Synthesis and selective N,O-functionalization of pyrazolone-fused 3-aminoazepinones

Article abstract of DOI:10.1002/ejoc.201500122

A new class of pyrazolone-fused 3-amino-1,3,4,7-tetrahydro-2H-azepin-2-ones was synthesized from azepane-based α,β-unsaturated esters. The latter compounds were obtained efficiently from 2-Cbz-amino-N-(2-bromoallyl)-4-pentenamide derivatives through initi

Full text of DOI:10.1002/ejoc.201500122

Job/Unit: O50122
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FULL PAPER
DOI: 10.1002/ejoc.201500122
Synthesis and Selective N,O-Functionalization of Pyrazolone-Fused
3
-Aminoazepinones
[a]
[b]
[a]
Ben Schurgers, Guy Van Lommen, and Guido Verniest*
Keywords: Fused-ring systems / Nitrogen heterocycles / Regioselectivity / Alkylation / Metathesis
A new class of pyrazolone-fused 3-amino-1,3,4,7-tetrahydro-
aminotetrahydroazepinone esters were condensed with
2
H-azepin-2-ones was synthesized from azepane-based α,β- hydrazine and oxidized under mild conditions using CuCl .
2
unsaturated esters. The latter compounds were obtained ef-
ficiently from 2-Cbz-amino-N-(2-bromoallyl)-4-pentenamide
derivatives through initial Pd-catalyzed methoxycarb-
onylation followed by ring-closing metathesis. These new 3-
The resulting bicyclic pyrazolones were transformed into
valuablebuildingblocksformedicinalchemistrythroughO-tri-
flation and through selective N-1- and O-alkylation of the
pyrazolone core using (bis)electrophiles.
Introduction
3-Aminobenzazepinones of type 1 have been synthesized
and successfully used as constrained phenylalanine deriva-
tives for incorporation in bioactive peptidomimetic com-
pounds. Related heterocyclic fused 3-aminoazepinone de-
rivatives are not widespread (Figure 1).[ Indole-fused ana-
logues 2 are, for example, available through intramolecular
cyclizations of tryptophan derivatives.[2] The lack of other
types of heterocycles fused at the azepane core structure
impedes a broader evaluation of these promising bicyclic
compounds as building blocks for medicinal chemistry.
Nonheterocyclic fused azepinones are generally synthesized
through lactamizations or Pictet–Spengler reactions with
electron-rich aromatics. Therefore, synthetic methods that
enable the introduction of heterocycles at the azepane core
through alternative pathways are of importance.
1]
In this respect, we envisaged that new azepane esters 4
could serve as valuable precursors for new types of bicyclic
compounds 3, given the various transformations of α,β-un- Figure 1. (Hetero)aromatic fused 3-amino-1,3,4,7-tetrahydro-2H-
[
3]
benzazepin-2-ones.
saturated carbonyl compounds towards heterocycles. The
majority of 4,5-disubstituted pyrazolones are synthesized
by reaction of hydrazines with β-keto esters or α,β-unsatu- receptor antagonists.[5] The presence of multiple, spatially
rated esters. Several pyrazolones are known for their antipy- separated sites that allow further orthogonal derivatization
retic and analgesic effects.[ More recently, this heterocyclic means that pyrazolone-fused azepinones 3 possess signifi-
motif has been successfully incorporated in molecules that cant potential as novel building blocks.
are potent against diabetes and as selective GABA subtype
4]
Results and Discussion
[
a] Research Group of Organic Chemistry, Department of
Chemistry and Department of Bio-Engineering Sciences,
Faculty of Science and Bio-Engineering Sciences, Vrije
Universiteit Brussel (VUB),
To obtain the proposed azepane esters 4 as starting
points for the construction of bicyclic compounds 3, a ring-
closing metathesis (RCM) approach was evaluated. This
was designed in analogy with our recently reported synthe-
sis of polyheterocyclic 3-aminoazepinones via chlorinated
Pleinlaan 2, 1050 Brussels, Belgium
E-mail: gvernies@vub.ac.be
http://we.vub.ac.be/en/organic-chemistry
[
b] Department of Medicinal Chemistry, Galapagos NV,
Generaal De Wittelaan L11-A3, 2800 Mechelen, Belgium
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500122.
[
6,7]
azepinones.
At first, a Claisen rearrangement of O-allyl-
N-Cbz-glycinate was used to prepare N-protected racemic
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G. Verniest et al.
FULL PAPER
Scheme 1. Synthesis of 3-amino-1,3,4,7-tetrahydro-2H-azepin-2-ones 9a–d.
Scheme 2. Condensation of α,β-unsaturated esters 9 with hydrazine towards new 3-aminoazepinone scaffolds 12. [a] Conversions based
on HPLC analysis.
allylglycine 5,[8] which was transformed into the corre- prepared without a 3-amino substituent, through [3 + 4]
sponding amides 7 (Scheme 1). Reported procedures using cycloaddition, intramolecular cyclocarbonylation, or by
1
-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) as ring opening of a nitrone followed by intramolecular cycli-
[
9]
[11–13]
coupling agent gave very low conversions in our hands,
zation.
Having in hand this new set of building blocks,
but the use of 1-[bis(dimethylamino)methylene]-1H-1,2,3- the synthesis of new heterocyclic fused 3-aminoazepinones
triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate using bisnucleophiles was attempted.
(HATU) gave access to amides 7a–d in good yields. Unfor-
Reactions of the obtained α,β-unsaturated esters 9a–c
tunately, these N-(2-bromoallyl)-4-pentenamides proved to with hydrazine monohydrate in EtOH at 80 °C furnished
be very poor substrates in RCM reactions, giving either no pyrazolidinones 11a–c with high conversion according to
cyclization at all or giving very low yields even under high HPLC/LCMS analysis. Slow oxidation was also observed,
[
10]
catalyst loading. Therefore, it was decided to first trans- and minor amounts (Ͻ 10%) of the corresponding pyrazo-
form the bromoallyl moiety of amides 7 prior to RCM. lones 12a–c were found in the reaction mixture. Encouraged
Methoxycarbonylation of 7a–c by using Pd(dppf)Cl (dppf by these results, a one-pot protocol towards 12a–c was
2
=
1,1Ј-bis(diphenylphosphino)ferrocene) under CO atmo- evaluated. Several reaction conditions and oxidants were
sphere in MeOH/THF resulted in formation of the corre- tested to force the oxidation to completion. The use of pal-
sponding esters 8a–c in excellent yields after one hour reac- ladium on carbon either with or without prior isolation of
tion at 75 °C. Analogous cyanation experiments using 7d, the pyrazolidinone 11 from the reaction mixture only par-
Zn(CN) , and catalytic amounts of Pd(PPh ) resulted in tially enhanced the oxidation. The use of MnO and 2,3-
2
3 4
2
8d, albeit in low isolated yields (37%). To cyclize the pre- dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in
pared dienes towards the envisaged 3-aminoazepinones 9, decomposition of the starting material, whereas treatment
the Umicore M2 ruthenium catalyst was used, which per- of 11 with CuCl in N,N-dimethylformamide (DMF) in a
2
formed as well as Grubbs’ II catalyst in these reactions. Cy- reaction vessel open to air, completed the oxidation reac-
[
14]
ano-substituted substrate 8d only yielded 25% of the corre- tion after 17 h at room temperature.
sponding lactam 9d, but the related esters 8a–c nicely re- An attempt was made to investigate whether pyrazolidi-
sulted in new seven-membered cyclic α,β-unsaturated esters none formation occurred through initial addition of hydraz-
a–c in good yield (Scheme 2). Related azepinone-based ine to the double bond or through initial transformation of
α,β-unsaturated esters have, to our knowledge, only been the ester function. To this end, a mixture of the α,β-unsatu-
9
2
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N,O-Functionalization of Pyrazolone-Fused 3-Aminoazepinones
rated ester 9a and hydrazine hydrate was stirred in CH CN ation products, according to HPLC/LCMS analysis. When
3
at room temperature. The change in solvent was required an excess of Ac O was used even triple acylation took place.
2
for solubility reasons. This converted the starting material To evaluate a selective deacylation of these overacylated
cleanly into the Michael adduct in a few hours, as con- compounds towards isolable monoacylated 12a, the ob-
1
firmed by LCMS and H NMR analyses (see the Support- tained mixture was treated with nucleophiles. A full deacyl-
ing Information). Evaporation of the liquids, dissolving the ation towards starting material 12a was observed when hy-
crude material in EtOH followed by heating to 80 °C, re- droxide or benzylamine was used at room temperature. In
sulted in the formation of a mixture of the original Michael all, selective deacylation proved impossible and the isolated
acceptor 9a, Michael adduct 10a, and pyrazolidinone 11a. trace amounts of acylated compounds even slowly con-
This result, combined with the low temperature required verted into starting materials 12 upon standing. To trans-
for the condensation reaction, indeed suggests a reversible form pyrazolones 12 into building blocks that were
Michael addition and a subsequent ring formation through equipped with multidirectional diversification points, pyraz-
a 5-exo-trig cyclization, which is consistent with previous olone 12b was treated with Tf O and pyridine at 0 °C. This
2
[
15]
reports.
provided valuable new building blocks 13 for further Pd-
Although several examples of condensation reactions of catalyzed functionalizations. Treatment of pyrazolones 12
substituted hydrazines with α,β-unsaturated esters have with POCl3 towards analogous building blocks unfortu-
[
16]
been reported, this was unsuccessful when performed on nately did not result in the corresponding chlorinated
substrate 9a. The use of benzyl or methyl hydrazine either pyrazolones.
with or without a base, gave mainly starting material with
Next, the selectivity of N- vs. O-alkylation was evaluated.
minor amounts of the Michael adduct (ca. 5% based on This selectivity in pyrazolone alkylation is known to be de-
HPLC analysis). Even conducting reaction in a microwave pendent on the substrate, alkylating reagent, and reaction
[
17,18]
at 225 °C for 60 min only gave starting material and side conditions.
For instance, double deprotonation of
products. The use of other bisnucleophiles such as amidines, pyrazolones using 2 equiv. of strong base followed by treat-
guanidines, or hydroxylamine did not result in clean forma- ment with 1 equiv. of alkyl halides can give selective N-1-
tion of the corresponding imidazolidines or oxazolidines.
alkylated pyrazolones. Analogous reactions using K CO in
2 3
It should be noted that pyrazolones 12a–c are relatively CH CN give rise to mixtures of mono- and different dial-
3
[
19]
insoluble in standard organic solvents such as CH Cl , kylated products.
To regioselectively alkylate a pyrazol-
2
2
EtOAc, alcohols, and ethers. For the envisaged further py- one at oxygen, Boc-protection of the most reactive N-1 ni-
[
20]
razolone transformations, crude reaction mixtures of 12 trogen is often required.
were used. Analytical samples were purified by preparative
HPLC prior to characterization.
To verify the reactivity of bicyclic pyrazolones 12 in alk-
ylation reactions, 12a was treated with 3-fluorobenzylbrom-
To investigate the reactivity of substrates 12, acylation ide. After reaction in DMF for 2 h at room temperature,
reactions of the pyrazolone moiety were attempted. Reac- 50% yield of monofluorobenzylated pyrazolone 14g was
tions with several different acyl chlorides did not give rise formed and could be separated from the double benzylated
to acylated pyrazolones and, instead, resulted in complex pyrazolone (20%) by preparative HPLC in 28% isolated
reaction mixtures. The use of one equivalent of Ac O re- yield (Scheme 3). In contrast, the alkylation reaction using
2
sulted in a mixture of starting material and double acyl- MeI gave rise to a mixture of mono- and double-methylated
Scheme 3. Synthesis of (poly)heterocyclic fused 3-aminoazepinones 14a–g.
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G. Verniest et al.
FULL PAPER
compounds (mono/double ratio 1:19; LCMS). Only the hydroazepinonecarboxylates. These substrates proved to be
major double alkylated pyrazolone 14f could be isolated in suitable for condensation reactions with hydrazine towards
1
13
high purity. NMR ( H, C, HSQC and HMBC) data of the corresponding tetrahydroazepinone-fused pyrazolones.
the obtained alkylated pyrazolones were compared with re- These compounds can be regarded as a new class of hetero-
ported data to determine whether O-, N-1- or N-2-alkyl- cyclic analogues of related benzazepinones, which have been
ation took place. Reference data were chosen from reports successfully used in bioactive peptidomimetics. The regiose-
in which related pyrazolones were synthesized unambigu- lective reaction of the obtained pyrazolones with (bis)elec-
ously through intramolecular cyclizations, condensation of trophiles resulted in a range of new substituted polyhetero-
β-keto esters with substituted hydrazines, or cycloaddition cycles with potential use as building blocks in medicinal
of dienes to 3H-pyrazol-3-ones (i.e., different from N- or O- chemistry.
alkylations of the pyrazolone). This suggested the forma-
tion of 14f and 14g.[ Given that both alkylation reactions
21]
did not seem promising in terms of isolated yield, the use
of biselectrophiles was evaluated to establish selective and
preparatively useful pyrazolone derivatizations. Most re-
ported data show that when pyrazolones are treated with
Experimental Section
6
1
-{[(Benzyloxy)carbonyl]amino}-1-methyl-7-oxo-2,5,6,7-tetrahydro-
H-azepine-3-carboxylates 9a–d; Typical RCM Procedure for 9c:
Diene 8c (1.0 equiv., 2.23 mmol) was dissolved in freshly distilled
and degassed CH Cl to a final concentration of 0.01 m. The Ruth-
1,2-dibromoethane or 1,3-dibromopropane, alkylation pro-
2
2
ceeds at the O and at N-1, forming oxazolines or the corre-
enium Umicore M2 catalyst {[1,3-bis(2,4,6-trimethylphenyl)-2-
imidazolidinylidene] dichloro(3-phenyl-1H-inden-1-ylidene)(tricy-
clohexylphosphine)ruthenium(II), 0.1 equiv., 0.22 mmol} was
added and degassing was continued for 5 min. The mixture was
sponding six-membered rings, respectively.[
16,22]
However,
reactions of pyrazolones with biselectrophiles giving N-1/
[
23]
N-2-alkylation
or regioisomeric mixtures of alkylation
products are also reported.[ Related benzo-fused pyrazo- then heated to reflux (65 °C) and stirred for 16 h under a N atmo-
24]
2
lones such as 1,2-dihydro-3H-indazol-3-ones, react with 1- sphere. The solvent was removed under reduced pressure, and the
bromo-3-chloropropane to give mainly the N-1/N-2-alkyl- residue was purified by silica column chromatography (EtOAc/pe-
[
25]
troleum ether, 3:1Ǟ2.5:1) to give 9c (0.471 g, 63%) as brown crys-
tals; m.p. 94.7–97.5 °C. IR (ATR): ν˜ = 3251, 2953, 2924, 1705,
ated product.
In our hands, the reaction of biselectro-
philes with pyrazolones 12a resulted in selective N-1 and
O-alkylation towards oxazolidine (14a), oxazane (14b), and
benzoxazepane (14c) fused heterocycles. No N-2,N-1-alkyl-
ation was observed, as was demonstrated by NMR analysis
and comparison with reported data. The scope of the reac-
tion was further elaborated by making use of dichloroiso-
–
1 1
1
645, 1526, 1437, 1252 and 1044 cm
.
H NMR (500 MHz,
CDCl
3
): δ = 0.84 (d, J = 6.3 Hz, 3 H), 0.87 (d, J = 6.3 Hz, 3 H),
1.80–1.88 (m, 1 H), 2.34–2.41 (m, 1 H), 2.95–3.02 (m, 1 H), 3.14
(
(
dd, J = 13.7, 3.6 Hz, 1 H), 3.41 (dd, J = 13.7, 3.6 Hz, 1 H), 3.77
s, 3 H), 4.14 (d, J = 17.6 Hz, 1 H), 4.39 (dd, J = 17.6, 2.6 Hz, 1
H), 4.98–5.03 (m, 1 H), 5.9 (d, J = 12.3 Hz, 1 H), 5.11 (d, J =
butene and 3,3-bis(bromoethyl)oxetane, resulting in the cor- 12.3 Hz, 1 H), 6.18 (br. d, J = 6.0 Hz, 1 H), 7.04 (br. t, J = 4.9 Hz,
1
3
responding new polyheterocycles 14e and 14d. To verify the 1 H), 7.29–7.35 (m, 5 H) ppm. C NMR (126 MHz, CDCl
3
): δ =
possibility of deprotecting the N-atoms of the obtained 19.9, 20.1, 27.4, 33.7, 44.7, 49.5, 52.4, 56.0, 66.8, 128.0, 128.1 (2ϫ),
1
28.5 (2ϫ), 129.1, 136.4, 141.5, 155.5, 166.2, 171.2 ppm. HRMS:
compounds orthogonally, 14b was treated with hydrogen
gas under Pd-C catalysis. This resulted in clean formation
of 15 in 94% yield (Scheme 4). Subsequent acylation reac-
+
m/z calcd. for [C20
26 2 5
H N O + H ] 375.1914; found 375.1925; calcd.
+
for [C20 + Na ] 397.1734; found 397.1756.
26 2 5
H N O
tions of the free amino group of 15 using HATU as cou- Synthesis of Pyrazolones 12a–c. Typical Procedure for 12b: α,β-Un-
pling agent gave good conversions towards the correspond- saturated ester 9b (1.0 equiv., 1.19 mmol) was suspended in de-
gassed EtOH, and hydrazine monohydrate (2.4 equiv., 2.91 mmol,
ing acylated compounds, as evidenced by HPLC and
6
1
5 wt.-% in water) was added. The reaction mixture was stirred for
5 h at 80 °C under a N atmosphere. The resulting solution was
2
HRMS analyses. Unfortunately, because of troublesome
purification by silica gel chromatography, the latter deriva-
tives could not be isolated and fully characterized (see the
Supporting Information for details).
left to cool to room temperature, after which the solvent was re-
moved under reduced pressure. The residue was dissolved in DMF
and CuCl ·2H O (0.2 equiv., 0.24 mmol) was added. The reaction
2 2
mixture was stirred open to the atmosphere for 8 h, after which the
DMF was removed under reduced pressure to give a green residue.
The limited solubility of these pyrazolones meant that the obtained
crude residue was used in the next step for further derivatization
with (bis)electrophiles without purification. An analytical sample
was purified by preparative HPLC to afford 12b as a white powder;
m.p. 203.5–205.4 °C (decomp.). IR (ATR): ν˜ = 3246, 2924, 2356,
–
1
2
341, 1716, 1634, 1522, 1493, 1445, 1248, 1197, 1127, 1024 cm .
1
H NMR (500 MHz, [D
H), 2.90 (dd, J = 8.3, 4.5 Hz, 1 H), 3.87 (d, J = 16.8 Hz, 1 H), 4.18
d, J = 15.3 Hz, 1 H), 4.46 (d, J = 16.8 Hz, 1 H), 4.72 (d, J =
6
]DMSO): δ = 2.67 (app. t, J = 15.5 Hz, 1
Scheme 4. Deprotection of N-Cbz-3-aminoazepinone 14b.
(
1
5.3 Hz, 1 H), 4.79–4.84 (m, 1 H), 5.06 (s, 2 H), 5.96 (s, 2 H), 6.69–
Conclusions
6.73 (m, 2 H), 6.81–6.82 (m, 1 H), 7.30–7.38 (m, 5 H), 7.54 (d, J
1
3
It can be stated that an efficient CO-insertion and RCM = 7.0 Hz, 1 H), 8.42 (br. s, 1 H) ppm. C NMR (126 MHz, [D6]-
approach resulted in the formation of new 3-aminotetra- DMSO): δ = 27.9, 40.4, 50.6, 51.1, 66.0, 98.5, 101.3, 108.3, 108.6,
4
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N,O-Functionalization of Pyrazolone-Fused 3-Aminoazepinones
1
21.2, 128.0, 128.3 (2ϫ), 128.8 (2ϫ), 131.8, 137.5, 146.8, 147.8
[6] S. J. Miller, H. E. Blackwell, R. H. Grubbs, J. Am. Chem. Soc.
1996, 118, 9606.
(2ϫ), 156.1, 160.4, 172.1 ppm. HRMS: m/z calcd. for [C23
22 4 6
H N O
+
[7] Schurgers, B. Brigou, Z. Urbanczik-Lipkowska, D. Tourwé, S.
Ballet, F. De Proft, G. Van Lommen, G. Verniest, Org. Lett.
2014, 16, 3712.
+
H ] 451.1612; found 451.1619.
Synthesis of Pyrazolones 14a–e. Typical Procedure for 14a: Pyraz-
olone 12a (1.0 equiv., 0.229 mmol) was added to a suspension of
[8] M. Kamber, G. Just, Can. J. Chem. 1985, 63, 823.
[
9] J. Gardiner, S. G. Aitken, S. B. McNabb, S. Zaman, A. D.
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K
2
CO
-chloroethane (1.2 equiv., 0.275 mmol) was added. The mixture
was heated at 80 °C for 3 h, then the solvent was removed under
reduced pressure. The residue was taken up in CH Cl (10 mL) and
this solution was washed with H O (3 ϫ 5 mL) and brine (3 ϫ
mL). The organic phase was dried with MgSO and the solvents
3
(3.5 equiv., 0.802 mmol) in DMF (2.3 mL), and 1-bromo-
2
[
10] a) D. V. Paone, A. W. Shaw, D. N. Nguyen, C. S. Burgey, J. Z.
Deng, S. A. Kane, K. S. Koblan, C. A. Salvatore, S. D. Mosser,
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2
2
2
5
4
were evaporated. The resulting residue was purified by silica gel
column chromatography (2% MeOH in petroleum ether/EtOAc,
1
:2) to afford 14a (22 mg, 35%) as an off-white oil. IR (ATR): ν˜ =
–
1
[11] H. M. L. Davies, L. M. Hodges, J. Org. Chem. 2002, 67, 5683.
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3
312, 2915, 2846, 1686, 1632, 1608, 1507, 1443, 1246, 1210 cm .
1
H NMR (250 MHz, CDCl
3
): δ = 2.79 (dd, J = 16.3, 6.9 Hz, 1 H),
[
13] F. Sanchez-Izquierdo, P. Blanco, F. Busqué, R. Alibés, P.
3
1
4
.31 (dd, J = 16.3, 1.9 Hz, 1 H), 3.78 (s, 3 H), 3.82 (d, J = 10.6 Hz,
H), 4.42 (d, J = 10.63 Hz, 1 H), 4.16 (dt, J = 7.5, 2.5 Hz, 2 H),
.35 (d, J = 15.0 Hz, 1 H), 4.80 (d, J = 15.0 Hz, 1 H), 4.92 (dt, J
de March, M. Figuerdo, J. Font, T. Parella, Org. Lett. 2007, 9,
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[
[
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=
7.5, 5.0 Hz, 2 H), 4.99–5.09 (m, 1 H), 5.14 (s, 2 H), 6.20 (d, J =
7.5 Hz, 1 H), 6.81 (d, J = 10.0 Hz, 2 H), 7.12 (d, J = 10.0 Hz, 2
13
H), 7.32–7.38 (m, 5 H) ppm. C NMR (63 MHz, CDCl
3
): δ = 32.5,
9.7, 45.4, 50.1, 50.6, 55.3, 66.8, 75.2, 89.1, 114.0 (2 ϫ), 128.0,
28.1, 128.5 (2ϫ), 128.6, 129.1, 129.5 (2ϫ), 136.5, 152.5, 155.0,
55.5, 159.1, 171.8 ppm. HRMS: m/z calcd. for [C25H N O + H ]
26 4 5
63.1976; found 463.1965.
3
1
1
4
[
[
[
16] For an example, see: A. Otto, B. Ziemer, J. Liebscher, Eur. J.
+
Org. Chem. 1998, 2667.
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Acknowledgments
The authors are indebted to the Vrije Universiteit Brussel (VUB),
the Agency for Innovation by Science and Technology (IWT) and
Galapagos NV for financial support.
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Received: January 26, 2015
Published Online: ᭿
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5

Job/Unit: O50122
/KAP1
Date: 27-04-15 12:00:59
Pages: 6
G. Verniest et al.
FULL PAPER
Heterocyclic Fused-Ring Systems
B. Schurgers, G. Van Lommen,
G. Verniest* ...................................... 1–6
Synthesis and Selective N,O-Functionali-
zation of Pyrazolone-Fused 3-Aminoazep-
inones
The synthesis of new pyrazolone-fused
(2-bromoallyl)-4-pentenamides was fol-
lowed by ring-closing metathesis and con-
densation with hydrazine. The pyrazolones
were alkylated regioselectively, yielding
polyheterocyclic fused 3-aminoazepinones.
3
-amino-1,3,4,7-tetrahydro-2H-azepin-2-
Keywords: Fused-ring systems / Nitrogen
heterocycles / Regioselectivity / Alkylation /
Metathesis
ones starting from azepane-based α,β-
unsaturated esters is described. Initial
methoxycarbonylation of 2-Cbz-amino-N-
6
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Eur. J. Org. Chem. 0000, 0–0