassi-
um tert-butanolate.16 We then envisioned a two-step ap-
proach, first preparing an intermediate silyl-protected
aminal using tert-butyldimethylsilyl triflate (TBSOTf)17
and then to eliminate silanol to finally obtain enamine 9.
Surprisingly, after five days reaction time compound 9
was obtained in only one step using an excess of TBSOTf
in dichloromethane.18 This reaction, to our knowledge, is
undescribed in literature and should in general be applica-
ble to the synthesis of cylic enamines containing five, six
or more ring atoms, and which have an electron-with-
drawing group in the 3-position. Alcohol 10 was then
obtained by protection of the amino group and reaction
with tetrabutylammonium fluoride. Another Dess–Martin
oxidation finally afforded 6,6-dimethyl-5-oxo-4,5,6,7-
tetrahydroazepine-1,3-dicarboxylic acid 1-tert-butyl ester
3-ethyl ester (1) in 92% yield.19
In conclusion, we have synthesised the desired azepine 1
in 11 steps and in 11% overall yield, starting from readily
available starting materials. The key step in the synthesis
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156.
Synlett 2007, No. 3, 497–499 © Thieme Stuttgart · New York

LETTER
New TBSOTf-Mediated Azepine Synthesis
499
(12) Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc.
2000, 122, 712.
(13) Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347.
(14) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936.
(15) (a) Kato, T.; Chiba, T.; Okada, T. Chem. Pharm. Bull. 1979,
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(16) Verboom, W.; Orlemans, E. O. M.; Berga, H. J.; Scheltinga,
M. W.; Reinhoudt, D. N. Tetrahedron 1986, 42, 5053.
(17) Very recently Hoye et al. published their remarkable results
on silylative Dieckmann-like cyclisations of ester-amides
which yield silylated aminals using the same reagent
combination. They also discuss the mechanism of this
reaction in more detail: Hoye, T. R.; Dvornikovs, V.; Sizova,
E. Org. Lett. 2006, 8, 5191.
and TBSOTf (1.73 g, 1.5 mL, 6.53 mmol). After stiring at r.t.
for 5 d 20 mL CH2Cl2 were added and the solution was
washed successively with sat. NaHCO3 solution and sat.
NH4Cl solution. The organic phase was then filtered through
a hydrophobic filter and concentrated. Purification of the
residue via flash chromatography on silica eluting with 1:3
EtOAc in hexane afforded 170 mg (51%) of 9 as a pale
yellow oil.
1H NMR: (300 MHz, DMSO-d6): d = 0.82 (s, 3 H), 1.01 (br
s, 24 H), 1.12 (t, 3J = 7.1 Hz, 3 H), 2.49 (m, 1 H), 2.61 (m, 2
H), 3.13 (dd, 2J = 11.9 Hz, 3J = 3.1 Hz, 1 H), 3.76 (dd,
2J = 11.9 Hz, 3J = 2.2 Hz, 1 H), 3.96 (m, 2 H), 6.54 (br s, 1
H), 7.32 (d, 3J = 6.5 Hz, 1 H). MS (ESI): m/z = 370 [M + H+].
(19) Analytical Data for 1.
1H NMR: (300 MHz, DMSO-d6): d = 0.80 (s, 3 H), 0.95 (s,
3 H), 1.19 (t, 3J = 7.1 Hz, 3 H), 1.44 (s, 9 H), 3.09 (d,
2J = 14.2 Hz, 1 H), 3.31 (m, 1 H), 3.67 (d, 2J = 14.2 Hz, 1 H),
4.09 (q, 3J = 7.1 Hz, 2 H), 4.80 (m, 1 H), 7.82 (s, 1 H). MS
(ESI): m/z = 336 [M + Na+].
(18) Procedure for the Preparation of 9.
To a solution of formamide 8 (353 mg, 912 mmol) in 10 mL
anhyd CH2Cl2 were added Et3N (1.39 g, 1 mL, 13.7 mmol)
Synlett 2007, No. 3, 497–499 © Thieme Stuttgart · New York