Synthesis of Benzo[b]azocin-2-ones by Aryl Amination and Ring-Expansion of α-(Iodophenyl)-β-oxoesters

Article abstract of DOI:10.1002/chem.201903139

Transformation of β-oxoesters with PhI(OCOCF₃)₂ leads to α-(ortho-iodophenyl)-β-oxoesters. These materials are the starting point for the synthesis of 6-carboxybenzo[b]azocin-2-ones by a sequence of aryl amination and ring transformation. This reaction sequence starts with copper-catalyzed formation of N-alkyl anilines from the iodoarenes and primary amines in the presence of K₃PO₄ as stoichiometric base. The intermediate products underwent ring transformation by addition of the nitrogen into the carbonyl group of the cycloalkanone, furnishing benzo-annulated eight-membered ring lactams. Under the same reaction conditions, the cyclohexanone and cycloheptanone derivatives gave no aminated products, but ring-transformed to benzofuran derivatives. The title compounds of this investigation contain two points for further diversification (the lactam nitrogen and the carboxylate function), thus, the suitability of this compound class as a scaffold was proven by appropriate functionalizations. The first series of derivatizations of the scaffold was initiated by hydrogenolytic debenzylation of N-benzyl derivative to provide the NH-congener, which could be deprotonated with LDA and alkylated at nitrogen to give further examples of this compound class. Secondly, the ester function was submitted to saponification and the resulting carboxylic acid could be amidated using HATU as coupling reagent to furnish different amides.

Full text of DOI:10.1002/chem.201903139

A Journal of
Accepted Article
Title: Synthesis of Benzo[b]azocin-2-ones by Aryl Amination and Ring-
Expansion of α-(Iodophenyl)-β-oxoesters
Authors: Jens Christoffers, Anna Dierks, Jan Tönjes, and Marc
Schmidtmann
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10.1002/chem.201903139
Chemistry - A European Journal
Synthesis of Benzo[b]azocin-2-ones by Aryl Amination and Ring-
Expansion of α-(Iodophenyl)-β-oxoesters
Anna Dierks,[a] Jan Tönjes,[a] Marc Schmidtmann,[a] Jens Christoffers*[a]
[a]M.Sc. A. Dierks, B.Sc. J. Tönjes, Dr. M. Schmidtmann, Prof. Dr. J. Christoffers
Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg (Germany)
E-mail: jens.christoffers@uol.de
Homepage: http://www.uni-oldenburg.de/oc-christoffers/
Graphical Abstract
R
O
R
xs. R-NH2
cat. CuI
I
N
O
N
HO
K3PO4
110 °C, 16 h
CO2Et
CO2Et
CO2Et
Key Topic: A sequence of aryl amination of α-(iodophenyl)-β-oxoesters followed by
ring transformation is the key to access hexahydrobenzo[b]azocin-2-on-6-carboxylic
esters
Abstract: Transformation of β-oxoesters with PhI(OCOCF3)2 leads to α-(ortho-
iodophenyl)-β-oxoesters. These materials are the starting point for the synthesis of 6-
carboxybenzo[b]azocin-2-ones by a sequence of aryl amination and ring
transformation. This reaction sequence starts with copper-catalyzed formation of N-
alkylanilines from the iodoarenes and primary amines in the presence of K3PO4 as
stoichiometric base. The intermediate products underwent ring transformation by
addition of the nitrogen into the carbonyl group of the cycloalkanone, furnishing
benzo-annulated eight-membered ring lactams. Under the same reaction conditions,
the cyclohexanone and cycloheptanone derivatives gave no aminated products, but
ring-transformed to benzofurane derivatives. The title compounds of this investigation
contain two points for further diversification (the lactam nitrogen and the carboxylate
function), thus, the suitability of this compound class as a scaffold was proven by
appropriate functionalizations. The first series of derivatizations of the scaffold was
initiated by hydrogenolytic debenzylation of N-benzyl derivative to provide the NH-
1
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10.1002/chem.201903139
Chemistry - A European Journal
congener, which could be deprotonated with LDA and alkylated at nitrogen to give
further examples of this compound class. Secondly, the ester function was submitted
to saponification and the resulting carboxylic acid could be amidated using HATU as
coupling reagent to furnish different amides.
Keywords: Ring expansion, aryl amination, medium sized rings, lactams, scaffolds
Introduction
Organic compounds that contain a benzannulated eight-membered lactam ring (i.e.
benzazocin-2-ones)[1] have been considered as potential drugs, for example as inhi-
bitors of the angiotensin converting enzyme (ACE).[2] Furthermore, they show affinity
[3]
as ligands for the dopamine D3 or the GABAA receptor.[4] Moreover, some natural
products possess this structural motif (Figure 1): Decursivine (1), an antimalarial in-
dole alkaloid from Rhaphidophora decursiva,[5] sulpinine C (2), an antiinsectan meta-
bolite from Aspergillus sulphureus,[6] the tryptamine derived balasubramide (3) from
Clausena indica[7] and asporyzin A (4) from the fugus Aspergillus oryzae associated
with the red alga Heterosiphonia japonica.[8] Benzazocinones possess two chiral
boat-like conformations, where the phenylene ring defines an element of planar chira-
lity; the inversion barrier has been studied by NMR investigations and DFT calcula-
tions to be in the range of 30–100 kJ mol–1.[9, 10]
O
O
H
O
H
O
H
O
N
H
H
O
OH
O
N
HO
H
N
H
O
1
2
Me
O
H
N
HO
O
H
O
H
N
HN
H
O
3
4
2
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Figure 1.
Four naturally occurring benzazocinone derivatives.
Synthetic routes to the azocane ring system were recently reviewed by
Voskressensky.[11, 12] An obvious synthetic access to hexahydrobenzo[b]azocin-2-one
derivatives is provided by Beckmann rearrangement of oximes from benzosube-
rones.[13] A less evident, though very efficient access to the target structure is achie-
ved by oxidative cleavage of cyclopenta[b]indole derivatives with periodate.[14] Not
necessarily most effective, but very interesting routes to eight-membered ring lac-
tams involve ring expanding transformations.[15] For example, Tan et al.[16] accessed
the target structure by ring expansion of indanones in a reaction sequence, which
started with an aldol reaction with the ester enolate of ethyl acetate followed by
Weinreb-amide formation. The ring expanding transformation was then initiated by
oxidation of the aromatic ring with PIFA, which led to intramolecular ipso-substitution
with trans-annular C–C-bond cleavage. Very similar was the route published by Liu et
al.,[17] who have replaced the PIFA-oxidation step by photocatalysis with a Ru-
complex. A formal [6 + 2] cyclization of silyloxy alkynes and vinylazetidines leading to
monocyclic azocanones was very recently reported by Wu et al.[18]
We have reported an access to eight-membered ring lactams by ring transformation
of ten different β-oxoesters 5 with 1,4-dicarbonyl motif (Scheme 1). Bi-catalyzed con-
version with 25 primary amines R2-NH2 via azabicyclo[3.3.0]-intermediates 8 fur-
nished a library of about 250 hexahydroazocinones 9.[19] This transformation was
then applied to pyrrolidine 6 and tetrahydrothiophene derivatives 7 to furnish diazoca-
nes 10[20] and thiazocanes 11.[21] Furthermore, benzo- (products 12),[10] pyrido- (pro-
ducts 13 and two regioisomers)[22] and thienoannulated congeners 14 (and two regio-
isomers)[23] were prepared.
3
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R2
O
R2
R1
O
O
R1
N
R1
R2-NH2
N
HO
X
CO2R cat. [Bi]
CO2R
X
X
CO2R
9 (X = CH2)
10 (X = N-Boc)
(X = S)
11
R2
O
5 (X = CH2)
6 (X = N-Boc)
7
8
(X = S)
R2
R2
O
O
N
N
N
R1
R1
R1
N
S
CO2R
CO2R
CO2R
12
13
14
three regiosiomers
three regiosomers
Scheme 1. Preparation of eight-membered ring lactams 9–14 by Bi-catalyzed ring
transformation of 1,4-diketones 5–7 with primary amines; [Bi] = Bi(NO3)3 ∙ 5 H2O.
A very elegant, asymmetric organocatalytic approach to benzo[b]azocinones 16 was
recently published by Rodrigues, Coquerel and coworkers, who ring-expanded cyclo-
butanone derivatives.[24] An illustrative example is given in Scheme 2: Cyclobutanon-
carboxamide 15 was converted in an organocatalyzed Michael addition with ortho-
(Boc-amino)-ω-nitrostyrene to furnish the lactam 16 with good yield and remarkable
stereoselectivity. The transformation proceeded via the product of the conjugated ad-
dition, compound 17, which underwent ring transformation via an azabicyclo[4.2.0]-
intermediate after addition of the carbamate nitrogen to the carbonyl group within the
four-membered ring.
BocHN
O
Boc
N
O
O
O2N
NHAr
organocat.*
toluene, 22 °C, 40 h
O
NO2
15
NHAr
16, 70%,
5:1 , 96%
dr
ee
O
NHBoc
NO2
CONHAr
17
Scheme 2. Ring transformation after organocatalyzed Michael addition; Ar = 4-
4
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C6H4CO2Et.
In the present work we propose the preparation of hexahydrobenzo[b]azocin-2-on-6-
carboxylates 18 by ring transformation of β-oxoesters 20 with an α-(ortho-iodo-
phenyl)-residue. Our plan is to perform aryl amination with primary amines R-NH2.
Expected products would undergo cyclization to azabicyclo[3.3.0]-intermedates 19 si-
milar to intermediates 8 in Scheme 1. The project is actually based on the availability
of compounds 20, which can be conveniently accessed by iodophenylation of a β-
oxoester with PhI(OCOCF3)2 [PIFA, phenyliodobis(trifluoroacetate)], which was
recently reported by Shafir and coworkers.[25]
R
O
R
I
N
R-NH2
O
N
HO
CO2Et
CO2Et
20a
CO2Et
18
19
Scheme 3. Preparation of hexahydrobenzo[b]azocin-2-on-6-carboxylates 18 from β-
oxoesters 20 with an α-(ortho-iodophenyl)-residue.
Results and Discussion
The starting materials of this study, α-(ortho-iodophenyl)-β-oxoesters 20a–20c were
accessed from the β-oxoesters 21a–21c following the original report[25] with stoichio-
metric amount of PIFA and TFAA (trifluoroacetic anhydride) in a mixture of MeCN
and TFA (trifluoroacetic acid). In our hands, the yields in the range of 47–63% were a
little bit better compared to the literature (Scheme 4). The product constitution is pro-
posed to result from a [3,3]-sigmatropic rearrangement ("ioda-Claisen reaction") of an
intermediate 22 which was formed by substitution of a trifluoroacetate residue by the
enol tautomer of the oxoesters 21a–21c at the hypervalent iodine atom. This rear-
rangement is followed by rearomatization by tautomerization and reductive elimina-
tion of TFA from a hypervalent iodine species.
5
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OCOCF3
I
I
O
O
O
1.3 eq. PIFA
1.5 eq. TFAA
CO2R
E
CO2R
n
MeCN, TFA
16 h, 23 °C
n
n
21a, R = Et, = 1,
, 57%,
20b, 63%,
20c, 47%
n
22
20a
, R = Et, = 2,
21b
n
E = CO2R
21c, R = Me, = 3
n
Scheme 4. Literature known preparation of starting materials 20a–20c from oxo-
esters 20a–20c and PIFA.
We have chosen the Buchwald-Hartwig[26] coupling reaction[27] for our first efforts for
aryl amination of compound 20a with the primary amine BnNH2. As precatalysts we
have chosen Pd2(dba)3 with BINAP, DPPF, and Xantphos as ligands and Cs2CO3,
KHMDS and NaOtBu as bases in refluxing toluene, however, acyclic product 24a
was observed as the only isolable and unique compound together with several un-
specified decompositions products. Compound 24a results from two processes: Pd-
catalyzed reductive deiodination and retro-Claisen reaction induced by intermolecular
nucleophilic attack of the amine to the endocyclic carbonyl group. Therefore, we tur-
ned to Ullmann-type[28] condensations[29] with catalytic amounts of CuI and Cs2CO3
(with or without phenanthroline as ligand) in solvents like 1,4-dioxane, DMF, and ace-
tonitrile, and we were indeed able to detect the target structure 18a in the reaction
mixture. Finally, inspired by reports of Buchwald et al.,[30] we used K3PO4 as base,
and the amount of product 18a increased (Scheme 5). After screening of reaction
temperature and solvent, we ultimately identified the following optimal reaction condi-
tions for the formation of compound 18a: 0.15 equiv CuI and 2 equiv. K3PO4 in neat
BnNH2 at 110 °C for 16 h gave 56% yield of product 18a. Cyclopenta[b]benzofurane
derivative 23a was formed as a byproduct and could be isolated in 9% yield, which
results presumably from Cu-mediated carbon-oxygen coupling and subsequent elimi-
nation of water from an intermediate hemiacetal. Furthermore, deiodinated and ring-
opened byproduct 24a was isolated in 16%. We then submitted various primary ami-
nes to the conversion with oxoester 18a under the optimized conditions and were
able to isolate further five lactams 18b–18f together with varying amounts of benzofu-
rane 23a as well as acyclic products 24 and 25 with (X = H) or without (X = I) reducti-
ve deiodination as byproducts (see Table 1). For alkylamines (R = nBu, nHex, Cy
and allyl) the products 18b–18e were obtained in ca. 50% yield. For 2-ethoxyethyl-
6
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amine, the yield was slightly lower (product 18f in 38% yield). Table 1 lists the yields
of the major products 18a–18f as well as the yields of byproducts 23a, 24a, 24c–24e,
25b, and 25c.
O
R
N
xs. R-NH2
0.15 eq. CuI
I
O
K3PO4
110 °C, 16 h
CO2Et
20a
CO2Et
18a18f
O
CO2Et
O
+
+
RNH
CO2Et
23a
X
24a, 24c24e (X = H)
(X = I)
,
25b 25c
Scheme 5. Benzazocinone formation after Ullmann-type aryl amination, for resi-
dues R and X as well as yields see Table 1.
Table 1.
Residues R, X and yields of benzoazocinones 18 and byproducts 23a,
24 and 25.
R
Product 18
Byproduct 23a Byproduct 24 Byproduct 25
Bn
56% (18a)
51% (18b)
50% (18c)
50% (18d)
49% (18e)
38% (18f)
9%
0%
16% (24a)
0%
0%
nBu
nHex
Cy
15% (25b)
2% (25c)
0%
4%
16% (24c)
13% (24d)
20% (24e)
0%
11%
0%
allyl
0%
CH2CH2OEt
0%
0%
Conversion of the congeners 20b and 20c under the respective reaction conditions
with benzyl- or butylamine did not give lactams as products, but the dibenzofurane
and cyclohepta[b]benzofuran derivatives 23b and 23c were isolated (in 43% and
18% yield, resp., Scheme 6).
I
xs. R'-NH2
0.15 eq. CuI
O
O
K3PO4
110 °C, 16 h
CO2R
n
CO2R
n
20b, R = Et, = 1,
n
23b, 43% (with BuNH )
n
2
23c, 18% (with BnNH2)
20c, R = Me, = 2
n
7
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Scheme 6. Formation of dibenzofurane and cyclohepta[b]benzofuran derivatives 23b
and 23c.
Compound 18b was obtained as a crystalline material suitable for single crystal X-ray
structure determination.[31] In Figure 2, a representation of the molecular structure is
given. A being an carboxamide, the nitrogen atom N1 is planar (angles C2-N1-C10a
123.26°, C2-N1-C1' 120.30°, C1'-N1-C10a 116.12°, sum 359.68°) and the C2-N1
bond with 1.3658 Å is rather a double bond. The bond N1-C10a with 1.4289 Å is a
single bond. The eight and six membered rings are almost perpendicular at their
junction (dihedral angles C2-N1-C10a-C6a 60.75° and C4-C5-C6-C6a 86.16°).
Therefore, there seems to be no electronic influence of the amide group towards the
aromatic ring, which is also reflected by the chemical shifts of the four aromatic
protons in the 1H NMR spectrum (δ 7.21–7.35 ppm).
Figure 2.
The ORTEP-representation of the molecular structure of compound 18b
in the solid state proves the constitution.
In order to proof the versatility of the benzoazocinones 18 as new heterocyclic scaf-
folds, we envisioned diversifying transformations at the lactam-nitrogen and the exo-
cyclic carboxyl function. First of all, the benzyl group of compound 18a was hydroge-
nolytically cleaved to furnish compound 18g (79%, Scheme 7). In order to achieve full
conversion, the temperature had to be raised to 50 °C, upon which the aromatic ring
of part of the starting material was hydrogenated to furnish the N-(cyclohexylmethyl)
8
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congener 18h (10%). Anyhow, after NH deprotonation with LDA it was converted with
various alkylbromides. First of all, the N-allyl compound 18e isolated in surprisingly
low yield (24%, 46% brsm) together with some starting material 18g. On the other
hand, the prenylation proceeded straightforwardly without allylic inversion (75% of
product 18i). With methyl bromoacetate, compound 18j was obtained in 79% yield.
Introducing some steric hindrance with the secondary halide ethyl α-bromopropionate
gave again lower yield (product 18k in 34%, 53% brsm) together with recovered star-
ting materials 18g. Interestingly, this compound was isolated as two diastereoisomers
with 87:13 dr, which is rather a remarkable selectivity considering the 1,5-distance of
the two stereocenters.
Cy
O
Bn
N
O
O
H
1 atm H2
cat. Pd/C
N
N
+
PrOH
50 °C, 2 d
i
CO2Et
18a
CO2Et
CO2Et
18h, 10%
18g, 79%
1. LDA, 78 °C, 0.5 h, THF,
2. R-Br, 78 °C, 1.5 h;
23 °C, 2 h
O
R
N
CO2Et
18e, R = allyl, 24% (46% brsm)
18i, CH2CH=CMe2, 75%
18j, R = CH2CO2Me, 79%
, R = CH(Me)CO Et, 34% (53% brsm), 87:13
18k
dr
2
Scheme 7. Hydrogenolytic debenzylation of the lactam-nitrogen followed by alkyla-
tion reaction.
For the second diversifying strategy we first submitted compound 18a to ester sapo-
nification yielding compound 26 in 81% yield (Scheme 8). It was then coupled with
the HATU-DIPEA protocol[32] [HATU = O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetrame-
thyluronium hexafluorophosphate), DIPEA = ethyldiisopropylamine] with the ethyl
esters of aminoisobutyric acid and β-alanine to give the amides 27a and 27b in good
yield (87% and 85%, resp.). By application of the same reaction conditions, trifluoro-
ethylamine could be coupled to furnish compound 27c with 88% yield.
9
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O
Bn
O
Bn
O
Bn
N
N
N
(a)
(b)
CO2Et
18a
CO2H
NHR
O
26, 81%
27a, R = C(Me)2CO2Et, 87%
27b, R = CH2CH2CO2Et, 85%
27c, R = CH2CF3, 88%
Scheme 8. Ester saponification and amide coupling. Reagents and conditions: (a)
NaOH, H2O–EtOH, 80 °C, 16 h; (b) HATU, DIPEA, 1.5 equiv. R-NH2, CH2Cl2, 23 °C,
16 h.
Furthermore, we intended to prepare the 6-amino derivative of the scaffold by Hof-
mann degradation of the carboxylate function in compound 26. We relied on a litera-
ture procedure applying the hypervalent iodine reagent PIDA [PhI(OAc)2] (Scheme
9).[20] First of all, the parent unsubstituted amide 27d was prepared in 70% yield by
activation of the acid 26 with Boc2O and conversion of the mixed anhydride with
hartshorn salt. The degradation proceeded with PIDA and the intermediate isocya-
nate was solvolyzed with MeOH to furnish the carbamate 28, however, the yield was
moderate.
O
Bn
O
Bn
O
Bn
N
N
N
(a)
(b)
CO2H
CONH2
27d, 70%
NHCO2Me
26
28, 30%
Scheme 9. Preparation and Hofmann degradation of amide 27d. Reagents and
conditions: (a) 1. 1.5 equiv. Boc2O, 1.8 equiv. pyridine, 1,4-dioxane, 23 °C, 0.5 h; 2.
2.8 equiv. (NH4)2CO3, 23 °C, 16 h; (b) 1.0 equiv. PIDA, 2.5 equiv. KOH, MeOH,
CH2Cl2, 0 °C23 °C, 16 h.
Finally, the N-allyl group of compound 18e seemed to be perfectly suited for further
transformations, e.g. olefin cross-metathesis. Therefore, we converted it with an ex-
cess of methyl acrylate in the presence of one of Evonik's catMETium RF catalysts[33]
(Scheme 10). The internal olefin 18l was obtained exclusively as trans-diastereoiso-
mer together with some unreacted starting material (44% yield, 59% brsm).
10
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CO2
Me
O
O
5 equiv.
CH2Cl2, 40 °C, 16 h
CO2Me
N
N
Me
Me
CO2Et
18e
CO2Et
N
N
Mes
Mes
Ph
18l, 44% (59%
Cl
brsm)
Ru
Cl
PCy3
5 mol%
Scheme 10. Olefin cross-metathesis of allylic amide 18e; Mes = 2,4,6-Me3C6H2.
Conclusion
A novel synthesis of benzo[b]azocin-2-ones by a sequence of aryl amination and ring
transformation of ethyl 1-(ortho-iodophenyl)-2-oxocyclopentancarboxylate 20a was
introduced. Additionally, the nitrogen atom and the carboxylate function define two
points for further diversification, thus, the suitability of this compound class as a scaf-
fold was proven by appropriate functionalization. Starting point of this investigation
was the preparation of α-(ortho-iodophenyl)-β-oxoesters 20a–20c by transformation
of β-oxoesters 21a–21c with PhI(OCOCF3)2 (PIFA). After aryl amination of the cyclo-
pentanone congener 20a with six primary amines, which was accomplished with ca-
talytic amounts of CuI and K3PO4 as stoichiometric base, the intermediate N-alkylani-
lines underwent ring transformation by addition of the nitrogen into the carbonyl
group of the cycloalkanone, furnishing the benzo-annulated eight-membered ring
lactams 18a–18f (56–38% yield). Under the same reaction conditions, the cyclohex-
anone and cycloheptanone derivatives 20b and 20c gave no aminated products, but
ring-transformed to benzofurane derivatives 23b and 23c. The first series of derivati-
zations of the scaffold was initiated by hydrogenolytic debenzylation of N-benzyl deri-
vative 18a to provide the NH-congener 18g, which could be deprotonated with LDA
and alkylated at nitrogen to give further examples 18i–18k of this compound class.
Another representative (product 18l) was obtained by olefin cross-metathesis of N-
allyl lactam 18e with methyl acrylate. Secondly, the ester function of compound 18a
was submitted to saponification (81% yield) and the resulting carboxylic acid 26 could
be amidated using HATU as coupling reagent to furnish three different amides 27a–
27c (85–88% yield). The N-unsubstituted parent amide 27d was obtained by
11
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amidation with (NH4)2CO3 and could be further transformed by Hofmann degradation
using PhI(OAc)2 (PIDA) and MeOH to give carbamate 28 (30% yield).
Experimental Section
General: Preparative column chromatography was carried out using Merck SiO2 (35–
70 µm, type 60 A) with hexanes (mixture of isomers, bp. 64–71 °C), tert-butyl methyl
ether (MTBE), EtOAc, and MeOH as eluents. TLC was performed on aluminum pla-
1
19
13
tes coated with SiO2 F254. H-, F- and C-NMR spectra were recorded on Bruker
Avance DRX 500 and 300 instruments. Multiplicities of carbon signals were determi-
ned with DEPT experiments. MS and HRMS spectra of products were obtained with
a Waters Q-TOF Premier (ESI, pos. mode) or Thermo Scientific DFS (EI) spectrome-
ters. IR spectra were recorded on a Bruker Tensor 27 spectrometer equipped with a
diamond ATR unit. Compounds 20a–20c were literature known and prepared accor-
dingly.[25] All other starting materials were commercially available.
General procedure A (GPA) for the α-arylation of β-oxoesters 21a–21c.[25] Under
exclusion of air and moisture (nitrogen atmosphere), TFAA (1.5 equiv) was added
dropwise to a stirred solution of PIFA (1.3 equiv) and TFA (1.5 L mol–1 PIFA) in
MeCN (1.5 L mol–1 PIFA) and the resulting mixture was stirred at ambient temperatu-
re for 15 min. Then β-oxoester 21 (1.0 equiv) was added and the resulting mixture
was further stirred at ambient temperature for 16 h. The solvent was removed in
vacuum and the residue was purified by column chromatography to yield arylated β-
oxoesters 20a–20c.
Ethyl 1-(2-iodophenyl)-2-oxocyclopentane-1-carboxylate (20a).[25] According to
GPA, TFAA (2.52 g, 12.0 mmol), PIFA (4.47 g, 10.4 mmol) and β-oxoester 21a (1.25
g, 8.00 mmol) were converted in TFA (16 mL) and MeCN (16 mL) to furnish the title
compound 20a (1.64 g, 4.58 mmol, 57%) after chromatography (SiO2, hex-
1
anes/MTBE 3:1, Rf = 0.30) as a colorless solid, mp 74 °C. H-NMR (300 MHz,
CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3H), 1.63–1.80 (m, 1H), 2.03–2.15 (m, 1H), 2.44–2.57
(m, 3H), 3.20 (ddd, J = 13.5 Hz, J = 9.7 Hz, J = 7.0 Hz, 1H), 4.14–4.30 (m, 2H), 6.92–
6.97 (m, 2H), 7.28 (td, J = 7.8 Hz, J = 1.3 Hz, 1H), 7.93 (dd, J = 8.3 Hz, J = 1.2 Hz,
12
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1H) ppm. All spectroscopic data are in accordance with the literature.[25] C14H15IO3
(358.18 g mol–1).
Ethyl 1-(2-iodophenyl)-2-oxocyclohexane-1-carboxylate (20b).[25] According to
GPA, TFAA (630 mg, 3.00 mmol), PIFA (1.12 g, 2.60 mmol) and β-oxoester 21b (340
mg, 2.00 mmol) were converted in TFA (4 mL) and MeCN (4 mL) to furnish the title
compound 20b (468 mg, 1.26 mmol, 63%) after chromatography (SiO2, hex-
anes/MTBE 5:1, Rf = 0.29) as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ = 1.27 (t,
J = 7.1 Hz, 3H), 1.75–1.91 (m, 2H), 1.97–2.07 (m, 2H), 2.58–2.85 (m, 4H), 4.20–4.37
(m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H),
7.96 (d, J = 7.8 Hz, 1H) ppm. All spectroscopic data are in accordance with the litera-
ture.[25] C15H17IO3 (372.20 g mol–1).
Methyl 1-(2-iodophenyl)-2-oxocycloheptane-1-carboxylate (20c).[25] According to
GPA, TFAA (315 mg, 1.50 mmol), PIFA (559 mg, 1.30 mmol) and β-oxoester 21c
(170 mg, 1.00 mmol) were converted in TFA (2 mL) and MeCN (2 mL) to furnish the
the title compound 20c (173 mg, 465 µmol, 47%) after chromatography (SiO2, hex-
1
anes/MTBE 2:1, Rf = 0.43) as a colorless oil. H-NMR (300 MHz, CDCl3): 1.47–1.58
(m, 1H), 1.68–1.80 (m, 5H), 2.11–2.19 (m, 1H), 2.73–2.81 (m, 1H), 2.96–3.03 (m,
1H), 3.16–3.24 (m, 1H), 3.73 (s, 3H), 6.96 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.7 Hz,
1H), 7.32 (t, J = 7.7 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H) ppm. All spectroscopic data are
in accordance with the literature.[25] C15H17IO3 (372.20 g mol–1).
General procedure B (GPB) for the Ullmann type coupling of β-oxoesters 20a–
20c with amines. Under exclusion of air and moisture (nitrogen atmosphere), a
Schlenk tube was charged with α-arylated β-oxoester 20 (1.0 equiv), K3PO4 (2.0–3.0
equiv) and CuI (15 mol%), three times evacuated and flushed with nitrogen. The
amine (1–1.8 L mol–1) was then added and the tube was tightly closed. The resulting
mixture was stirred at 110 °C for 16 h and subsequently cooled to ambient tempe-
rature. The mixture was diluted with MTBE (20 L mol–1), water (20 L mol–1) and sat.
aqueous NH4Cl solution (2 L mol–1) and the layers were separated. The aqueous
layer was extracted with MTBE (2 x 20 L mol–1). The combined organic layers were
dried (MgSO4), filtered and the solvent was removed in vacuo. The crude product
13
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was purified by column chromatography to furnish benzazocinones 18 together with
byproducts 23, 24, and 25.
Conversion of β-oxoester 20a with benzylamine. According to GPB, β-oxoester
20a (179 mg, 500 µmol), K3PO4 (212 mg, 1.00 mmol) and CuI (14 mg, 75 µmol) were
converted with benzylamine (0.5 mL). The crude product was purified by column
chromatography (SiO2, hexanes/MTBE 1:2) to yield the benzofuran 23a (10 mg, 43
µmol, 9%, Rf = 0.65) as a pale yellow oil. Secondly, the benzazocinone 18a (95 mg,
0.28 mmol, 56%, Rf = 0.30) was eluted as a pale yellow solid, mp 60–63 °C. As the
third fraction, the acyclic amide 24a (28 mg, 82 µmol, 16%, Rf = 0.12) was obtained
as a pale yellow oil.
Ethyl 1-benzyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18a).
1H-NMR (500 MHz, CDCl3): δ = 1.10 (t, J = 7.1 Hz, 3H), 1.49 (dddd, J = 14.1 Hz, J =
12.7 Hz, J = 11.2 Hz, J = 5.6 Hz, 1H), 1.76–1.85 (m, 1H), 1.88–1.96 (m, 2H), 2.30–
2.34 (m, 1H), 2.38 (dd, J = 14.1 Hz, J = 5.0 Hz, 1H), 3.20 (dd, J = 11.2 Hz, J = 0.9
Hz, 1H), 3.97–4.03 (m, 2H), 4.68 (d, J = 14.0 Hz, 1H), 5.33 (d, J = 14.0 Hz, 1H),
7.17–7.19 (m, 1H), 7.22–7.30 (m, 8H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ =
14.06 (CH3), 24.42 (CH2), 32.28 (CH2), 33.13 (CH2), 44.69 (CH), 52.69 (CH2), 60.59
(CH2), 125.95 (CH), 127.31 (CH), 127.40 (CH), 127.92 (CH), 128.42 (2 CH), 128.49
(CH), 129.26 (2 CH), 136.74 (C), 139.01 (C), 140.62 (C), 173.68 (C), 173.99 (C)
ppm. IR (ATR): nu(tilde) = 2941 (w), 2928 (w), 1728 (vs), 1651 (vs), 1493 (m), 1453
(m), 1393 (m), 1296 (m), 1225 (m), 1185 (vs), 1148 (m), 1027 (m), 759 (m), 733 (m),
+
701 (s) cm–1. HR-MS (EI, 70 eV): calcd. 337.1672 (for C21H23NO3 ), found 337.1665
[M+]. C21H23NO3 (337.42 g mol–1).
1
Ethyl 2,8b-dihydro-1H-cyclopenta[b]benzofuran-8b-carboxylate (23a). H-NMR
(500 MHz, CDCl3): δ = 1.16 (t, J = 7.1 Hz, 3H), 2.27 (ddd, J = 11.6 Hz, J = 9.9 Hz, J =
7.9 Hz, 1H), 2.44 (ddd, J = 14.9 Hz, J = 7.9 Hz, J = 4.0 Hz, 1H), 2.78 (dddd, J = 14.9
Hz, J = 9.9 Hz, J = 5.3 Hz, J = 1.5 Hz, 1H), 2.85 (dd, J = 11.6 Hz, J = 5.3 Hz, 1H),
4.07–4.13 (m, 2H), 5.24 (dd, J = 4.0, J = 1.5 Hz, 1H), 6.97–7.01 (m, 2H), 7.23 (td, J =
7.9 Hz, J = 1.5 Hz, 1H), 7.33 (dd, J = 7.4 Hz, J = 1.1 Hz, 1H) ppm. 13C{1H}-NMR (125
MHz, CDCl3): δ = 13.98 (CH3), 31.32 (CH2), 37.84 (CH2), 61.40 (CH2), 63.00 (C),
101.56 (CH), 110.74 (CH), 122.51 (CH), 124.81 (CH), 129.03 (C), 129.17 (CH),
14
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161.67 (C), 162.25 (C), 171.76 (C) ppm. IR (ATR): nu(tilde) = 2958 (m), 2929 (m),
2859 (m), 1727 (vs), 1686 (m), 1607 (m), 1456 (s), 1239 (s), 1152 (s), 1101 (m),
+
1017 (m), 835 (m), 751 (s) cm–1. HR-MS (ESI): calcd. 237.1097 (for C14H14LiO3 ),
found 237.1105 [M + Li+]. C14H14O3 (230.26 g mol–1).
Ethyl 6-(benzylamino)-6-oxo-2-phenylhexanoate (24a). 1H-NMR (500 MHz,
CDCl3): δ = 1.18 (t, J = 7.1 Hz, 3H), 1.54–1.69 (m, 2H), 1.75–1.82 (m, 1H), 2.04–2.12
(m, 1H), 2.15–2.25 (m, 2H), 3.52 (t, J = 7.6 Hz, 1H), 4.02–4.16 (m, 2H), 4.40 (d, J =
5.8 Hz, 2H), 5.80 (br s, 1H), 7.22–7.33 (m, 10H) ppm. 13C{1H}-NMR (125 MHz,
CDCl3): δ = 14.08 (CH3), 23.63 (CH2), 33.01 (CH2), 36.25 (CH2), 43.55 (CH2), 51.52
(CH), 60.77 (CH2), 127.21 (CH), 127.46 (CH), 127.80 (4 CH), 128.59 (2 CH), 128.65
(2 CH), 138.25 (C), 138.89 (C), 172.16 (C), 173.82 (C) ppm. IR (ATR): nu(tilde) =
3294 (w), 2931 (w), 1731 (s), 1646 (s), 1546 (m), 1456 (m), 1174 (m), 1150 (s), 1030
+
(m), 734 (m), 699 (vs) cm–1. HR-MS (EI, 70 eV): calcd. 339.1829 (for C21H25NO3 ),
found 339.1817 [M+]. C21H25NO3 (339.44 g mol–1).
Conversion of β-oxoester 20a with n-butylamine. According to GPB, β-oxoester
20a (179 mg, 500 µmol), K3PO4 (212 mg, 1.00 mmol) and CuI (14 mg, 75 µmol) were
converted with n-butylamine (0.5 mL). The crude product was purified by column
chromatography (SiO2, hexanes/MTBE 1:1) to yield the benzazocinone 18b (78 mg,
0.26 mmol, 51%, Rf = 0.33) as a colorless solid, mp 78 °C. As a second fraction, the
acyclic amide 25b (33 mg, 77 µmol, 15%, Rf = 0.17) was obtained as a colorless oil.
Ethyl 1-butyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18b).
1H-NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H),
1.24–1.37 (m, 2H), 1.40–1.49 (m, 1H), 1.50–1.65 (m, 2H), 1.76–1.85 (m, 2H), 1.89–
1.94 (m, 1H), 2.23 (dd, J = 11.0 Hz, J = 7.8 Hz, 1H), 2.44 (dd, J = 13.4 Hz, J = 4.5
Hz, 1H), 3.26 (ddd, J = 13.3 Hz, J = 10.4 Hz, J = 5.0 Hz, 1H), 3.55 (d, J = 11.0 Hz,
1H), 4.08 (dq, J = 10.8 Hz, J = 7.1 Hz, 1H), 4.16 (dq, J = 10.8 Hz, J = 7.1 Hz, 1H),
4.38 (ddd, J = 13.3 Hz, J = 10.4 Hz, J = 5.9 Hz, 1H), 7.21–7.24 (m, 1H), 7.28–7.32
13
(m, 2H), 7.33–7.35 (m, 1H) ppm. C{1H}-NMR (125 MHz, CDCl3): δ = 13.85 (CH3),
13.98 (CH3), 20.43 (CH2), 24.27 (CH2), 29.22 (CH2), 31.95 (CH2), 33.16 (CH2), 44.78
(CH), 48.98 (CH2), 61.88 (CH2), 125.83 (CH), 126.87 (CH), 128.08 (CH), 128.41
(CH), 139.16 (C), 140.72 (C), 173.87 (C), 173.88 (C) ppm. IR (ATR): nu(tilde) = 2960
15
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(w), 2937 (w), 2869 (w), 1734 (s), 1653 (vs), 1495 (m), 1456 (m), 1397 (m), 1302 (m),
1226 (m), 1187 (s), 1154 (m), 1102 (m), 1047 (m), 1028 (m), 767 (m), 741 (m) cm–1.
+
HR-MS (ESI): calcd. 310.1989 (for C18H25LiNO3 ), found 310.1996 [M + Li+].
C18H25NO3 (303.40 g mol–1).
1
Ethyl 6-(butylamino)-2-(2-iodophenyl)-6-oxohexanoate (25b). H-NMR (500 MHz,
CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.33 (sext, J = 7.3 Hz,
2H), 1.43–1.49 (m, 2H), 1.59–1.69 (m, 2H), 1.73–1.80 (m, 1H), 1.99–2.07 (m, 1H),
2.18 (t, J = 7.5 Hz, 2H), 3.23 (q, J = 7.0 Hz, 2H), 4.01 (t, J = 7.4 Hz, 1H), 4.07–4.18
(m, 2H), 5.53 (br s, 1H), 6.90–6.95 (m, 1H), 7.30–7.31 (m, 2H), 7.84 (d, J = 7.9 Hz,
1H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 13.73 (CH3), 14.09 (CH3), 20.05
(CH2), 23.53 (CH2), 31.66 (CH2), 32.93 (CH2), 36.37 (CH2), 39.21 (CH2), 54.68 (CH),
60.99 (CH2), 101.62 (C), 127.67 (CH), 128.65 (CH), 128.83 (CH), 139.75 (CH),
141.89 (C), 172.17 (C), 173.27 (C) ppm. IR (ATR): nu(tilde) = 3300 (w), 2938 (w),
1731 (vs), 1640 (vs), 1548 (s), 1465 (m), 1369 (m), 1178 (m), 1149 (s), 1010 (s), 746
+
(s) cm–1. HR-MS (EI, 70 eV): calcd. 431.0952 (for C18H26INO3 ), found 431.0952 [M+].
C18H26INO3 (431.31 g mol–1).
Conversion of β-oxoester 20a with n-hexylamine. According to GPB, β-oxoester
20a (179 mg, 500 µmol), K3PO4 (212 mg, 1.00 mmol) and CuI (14 mg, 75 µmol) were
converted with n-hexylamine (0.5 mL). The crude mixture was separated by column
chromatography (SiO2, hexanes/MTBE 1:2) to yield as the first fraction the benzofu-
ran 23a (4 mg, 0.02 mmol, 4%, Rf = 0.65) as a pale yellow oil. Secondly, the benz-
azocinone 18c (83 mg, 0.25 mmol, 50%, Rf = 0.34) was eluted as a colorless oil. As
third and fourth fractions, the acyclic amide 25c (5 mg, 0.01 mmol, 2%, Rf = 0.21)
and the acylic amide 24c (26 mg, 78 µmol, 16%, Rf = 0.18) were obtained, both as a
colorless oils.
Ethyl 1-hexyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18c).
1H-NMR (500 MHz, CDCl3): δ = 0.80–0.82 (m, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.21–
1.23 (m, 5H), 1.26–1.32 (m, 1H), 1.39–1.64 (m, 3H), 1.74–1.85 (m, 2H), 1.87–1.92
(m, 1H), 2.21 (dd, J = 11.0 Hz, J = 7.8 Hz, 1H), 2.40–2.44 (m, 1H), 3.23 (ddd, J =
13.2 Hz, J = 10.8 Hz, J = 4.9 Hz, 1H), 3.53 (d, J = 10.7 Hz, 1H), 4.06 (dq, J = 10.8
Hz, J = 7.1 Hz, 1H), 4.13 (dq, J = 10.8 Hz, J = 7.1 Hz, 1H), 4.35 (ddd, J = 13.2 Hz, J
16
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= 10.8 Hz, J = 5.8 Hz, 1H), 7.19–7.22 (m, 1H), 7.26–7.33 (m, 3H) ppm. 13C{1H}-NMR
(125 MHz, CDCl3): δ = 13.92 (2 CH3), 22.36 (CH2), 24.21 (CH2), 26.70 (CH2), 26.90
(CH2), 31.51 (CH2), 31.92 (CH2), 33.09 (CH2), 44.72 (CH), 49.17 (CH2), 60.82 (CH2),
125.81 (CH), 126.80 (CH), 128.03 (CH), 128.36 (CH), 139.10 (C), 140.65 (C), 173.74
(C), 173.83 (C) ppm. IR (ATR): nu(tilde) = 2931 (w), 2864 (w), 1733 (s), 1652 (vs),
1493 (m), 1454 (m), 1396 (m), 1300 (m), 1224 (m), 1183 (s), 1150 (m), 1098 (m),
1046 (m), 1025 (m), 765 (m), 738 (m) cm–1. HR-MS (EI, 70 eV): calcd. 331.2142 (for
+
C20H29NO3 ), found 310.2140 [M+]. C20H29NO3 (331.46 g mol–1).
Ethyl 6-(hexylamino)-2-(2-iodophenyl)-6-oxohexanoate (25c). 1H-NMR (500 MHz,
CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.28–1.33 (m, 6H), 1.45–
1.49 (m, 2H), 1.62–1.68 (m, 2H), 1.73–1.80 (m, 1H), 2.00–2.07 (m, 1H), 2.19 (t, J =
7.5 Hz, 2H), 3.22 (q, J = 7.0 Hz, 2H), 4.02 (dd, J = 8.1 Hz, J = 6.7 Hz, 1H), 4.08–4.19
(m, 2H), 5.49 (br s, 1H), 6.91–6.96 (m, 1H), 7.30–7.31 (m, 2H), 7.85 (d, J = 7.9 Hz,
1H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.02 (CH3), 14.10 (CH3), 22.55
(CH2), 23.55 (CH2), 26.59 (CH2), 29.58 (CH2), 31.47 (CH2), 32.94 (CH2), 36.41 (CH2),
39.53 (CH2), 54.70 (CH), 61.01 (CH2), 101.64 (C), 127.69 (CH), 128.67 (CH), 128.85
(CH), 139.77 (CH), 141.91 (C), 172.16 (C), 173.30 (C) ppm. IR (ATR): nu(tilde) =
3276 (w), 2929 (s), 2861 (m), 1733 (vs), 1642 (vs), 1549 (s), 1465 (s), 1437 (m),
1370 (m), 1178 (m), 1150 (s), 1010 (s), 747 (s) cm–1. HR-MS (EI, 70 eV): calcd.
+
459.1265 (for C20H30INO3 ), found 459.1262 [M+]. C20H30INO3 (459.37 g mol–1).
Ethyl 6-(hexylamino)-6-oxo-2-phenylhexanoate (24c). 1H-NMR (500 MHz, CDCl3):
δ = 0.86–0.88 (m, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.25–1.32 (m, 6H), 1.43–1.49 (m,
2H), 1.53–1.66 (m, 2H), 1.73–1.82 (m, 1H), 2.03–2.12 (m, 1H), 2.12–2.17 (m, 2H),
3.19–3.23 (m, 2H), 3.52 (t, J = 7.6 Hz, 1H), 4.07 (dq, J = 10.8 Hz, J = 7.1 Hz, 1H),
4.14 (dq, J = 10.8 Hz, J = 7.1 Hz, 1H), 5.48 (br s, 1H), 7.22–7.32 (m, 5H) ppm.
13C{1H}-NMR (125 MHz, CDCl3): δ = 13.99 (CH3), 14.09 (CH3), 22.52 (CH2), 23.72
(CH2), 26.56 (CH2), 29.55 (CH2), 31.44 (CH2), 33.05 (CH2), 36.39 (CH2), 39.50 (CH2),
51.55 (CH), 60.77 (CH2), 127.20 (CH), 127.80 (2 CH), 128.59 (2 CH), 138.94 (C),
172.22 (C), 173.88 (C) ppm. IR (ATR): nu(tilde) = 3294 (w), 2954 (m), 2927 (m),
2857 (m), 1732 (vs), 1641 (vs), 1549 (m), 1455 (m), 1175 (m), 1148 (m), 1026 (m),
+
732 (m), 698 (s) cm–1. HR-MS (EI, 70 eV): calcd. 333.2298 (for C20H31NO3 ), found
333.2297 [M+]. C20H31NO3 (333.47 g mol–1).
17
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Conversion of β-oxoester 20a with cyclohexylamine. According to GPB, β-oxo-
ester 20a (179 mg, 500 µmol), K3PO4 (212 mg, 1.00 mmol) and CuI (14 mg, 75 µmol)
were converted with cyclohexylamine (0.5 mL). The crude mixture was separated by
column chromatography (SiO2, hexanes/MTBE 1:2) to yield the benzofuran 23a (13
mg, 56 µmol, 11%, Rf = 0.65) as a pale yellow oil in the first fraction. Secondly, the
benzazocinone 18d (83 mg, 0.25 mmol, 50%, Rf = 0.31) was eluted as as a colorless
solid, mp 120–123 °C. As third fraction, the acyclic amide 24d (22 mg, 66 µmol, 13%,
Rf = 0.19) was obtained as a colorless oil.
Ethyl 1-cyclohexyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate
1
(18d). H-NMR (500 MHz, CDCl3): δ = 0.97–1.05 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H),
1.33–1.39 (m, 1H), 1.43–1.53 (m, 3H), 1.55–1.60 (m, 1H), 1.68–1.70 (m, 2H), 1.77–
1.84 (m, 3H), 1.86–1.92 (m, 1H), 2.14–2.23 (m, 2H), 2.40–2.44 (m, 1H), 3.63 (d, J =
11.1 Hz, 1H), 4.09 (dq, J = 10.7 Hz, J = 7.2 Hz, 1H), 4.16 (dq, J = 10.7 Hz, J = 7.2
Hz, 1H), 4.56 (tt, J = 12.0 Hz, J = 3.5 Hz, 1H), 7.20–7.21 (m, 1H), 7.27–7.30 (m, 1H),
7.32–7.37 (m, 2H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 13.89 (CH3), 24.43
(CH2), 25.45 (CH2), 25.80 (CH2), 25.92 (CH2), 29.97 (CH2), 32.15 (CH2), 32.78 (CH2),
33.57 (CH2), 44.86 (CH), 55.36 (CH), 60.77 (CH2), 126.81 (CH), 127.30 (CH), 127.82
(CH), 128.85 (CH), 138.30 (C), 140.51 (C), 173.77 (C), 173.84 (C) ppm. IR (ATR):
nu(tilde) = 2930 (m), 2856 (w), 1732 (vs), 1645 (vs), 1492 (m), 1446 (m), 1369 (m),
1302 (m), 1222 (m), 1186 (s), 1143 (m), 1024 (m), 769 (m), 745 (m) cm–1. HR-MS
+
(EI, 70 eV): calcd. 329.1985 (for C20H27NO3 ), found 329.1985 [M+]. C20H27NO3
(329.44 g mol–1).
1
Ethyl 6-(cyclohexylamino)-6-oxo-2-phenylhexanoate (24d). H-NMR (500 MHz,
CDCl3): δ = 1.04–1.15 (m, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.29–1.39 (m, 2H), 1.55–1.62
(m, 3H), 1.67–1.70 (m, 2H), 1.74–1.81 (m, 1H), 1.87–1.89 (m, 2H), 2.03–2.10 (m,
1H), 2.13 (t, J = 7.9 Hz, 2H), 3.52 (t, J = 7.6 Hz, 1H), 3.70–3.77 (m, 1H), 4.07 (dq, J =
10.8 Hz, J = 7.1 Hz, 1H), 4.14 (dq, J = 10.8 Hz, J = 7.1 Hz, 1H), 5.35 (br d, J = 7.6
Hz, 1H), 7.22–7.26 (m, 1H), 7.27–7.32 (m, 4H) ppm. 13C{1H}-NMR (125 MHz, CDCl3):
δ = 14.08 (CH3), 23.75 (CH2), 24.84 (2 CH2), 25.49 (CH2), 32.99 (CH2), 33.18 (2
CH2), 36.53 (CH2), 48.08 (CH), 51.54 (CH), 60.76 (CH2), 127.20 (CH), 127.80 (2 CH),
128.59 (2 CH), 138.95 (C), 171.36 (C), 173.88 (C) ppm. IR (ATR): nu(tilde) = 3288
18
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(w), 2929 (s), 2853 (m), 1731 (vs), 1637 (vs), 1544 (s), 1451 (m), 1146 (s), 1027 (m),
+
733 (m), 698 (s) cm–1. HR-MS (EI, 70 eV): calcd. 331.2142 (for C20H29NO3 ), found
331.2135 [M+]. C20H29NO3 (331.46 g mol–1).
Conversion of β-oxoester 20a with allylamine. According to GPB, β-oxoester 20a
(179 mg, 500 µmol), K3PO4 (212 mg, 1.00 mmol) and CuI (14 mg, 75 µmol) were
converted with allylamine (0.5 mL). The crude product was purified by column chro-
matography (SiO2, hexanes/MTBE 1:2) to yield the benzazocinone 18e (70 mg, 0.24
mmol, 49%, Rf = 0.28) as a colorless oil. As second fraction, the acyclic amide 24e
(30 mg, 0.10 mmol, 20%, Rf = 0.12) was obtained as a colorless oil.
Ethyl 1-allyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18e).
1H-NMR (500 MHz, CDCl3): δ = 1.17 (t, J = 7.0 Hz, 3H), 1.51–1.60 (m, 1H), 1.77–
1.94 (m, 3H), 2.25–2.29 (m, 1H), 2.42–2.46 (m, 1H), 3.52 (d, J = 11.2 Hz, 1H), 4.05–
4.18 (m, 3H), 4.76 (dd, J = 14.4 Hz, J = 6.3 Hz, 1H), 5.10 (d, J = 10.1 Hz, 1H), 5.15
13
(d, J = 17.1 Hz, 1H), 5.86–5.94 (m, 1H), 7.20–7.33 (m, 4H) ppm. C{1H}-NMR (125
MHz, CDCl3): δ = 13.96 (CH3), 24.28 (CH2), 32.01 (CH2), 33.06 (CH2), 44.78 (CH),
51.74 (CH2), 60.84 (CH2), 118.78 (CH2), 125.96 (CH), 126.95 (CH), 127.99 (CH),
128.57 (CH), 132.19 (CH), 139.04 (C), 140.48 (C), 173.81 (C), 173.82 (C) ppm. IR
(ATR): nu(tilde) = 2979 (w), 2935 (w), 1731 (vs), 1651 (vs), 1493 (m), 1454 (m), 1389
(m), 1225 (m), 1185 (s), 1150 (m), 1098 (m), 765 (m), 739 (m) cm–1. HR-MS (ESI):
+
calcd. 287.1516 (for C17H21NO3 ), found 287.1518 [M+]. C17H21NO3 (287.36 g mol–1).
1
Ethyl 6-(allylamino)-6-oxo-2-phenylhexanoate (24e). H-NMR (500 MHz, CDCl3):
δ = 1.16 (t, J = 7.1 Hz, 3H), 1.51–1.65 (m, 2H), 1.77 (dddd, J = 13.3 Hz, J = 10.2 Hz,
J = 7.3 Hz, J = 5.8 Hz, 1H), 2.05 (dddd, J = 13.3 Hz, J = 10.5 Hz, J = 7.9 Hz, J = 5.5
Hz, 1H), 2.13–2.19 (m, 2H), 3.50 (t, J = 7.6 Hz, 1H), 3.82 (tt, J = 5.7 Hz, J = 1.4 Hz,
2H), 4.01–4.14 (m, 2H), 5.08 (dq, J = 10.2 Hz, J = 1.4 Hz, 1H), 5.12 (dq, J = 17.2 Hz,
J = 1.6 Hz, 1H), 5.59 (br s, 1H), 5.78 (ddt, J = 17.2 Hz, J = 10.2 Hz, J = 5.7 Hz, 1H),
7.19–7.29 (m, 5H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.06 (CH3), 23.63
(CH2), 33.01 (CH2), 36.23 (CH2), 41.86 (CH2), 51.53 (CH), 60.75 (CH2), 116.33
(CH2), 127.20 (CH), 127.80 (2 CH), 128.58 (2 CH), 134.21 (CH), 138.89 (C), 172.16
(C), 173.83 (C) ppm. IR (ATR): nu(tilde) = 3288 (w), 2929 (w), 1731 (vs), 1642 (vs),
1547 (s), 1457 (m), 1372 (m), 1269 (m), 1174 (s), 1152 (vs), 1026 (m), 920 (m), 734
19
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+
(m), 700 (vs) cm–1. HR-MS (EI, 70 eV): calcd. 289.1672 (for C17H23NO3 ), found
289.1669 [M+]. C17H23NO3 (289.38 g mol–1).
Ethyl 1-(2-ethoxyethyl)-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carbox-
ylate (18f). According to GPB, β-oxoester 20a (179 mg, 500 µmol), K3PO4 (212 mg,
1.00 mmol) and CuI (14 mg, 75 µmol) were converted with 2-ethoxyethylamine (0.5
mL). The crude product was purified by column chromatography (SiO2, hex-
anes/MTBE 5:1) to yield the benzazocinone 18f (60 mg, 0.19 mmol, 38%, Rf = 0.26)
as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ = 1.12 (t, J = 7.0 Hz, 3H), 1.17 (t, J =
7.1 Hz, 3H), 1.53 (dddd, J = 14.3 Hz, J = 12.3 Hz, J = 11.1 Hz, J = 5.6 Hz, 1H), 1.75–
1.95 (m, 3H), 2.24 (dd, J = 11.4 Hz, J = 8.1 Hz, 1H), 2.44–2.48 (m, 1H), 3.41–3.47
(m, 2H), 3.50 (ddd, J = 9.2 Hz, J = 5.9 Hz, J = 4.4 Hz, 1H), 3.53–3.57 (m, 1H), 3.61
(ddd, J = 9.2 Hz, J = 7.6 Hz, J = 5.5 Hz, 1H), 3.67 (dd, J = 11.1 Hz, J = 1.0 Hz, 1H),
4.08–4.18 (m, 2H), 4.49 (ddd, J = 13.4 Hz, J = 7.6 Hz, J = 5.9 Hz, 1H), 7.29–7.31 (m,
3H), 7.31–7.35 (m, 1H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.02 (CH3), 15.01
(CH3), 24.34 (CH2), 32.14 (CH2), 33.06 (CH2), 44.54 (CH), 48.44 (CH2), 60.84 (CH2),
66.11 (CH2), 66.68 (CH2), 126.10 (CH), 127.05 (CH), 128.05 (CH), 128.47 (CH),
139.15 (C), 140.74 (C), 173.95 (C), 174.36 (C) ppm. IR (ATR): nu(tilde) = 2972 (w),
2942 (w), 2864 (w), 1730 (s), 1653 (vs), 1494 (m), 1454 (m), 1392 (m), 1300 (m),
1225 (m), 1186 (m), 1113 (s), 1045 (m), 1026 (m), 766 (m), 735 (m) cm–1. HR-MS
+
(EI, 70 eV): calcd. 319.1778 (for C18H25NO4 ), found 319.1772 [M+]. C18H25NO4
(319.40 g mol–1).
Ethyl 2,3,4,4a-tetrahydrodibenzofuran-4a-carboxylate (23b). According to GPB,
β-oxoester 20b (105 mg, 279 µmol), K3PO4 (178 mg, 837 µmol) and CuI (8 mg, 0.04
mmol) were converted in n-butylamine (0.5 mL) to yield the title compound 23b (29
mg, 0.12 mmol, 43%) after chromatography (SiO2, hexanes/MTBE 20:1, Rf = 0.23) as
a colorless oil. 1H-NMR (500 MHz, CDCl3): δ = 1.16 (t, J = 7.1 Hz, 3H), 1.57–1.64 (m,
2H), 1.86–1.90 (m, 1H), 2.19–2.31 (m, 2H), 2.83 (dd, J = 8.6 Hz, J = 3.1 Hz, 1H),
4.11 (q, J = 7.1 Hz, 2H), 5.31 (t, J = 3.8 Hz, 1H), 6.91–6.96 (m, 2H), 7.20 (td, J = 7.9
13
Hz, J = 1.2 Hz, 1H), 7.31 (dd, J = 7.4 Hz, J = 0.8 Hz, 1H) ppm. C{1H}-NMR (125
MHz, CDCl3,): δ = 13.96 (CH3), 19.03 (CH2), 21.97 (CH2), 29.84 (CH2), 54.13 (C),
61.46 (CH2), 99.97 (CH), 109.80 (CH), 121.78 (CH), 124.05 (CH), 128.62 (C), 129.32
(CH), 155.61 (C), 157.87 (C), 171.66 (C) ppm. IR (ATR): nu(tilde) = 2981 (w), 2936
20
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(w), 2916 (w), 1728 (vs), 1609 (w), 1596 (w), 1472 (m), 1461 (s), 1223 (vs), 1174 (m),
1157 (m), 1128 (m), 1102 (m), 1087 (vs), 1072 (m), 1022 (m), 751 (s) cm–1. HR-MS
+
(ESI): calcd. 251.1254 (for C15H16LiO3 ), found 251.1251 [M + Li+]. C15H16O3 (244.29
g mol–1).
Methyl
8,9,10,10a-tetrahydro-7H-cyclohepta[b]benzofuran-10a-carboxylate
(23c). According to GPB, β-oxoester 20c (105 mg, 279 µmol), K3PO4 (178 mg, 837
µmol) and CuI (8 mg, 0.04 mmol) were converted in benzylamine (0.5 mL) to yield
the title compound 23c (12 mg, 49 µmol, 18%) after chromatography (SiO2, hex-
1
anes/MTBE 20:1, Rf = 0.21) as a colorless solid, mp 75 °C. H-NMR (500 MHz,
CDCl3): δ = 1.38–1.47 (m, 1H), 1.68–1.80 (m, 3H), 2.04–2.10 (m, 1H), 2.12–2.16 (m,
2H), 2.59–2.63 (m, 1H), 3.73 (s, 3H), 5.66 (dd, J = 7.5 Hz, J = 6.5 Hz, 1H), 6.85 (d, J
= 8.0 Hz, 1H), 6.93 (td, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.20 (td, J = 8.0 Hz, J = 1.4 Hz,
1H), 7.27 (dd, J = 7.2 Hz, J = 1.1 Hz, 1H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ =
24.55 (CH2), 27.52 (CH2), 28.85 (CH2), 35.45 (CH2), 52.78 (CH3), 58.75 (C), 104.59
(CH), 109.47 (CH), 121.60 (CH), 123.81 (CH), 129.46 (CH), 129.57 (C), 156.98 (C),
159.98 (C), 171.15 (C) ppm. IR (ATR): nu(tilde) = 2926 (m), 2851 (w), 1732 (vs),
1701 (m), 1597 (m), 1476 (s), 1463 (s), 1237 (vs), 1221 (vs), 1158 (m), 1137 (m),
1093 (m), 1073 (m), 1057 (m), 999 (m), 820 (m), 749 (vs) cm–1. HR-MS (ESI): calcd.
+
251.1254 (for C15H16LiO3 ), found 251.1257 [M + Li+]. C15H16O3 (244.29 g mol–1).
N-Debenzylation of benzazocinone 18a. A suspension of 10% Pd/C (883 mg, 830
µmol) and benzazocinone 18a (560 mg, 1.66 mmol) in iPrOH (8 mL) was stirred at 50
°C for 2 d under an atmosphere of hydrogen (1 bar). The mixture was then filtered
and the solvent was removed in vacuo. The mixture was submitted to column chro-
matography (SiO2, hexanes/MTBE 1:5) to yield in the first fraction benzazocinone
18h (59 mg, 0.17 mmol, 10%, Rf = 0.40) as a colorless oil. Secondly, benzazocinone
18g (324 mg, 1.31 mmol, 79%, Rf = 0.16) was obtained as a colorless solid, mp 95–
100 °C.
1
Ethyl 2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18g). H-NMR
(500 MHz, CDCl3): δ = 1.18 (t, J = 7.1 Hz, 3H), 1.58–1.67 (m, 1H), 1.73–1.82 (m,
1H), 1.93–1.98 (m, 2H), 2.29–2.33 (m, 1H), 2.50–2.53 (m, 1H), 3.71 (d, J = 10.8 Hz,
1H), 4.09–4.19 (m, 2H), 7.16–7.18 (m, 1H), 7.26–7.32 (m, 2H), 7.35–7.36 (m, 1H),
21
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8.29 (s, 1H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.00 (CH3), 23.65 (CH2),
32.14 (CH2), 32.51 (CH2), 45.02 (CH), 60.95 (CH2), 125.68 (CH), 127.14 (CH),
127.84 (CH), 128.24 (CH), 135.52 (C), 137.55 (C), 173.92 (C), 176.67 (C) ppm. IR
(ATR): nu(tilde) = 3189 (w), 2945 (w), 1727 (s), 1659 (vs), 1495 (m), 1443 (m), 1390
(m), 1371 (m), 1301 (m), 1222 (m), 1185 (s), 1142 (m), 1096 (m), 1048 (m), 1017
+
(m), 764 (s), 734 (m) cm–1. HR-MS (EI, 70 eV): calcd. 247.1203 (for C14H17NO3 ),
found 247.1196 [M+]. C14H17NO3 (247.29 g mol–1).
Ethyl 1-(cyclohexylmethyl)-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-car-
1
boxylate (18h). H-NMR (500 MHz, CDCl3): δ = 1.05–1.19 (m, 4H), 1.17 (t, J = 7.1
Hz, 3H), 1.51–1.71 (m, 7H), 1.80–1.86 (m, 3H), 1.90–1.96 (m, 1H), 2.23 (dd, J = 11.1
Hz, J = 8.1 Hz, 1H), 2.43–2.46 (m, 1H), 3.22 (dd, J = 13.5 Hz, J = 5.2 Hz, 1H), 3.63
(d, J = 10.7 Hz, 1H), 4.06–4.21 (m, 3H), 7.20–7.22 (m, 1H), 7.27–7.31 (m, 2H), 7.33–
13
7.36 (m, 1H) ppm. C{1H}-NMR (125 MHz, CDCl3): δ = 14.12 (CH3), 24.27 (CH2),
25.80 (CH2), 26.00 (CH2), 26.25 (CH2), 31.51 (CH2), 31.91 (CH2), 32.16 (CH2), 33.26
(CH2), 36.82 (CH), 44.81 (CH), 55.38 (CH2), 60.91 (CH2), 125.52 (CH), 126.99 (CH),
128.02 (CH), 128.20 (CH), 138.68 (C), 141.46 (C), 173.93 (C), 174.43 (C) ppm. IR
(ATR): nu(tilde) = 2924 (m), 2851 (w), 1732 (vs), 1652 (vs), 1493 (m), 1450 (m), 1395
(m), 1299 (m), 1224 (m), 1183 (m), 1150 (m), 1097 (m), 1048 (m), 1025 (m), 764 (m),
+
735 (m) cm–1. HR-MS (EI, 70 eV): calcd. 343.2142 (for C21H29NO3 ), found 343.2152
[M+]. C21H29NO3 (343.47 g mol–1).
General procedure C (GPC) for the N-alkylation of benzazocinone 18g. Under
exclusion of air and moisture (nitrogen atmosphere) and at –78 °C, nBuLi (2.5 mol L–
1
in hexanes, 1.05 equiv) was added dropwise to a stirred solution of diisopropyl-
amine (1.05 equiv) in abs. THF (3 L mol–1). After stirring this mixture for 15 min at –
78 °C, a solution of benzazocinone 18g (1.00 equiv) in abs. THF (2 L mol–1) was ad-
ded and the resulting mixture was further stirred at –78 °C for 30 min. The alkyl bro-
mide (1.05 eq) was then added and the resulting mixture was stirred at –78 °C for 1.5
h and for further 2 h at ambient temperature. Subsequently, the mixture was diluted
with hydrochloric acid (1 mol L–1, 4 L mol–1) and extracted with MTBE (3 x 4 L mol–1).
The combined organic layers were dried (MgSO4), filtered and the solvent was
removed in vacuo. The crude product was purified by column chromatography to
yield benzazocinones 18e, 18i–18k.
22
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Ethyl 1-allyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18e).
According to GPC, benzazocinone 18g (124 mg, 500 µmol), nBuLi (0.21 mL, 2.5 mol
L–1 in hexanes, 0.53 mmol) and iPr2NH (54 mg, 0.53 mmol) were converted with allyl
bromide (64 mg, 0.53 mmol) to yield in the first fraction the title compound 18e (34
mg, 0.12 mmol, 24%, Rf = 0.39) after chromatography (SiO2, hexanes/MTBE 1:5) as
a colorless oil. Secondly, starting material 18g (60 mg, 0.24 mmol, 48%, Rf = 0.16)
was recovered in another fraction.
Ethyl 2-oxo-1-prenyl-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylate (18i).
According to GPC, benzazocinone 18g (124 mg, 500 µmol), nBuLi (0.21 mL, 2.5 mol
L–1 in hexanes, 0.53 mmol) and iPr2NH (54 mg, 0.53 mmol) were converted with
prenyl bromide (79 mg, 0.53 mmol) to yield the title compound 18i (119 mg, 377
µmol, 75%) after chromatography (SiO2, hexanes/MTBE 1:5, Rf = 0.43) as a color-
1
less oil. H-NMR (500 MHz, CDCl3): δ = 1.15 (t, J = 7.1 Hz, 3H), 1.46–1.55 (m, 1H),
1.49 (s, 3H), 1.61 (s, 3H), 1.72–1.91 (m, 3H), 2.21 (dd, J = 11.1 Hz, J = 7.9 Hz, 1H),
2.40 (dd, J = 13.5 Hz, J = 4.7 Hz, 1H), 3.51 (d, J = 11.2 Hz, 1H), 3.97 (dd, J = 14.4
Hz, J = 7.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.85 (dd, J = 14.4 Hz, J = 7.3 Hz, 1H),
5.24 (t, J = 7.3 Hz, 1H), 7.19–7.22 (m, 1H), 7.24–7.27 (m, 2H), 7.29–7.32 (m, 1H)
ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.08 (CH3), 17.69 (CH3), 24.24 (CH2),
25.58 (CH3), 32.14 (CH2), 32.99 (CH2), 44.75 (CH), 46.51 (CH2), 60.76 (CH2), 118.14
(CH), 126.01 (CH), 126.80 (CH), 127.86 (CH), 128.35 (CH), 136.63 (C), 139.10 (C),
140.55 (C), 173.52 (C), 173.95 (C) ppm. IR (ATR): nu(tilde) = 2924 (w), 1733 (s),
1652 (s), 1495 (m), 1456 (m), 1445 (m), 1395 (m), 1297 (m), 1227 (m), 1184 (s),
1149 (m), 1099 (m), 1049 (m), 1027 (m), 769 (m), 738 (m) cm–1. HR-MS (EI, 70 eV):
+
calcd. 315.1829 (for C19H25NO3 ), found 315.1835 [M+]. C19H25NO3 (315.41 g mol–1).
Ethyl
[1-(methoxycarbonyl)methyl]-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azo-
cine-6-carboxylate (18j). According to GPC, benzazocinone 18g (124 mg, 500
µmol), nBuLi (0.21 mL, 2.5 mol L–1 in hexanes, 0.53 mmol) and iPr2NH (54 mg, 0.53
mmol) were converted with methyl bromoacetate (81 mg, 0.53 mmol) to yield the title
compound 18j (126 mg, 395 µmol, 79%) after chromatography (SiO2, hexanes/MTBE
1:5, Rf = 0.28) as a colorless solid, mp 100–104 °C. 1H-NMR (500 MHz, CDCl3): δ =
1.16 (t, J = 7.1 Hz, 3H), 1.53 (dddd, J = 14.3 Hz, J = 12.9 Hz, J = 11.1 Hz, J = 5.4 Hz,
23
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1H), 1.80 (td, J = 12.9 Hz, J = 5.4 Hz, 1H), 1.88–1.95 (m, 2H), 2.27 (dd, J = 12.3 Hz,
J = 8.2 Hz, 1H), 2.47 (dd, J = 14.3 Hz, J = 5.4 Hz, 1H), 3.71 (s, 3H), 4.01 (dd, J =
11.1 Hz, J = 0.9 Hz, 1H), 4.06–4.17 (m, 2H), 4.35 (d, J = 17.0 Hz, 1H), 4.58 (d, J =
13
17.0 Hz, 1H), 7.24–7.30 (m, 3H), 7.33–7.35 (m, 1H) ppm. C{1H}-NMR (125 MHz,
CDCl3): δ = 13.94 (CH3), 24.19 (CH2), 32.15 (CH2), 32.53 (CH2), 44.44 (CH), 50.98
(CH2), 52.07 (CH3), 60.78 (CH2), 125.28 (CH), 127.49 (CH), 128.12 (CH), 128.68
(CH), 138.71 (C), 140.83 (C), 169.28 (C), 173.87 (C), 174.31 (C) ppm. IR (ATR):
nu(tilde) = 2973 (w), 2952 (w), 1757 (s), 1716 (vs), 1649 (vs), 1496 (m), 1441 (m),
1384 (m), 1220 (s), 1196 (vs), 1095 (m), 1025 (m), 977 (m), 781 (m), 742 (m), 722
+
(m) cm–1. HR-MS (EI, 70 eV): calcd. 319.1414 (for C17H21NO5 ), found 319.1426 [M+].
C17H21NO5 (319.36 g mol–1).
Ethyl 1-[1-(ethoxycarbonyl)ethyl]-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-
6-carboxylate (18k). According to GPC, benzazocinone 18g (124 mg, 500 µmol) in
abs. THF (1 mL), nBuLi (0.21 mL, 2.5 mol L–1 in hexanes, 0.53 mmol) and iPr2NH (54
mg, 0.53 mmol) were converted with ethyl 2-bromopropionate (96 mg, 0.53 mmol) to
yield in a first fraction the title compound 18k (59 mg, 0.17 mmol, 34%, Rf = 0.32)
after chromatography (SiO2, hexanes/EtOAc 1:1) as a colorless oil. The product 18k
1
was isolated as a mixture of two diastereomers (ratio 87:13 by H-NMR). In the se-
cond fraction, starting material 18g (45 mg, 0.18 mmol, 36%, Rf = 0.11) was recove-
1
red. H-NMR (500 MHz, CDCl3), major diastereomer: δ = 1.06–1.11 (m, 3H), 1.19–
1.25 (m, 6H), 1.42–1.53 (m, 1H), 1.65–1.77 (m, 1H), 1.80–1.89 (m, 2H), 2.18–2.23
(m, 1H), 2.35–2.39 (m, 1H), 3.64 (dd, J = 11.1 Hz, J = 6.5 Hz, 1H), 4.00–4.09 (m,
2H), 4.13–4.23 (m, 2H), 4.96–5.02 (m, 1H), 7.17–7.22 (m, 1H), 7.23–7.28 (m, 2H),
7.38–7.41 (m, 1H) ppm; minor diastereomer: δ = 1.06–1.11 (m, 3H), 1.19–1.25 (m,
3H), 1.42–1.53 (m, 4H), 1.65–1.89 (m, 3H), 2.11–2.17 (m, 1H), 2.35–2.39 (m, 1H),
3.74 (dd, J = 11.0 Hz, J = 6.7 Hz, 1H), 4.00–4.09 (m, 2H), 4.13–4.23 (m, 3H), 7.17–
7.22 (m, 1H), 7.23–7.28 (m, 3H) ppm. 13C{1H}-NMR (125 MHz, CDCl3), major diaste-
reomer: δ = 13.96 (CH3), 14.15 (CH3), 15.02 (CH3), 24.31 (CH2), 32.01 (CH2), 33.13
(CH2), 44.69 (CH), 54.86 (CH), 60.87 (CH2), 61.28 (CH2), 126.90 (2 CH), 127.81
(CH), 129.11 (CH), 138.45 (C), 139.88 (C), 172.20 (C), 173.76 (C), 174.26 (C) ppm;
minor diastereomer: δ = 13.96 (CH3), 14.30 (CH3), 14.91 (CH3), 24.13 (CH2), 32.05
(CH2), 33.06 (CH2), 44.80 (CH), 59.64 (CH), 60.91 (CH2), 61.20 (CH2), 126.53 (CH),
126.96 (CH), 128.21 (CH), 128.85 (CH), 139.27 (C), 140.46 (C), 171.01 (C), 173.41
24
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(C), 173.82 (C) ppm. IR (ATR): nu(tilde) = 2978 (w), 2941 (w), 1731 (vs), 1656 (vs),
1494 (m), 1452 (m), 1371 (m), 1303 (m), 1226 (m), 1186 (s), 1090 (m), 1049 (m),
1022 (m), 768 (m), 738 (m) cm–1. HR-MS (EI, 70 eV): calcd. 347.1727 (for
+
C19H25NO5 ), found 347.1734 [M+]. C19H25NO5 (347.41 g mol–1).
Ethyl (E)-1-[3-(methoxycarbonyl)-2-propenyl]-2-oxo-1,2,3,4,5,6-hexahydroben-
zo[b]azocine-6-carboxylate (18l). Methyl acrylate (215 mg, 2.50 mmol) and
catMETium RF {Benzylidenedichloro[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)-4-
imidazolin-2-ylidene](tricyclohexylphosphano)ruthenium(II)} (25 µmol, 22 mg) were
added to a solution of benzazocinone 18e (144 mg, 501 µmol) in degassed CH2Cl2
(1.5 mL) and the resulting mixture was stirred at 40 °C for 16 h. All volatile materials
were evaporated and the crude product was purified by column chromatography
(SiO2, hexanes/EtOAc 1:1) to yield the title compound 18l (76 mg, 0.22 mmol, 44%,
Rf = 0.27) as a colorless oil. As a second fraction, the starting material 18e (38 mg,
0.13 mmol, 26%, Rf = 0.35) was recovered. 1H-NMR (500 MHz, CDCl3): δ = 1.15 (t, J
= 7.1 Hz, 3H), 1.55 (dddd, J = 14.2 Hz, J = 12.4 Hz, J = 11.1 Hz, J = 5.6 Hz, 1H),
1.77–1.86 (m, 1H), 1.88–1.97 (m, 2H), 2.27–2.31 (m, 1H), 2.46 (dd, J = 14.2 Hz, J =
4.9 Hz, 1H), 3.46 (dd, J = 11.1 Hz, J = 0.8 Hz, 1H), 3.69 (s, 3H), 4.11 (q, J = 7.1 Hz,
2H), 4.32 (ddd, J = 15.4 Hz, J = 6.7 Hz, J = 1.1 Hz, 1H), 4.79 (ddd, J = 15.4 Hz, J =
6.4 Hz, J = 1.4 Hz, 1H), 5.92 (dt, J = 15.7 Hz, J = 1.3 Hz, 1H), 6.97 (dt, J = 15.7 Hz, J
13
= 6.5 Hz, 1H), 7.20–7.22 (m, 1H), 7.28–7.36 (m, 3H) ppm. C{1H}-NMR (125 MHz,
CDCl3): δ = 13.93 (CH3), 24.22 (CH2), 31.96 (CH2), 32.90 (CH2), 44.84 (CH), 49.98
(CH2), 51.49 (CH3), 60.98 (CH2), 123.88 (CH), 125.62 (CH), 127.20 (CH), 128.27
(CH), 128.92 (CH), 138.90 (C), 140.20 (C), 141.65 (CH), 166.13 (C), 173.60 (C),
174.10 (C) ppm. IR (ATR): nu(tilde) = 2949 (w), 1724 (vs), 1652 (vs), 1494 (m), 1454
(m), 1441 (m), 1390 (m), 1299 (m), 1276 (m), 1225 (m), 1185 (s), 1169 (s), 1150 (m),
1097 (m), 1045 (m), 1022 (m), 996 (m), 972 (m), 765 (m), 740 (m), 718 (m) cm–1.
+
HR-MS (EI, 70 eV): calcd. 345.1571 (for C19H23NO5 ), found 345.1566 [M+].
C19H23NO5 (345.40 g mol–1).
1-Benzyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylic acid (26). An
aqueous solution of NaOH (0.5 mol L–1, 40 mL) was added to a solution of benzazo-
cinone 18a (700 mg, 2.07 mmol) in EtOH (2 mL) and the resulting mixture was stirred
at 80 °C for 16 h. Subsequently, the mixture was acidified with hydrochloric acid (1
25
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10.1002/chem.201903139
Chemistry - A European Journal
mol L–1, 25 mL) and extracted with CH2Cl2 (3 x 30 mL). The combined organic layers
were dried (MgSO4), filtered and the solvent was removed in vacuo to yield the title
1
compound 26 (519 mg, 1.68 mmol, 81%) as a colorless solid, mp 166–170 °C. H-
NMR (500 MHz, CDCl3): δ = 1.51 (dddd, J = 14.1 Hz, J = 12.6 Hz, J = 11.0 Hz, J =
5.5 Hz, 1H), 1.77–1.86 (m, 1H), 1.90–1.97 (m, 2H), 2.40 (dd, J = 12.0 Hz, J = 8.2 Hz,
1H), 2.45 (dd, J = 14.1 Hz, J = 4.8 Hz, 1H), 3.29 (d, J = 11.0 Hz, 1H), 4.86 (d, J =
14.1 Hz, 1H), 5.17 (d, J = 14.1 Hz, 1H), 7.15 (dd, J = 7.8 Hz, J = 1.0 Hz, 1H), 7.21–
7.30 (m, 6H), 7.33 (td, J = 7.8 Hz, J = 1.4 Hz, 1H), 7.42 (dd, J = 7.8 Hz, J = 1.3 Hz,
13
1H), 10.45 (br s, 1H) ppm. C{1H}-NMR (125 MHz, CDCl3): δ = 24.18 (CH2), 31.90
(CH2), 32.78 (CH2), 44.59 (CH), 52.87 (CH2), 125.86 (CH), 127.46 (CH), 127.50
(CH), 128.02 (CH), 128.46 (2 CH), 128.74 (CH), 129.03 (2 CH), 136.27 (C), 138.57
(C), 140.36 (C), 174.68 (C), 177.26 (C) ppm. IR (ATR): nu(tilde) = 3044 (m), 2946
(m), 1728 (vs), 1625 (vs), 1598 (s), 1496 (m), 1456 (m), 1441 (m), 1411 (m), 1287
(m), 1224 (m), 1173 (s), 1145 (m), 781 (m), 761 (m), 722 (m), 701 (s), 681 (m), 640
+
(m) cm–1. HR-MS (EI, 70 eV): calcd. 309.1359 (for C19H19NO3 ), found 309.1368 [M+].
C19H19NO3 (309.37 g mol–1). The compound was reported in the literature before, but
insufficiently characterized.[14b]
General procedure D (GPD) for the amide coupling of benzazocinone 26. HATU
(1.1 equiv) and DIPEA (1.1–2.2 equiv) were added to a stirred solution of benzazoci-
none 26 (1.0 equiv) and the primary amine (1.5 equiv) in CH2Cl2 (5 L mol–1) and the
resulting mixture was stirred at ambient temperature for 16 h. Subsequently, the mix-
ture was washed with water (1 x 10 L mol–1), sat. aq. NaHCO3 solution (1 x 10 L mol–
1) and brine (1 x 10 L mol–1). The organic layer was dried (MgSO4), filtered and the
solvent was removed in vacuo. The crude product was purified by column chromato-
graphy to yield benzazocinones 27a–27c.
1-Benzyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylic acid N-[1-
methyl-1-(ethoxycarbonyl)ethyl]amide (27a). According to GPD, HATU (209 mg,
550 µmol), DIPEA (71 mg, 0.55 mmol) and ethyl 2-aminoisobutyrate (98 mg, 0.75
mmol) were converted with benzazocinone 26 (154 mg, 500 µmol) to yield the title
compound 27a (183 mg, 433 µmol, 87%) after chromatography (SiO2, hex-
anes/MTBE 1:7, Rf = 0.28) as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ = 1.14 (s,
3H), 1.19 (t, J = 7.1 Hz, 3H), 1.22 (s, 3H), 1.28–1.38 (m, 1H), 1.69–1.76 (m, 1H), 1.84
26
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10.1002/chem.201903139
Chemistry - A European Journal
(t, J = 12.4 Hz, 1H), 1.87–1.93 (m, 1H), 2.27–2.34 (m, 2H), 2.72 (d, J = 10.8 Hz, 1H),
4.04–4.13 (m, 3H), 4.16 (d, J = 13.9 Hz, 1H), 5.94 (d, J = 13.9 Hz, 1H), 7.22–7.28 (m,
13
6H), 7.32 (d, J = 4.0 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H) ppm. C{1H}-NMR (125 MHz,
CDCl3): δ = 13.98 (CH3), 24.38 (CH2), 24.82 (CH3), 24.84 (CH3), 31.94 (CH2), 33.06
(CH2), 44.93 (CH), 51.98 (CH2), 55.64 (C), 60.93 (CH2), 125.60 (CH), 127.85 (CH),
128.07 (CH), 128.13 (CH), 128.52 (CH), 128.64 (2 CH), 129.26 (2 CH), 137.00 (C),
139.48 (C), 139.57 (C), 171.91 (C), 173.55 (C), 173.86 (C) ppm. IR (ATR): nu(tilde) =
3410 (w), 2983 (w), 2938 (w), 1737 (s), 1676 (s), 1651 (s), 1493 (s), 1452 (s), 1393
(m), 1383 (m), 1276 (s), 1234 (m), 1214 (m), 1193 (m), 1174 (s), 1148 (vs), 1029 (m),
920 (m), 759 (s), 733 (s), 705 (s), 635 (m) cm–1. HR-MS (EI, 70 eV): calcd. 422.2200
+
(for C25H30N2O4 ), found 422.2196 [M+]. C25H30N2O4 (422.53 g mol–1).
1-Benzyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylic acid N-[2-
(ethoxycarbonyl)ethyl]amide (27b). According to GPD, HATU (209 mg, 550 µmol),
DIPEA (142 mg, 1.10 mmol) and β-alanine ethyl ester-hydrochloride (115 mg, 749
µmol) were converted with benzazocinone 26 (154 mg, 500 µmol) to yield the title
compound 27b (173 mg, 424 µmol, 85%) after chromatography (SiO2, hex-
anes/EtOAc 1:3, Rf = 0.33) as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ = 1.20 (t,
J = 7.1 Hz, 3H), 1.37 (dddd, J = 14.3 Hz, J = 12.6 Hz, J = 10.9 Hz, J = 5.5 Hz, 1H),
1.73 (dtdd, J = 14.6 Hz, J = 12.7 Hz, J = 5.5 Hz, J = 1.8 Hz, 1H), 1.83–1.93 (m, 2H),
2.26–2.32 (m, 4H), 2.57 (dd, J = 10.9 Hz, J = 0.9 Hz, 1H), 2.98 (dq, J = 13.1 Hz, J =
7.0 Hz, 1H), 3.18 (dq, J = 13.1 Hz, J = 6.6 Hz, 1H), 3.62 (br t, J = 5.8 Hz, 1H), 3.99–
4.09 (m, 2H), 4.13 (d, J = 13.7 Hz, 1H), 6.00 (d, J = 13.7 Hz, 1H), 7.22–7.27 (m, 4H),
7.28–7.31 (m, 3H), 7.31–7.36 (m, 2H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ =
14.14 (CH3), 24.42 (CH2), 31.54 (CH2), 33.11 (CH2), 33.70 (CH2), 35.11 (CH2), 45.19
(CH), 51.93 (CH2), 60.38 (CH2), 125.76 (CH), 127.20 (CH), 127.77 (CH), 128.09
(CH), 128.76 (CH), 128.83 (2 CH), 129.99 (2 CH), 136.79 (C), 139.22 (C), 140.20
(C), 171.43 (C), 172.98 (C), 173.79 (C) ppm. IR (ATR): nu(tilde) = 3412 (w), 3031
(w), 2939 (w), 2865 (w), 1731 (s), 1675 (s), 1650 (vs), 1513 (m), 1492 (m), 1452 (m),
1393 (m), 1181 (s), 1152 (m), 844 (m), 759 (m), 735 (m), 705 (s), 634 (m) cm–1. HR-
+
MS (EI, 70 eV): calcd. 408.2044 (for C24H28N2O4 ), found 408.2039 [M+]. C24H28N2O4
(408.50 g mol–1).
27
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10.1002/chem.201903139
Chemistry - A European Journal
1-Benzyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxylic
acid
N-
(2,2,2-trifluoroethyl)amide (27c). According to GPD, HATU (209 mg, 550 µmol),
DIPEA (71 mg, 0.55 mmol) and 2,2,2-trifluoroethylamine (74 mg, 0.75 mmol) were
converted with benzazocinone 26 (154 mg, 500 µmol) to yield the title compound 27c
(172 mg, 441 µmol, 88%) after chromatography (SiO2, hexanes/EtOAc 1:1, Rf = 0.29)
as a colorless solid, mp 127–128 °C. 1H-NMR (500 MHz, CDCl3): δ = 1.40 (dddd, J =
14.4 Hz, J = 12.8 Hz, J = 10.9 Hz, J = 5.5 Hz, 1H), 1.70–1.79 (m, 1H), 1.85–1.94 (m,
2H), 2.30–2.34 (m, 2H), 2.65 (dd, J = 10.9 Hz, J = 0.9 Hz, 1H), 3.25 (dqd, J = 14.8
Hz, J = 9.0 Hz, J = 5.8 Hz, 1H), 3.42 (br t, J = 6.6 Hz, 1H), 3.67 (dqd, J = 14.8 Hz, J =
9.1 Hz, J = 7.5 Hz, 1H), 4.09 (d, J = 13.7 Hz, 1H), 6.08 (d, J = 13.7 Hz, 1H), 7.21 (dd,
J = 7.9 Hz, J = 1.1 Hz, 1H), 7.25–7.28 (m, 6H), 7.35–7.40 (m, 2H) ppm. 13C{1H}-NMR
2
(125 MHz, CDCl3): δ = 24.31 (CH2), 31.45 (CH2), 33.06 (CH2), 40.20 (q, JCF = 34.8
1
Hz, CH2), 45.23 (CH), 51.79 (CH2), 123.68 (q, JCF = 279.1 Hz, C), 125.83 (CH),
127.16 (CH), 127.57 (CH), 128.47 (CH), 128.83 (2 CH), 128.92 (CH), 130.09 (2 CH),
19
136.87 (C), 139.08 (C), 139.30 (C), 173.08 (C), 173.64 (C) ppm. F{1H}-NMR (470
MHz, CDCl3): δ = –72.10 (s, CF3) ppm. IR (ATR): nu(tilde) = 3410 (m), 2969 (w),
2948 (w), 2865 (w), 1690 (s), 1644 (vs), 1598 (m), 1514 (m), 1493 (m), 1454 (m),
1438 (m), 1392 (s), 1276 (s), 1228 (m), 1195 (m), 1162 (s), 1144 (vs), 1083 (m), 989
(m), 833 (m), 780 (m), 764 (s), 733 (s), 711 (s), 664 (m), 633 (s) cm–1. HR-MS (EI, 70
+
eV): calcd. 390.1550 (for C21H21F3N2O2 ), found 390.1541 [M+]. C21H21F3N2O2
(390.41 g mol–1).
1-Benzyl-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azocine-6-carboxamide
(27d).
Pyridine (142 mg, 1.80 mmol) and Boc2O (327 mg, 1.50 mmol) were added to a solu-
tion of benzazocinone 26 (309 mg, 1.00 mmol) in 1,4-dioxane (2 mL) and the resul-
ting mixture was stirred at ambient temperature for 30 min. Then (NH4)2CO3 (269 mg,
2.80 mmol) was added and the reaction mixture was stirred at ambient temperature
for 16 h. Subsequently, H2O (5 mL) and MTBE (5 mL) were added and the crude pro-
duct 27d precipitated. It was filtered off, washed with MTBE (3 x 5 mL) and dried in
vacuum to yield the title compound 27d (216 mg, 700 µmol, 70%) as a colorless so-
1
lid, mp 225–227 °C. H-NMR (500 MHz, CDCl3): δ = 1.39 (dddd, J = 14.3 Hz, J =
12.7 Hz, J = 10.8 Hz, J = 5.5 Hz, 1H), 1.72–1.82 (m, 1H), 1.87–1.96 (m, 2H), 2.30–
2.35 (m, 2H), 2.72 (d, J = 10.8 Hz, 1H), 3.32 (br s, 1H), 4.16 (d, J = 13.7 Hz, 1H),
4.89 (br s, 1H), 6.05 (d, J = 13.7 Hz, 1H), 7.25–7.30 (m, 6H), 7.36–7.40 (m, 3H) ppm.
28
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10.1002/chem.201903139
Chemistry - A European Journal
13C{1H}-NMR (125 MHz, CDCl3): δ = 24.42 (CH2), 31.56 (CH2), 33.12 (CH2), 44.66
(CH), 51.88 (CH2), 125.74 (CH), 127.27 (CH), 127.86 (CH), 128.24 (CH), 128.84 (3
CH), 129.93 (2 CH), 136.82 (C), 139.19 (C), 139.85 (C), 173.77 (C), 175.13 (C) ppm.
IR (ATR): nu(tilde) = 3318 (m), 3132 (m), 2963 (w), 2928 (w), 1673 (s), 1628 (vs),
1595 (m), 1488 (m), 1450 (m), 1443 (m), 1427 (m), 1411 (m), 1392 (s), 1356 (m),
1333 (m), 1230 (m), 1203 (m), 1157 (m), 1020 (m), 994 (m), 776 (m), 759 (s), 727
(m), 715 (m), 694 (m), 670 (m), 637 (m), 579 (s) cm–1. HR-MS (EI, 70 eV): calcd.
+
308.1519 (for C19H20N2O2 ), found 308.1511 [M+]. C19H20N2O2 (308.38 g mol–1).
1-Benzyl-6-[(methoxycarbonyl)amino]-2-oxo-1,2,3,4,5,6-hexahydrobenzo[b]azo-
cine (28). A solution of KOH (68 mg, 1.21 mmol) in MeOH (1 mL) was added at 0 °C
to a solution of benzazocinone 27d (150 mg, 486 µmol) and PhI(OAc)2 (157 mg, 487
µmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at 0 °C for 15 min and for
further 16 h at ambient temperature. Subsequently, the reaction mixture was diluted
with water (5 mL) and the aqueous layer was extracted with CH2Cl2 (3 x 5 mL). The
combined organic layers were dried (MgSO4), filtered and the solvent was removed
in vacuo. The crude product was purified by column chromatography (SiO2, hexa-
nes/EtOAc/MeOH 1:1:0.1) to yield the title compound 28 (50 mg, 0.15 mmol, 30%, Rf
= 0.30) as a colorless solid, mp 114–130 °C. NMR spectra showed doubled and
broadened signal sets due to E/Z-isomers (ratio 1:0.15) at the carbamate C-N-bond.
1H-NMR (500 MHz, CDCl3), major isomer: δ = 1.60 (qd, J = 12.1 Hz, J = 5.6 Hz, 1H),
1.87–2.07 (m, 3H), 2.11–2.14 (m, 1H), 2.29–2.34 (m, 1H), 3.60 (s, 3H), 4.38 (br s,
1H), 4.56 (br d, J = 14.5 Hz, 1H), 5.25 (br d, J = 4.6 Hz, 1H), 5.40 (br s, 1H), 6.87 (br
d, J = 6.0 Hz, 1H), 7.15 (br t, J = 7.2 Hz, 1H), 7.22–7.34 (m, 6H), 7.39 (dd, J = 7.9
Hz, J = 1.4 Hz, 1H) ppm; minor isomer: δ = 1.73 (ddt, J = 14.3 Hz, J = 10.0 Hz, J =
4.2 Hz, 1H), 1.78–1.84 (m, 1H), 1.87–2.07 (m, 2H), 2.18 (dd, J = 11.9 Hz, J = 4.3 Hz,
1H), 2.29–2.34 (m, 1H), 3.58 (s, 3H), 4.80 (d, J = 14.2 Hz, 1H), 4.95–4.99 (m, 1H),
5.02 (d, J = 14.2 Hz, 1H), 7.01 (dd, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.22–7.34 (m, 8H)
13
ppm; a signal for the NH proton was not observed. C{1H}-NMR (125 MHz, CDCl3),
major isomer: δ = 23.65 (CH2), 32.72 (CH2), 36.43 (CH2), 50.51 (CH), 52.06 (CH3),
52.40 (CH2), 125.25 (CH), 126.15 (CH), 127.27 (CH), 127.67 (CH), 128.37 (2 CH),
128.86 (CH), 128.88 (2 CH), 137.53 (C), 139.87 (C), 141.94 (C), 155.78 (C), 174.04
(C) ppm; minor isomer: δ = 20.80 (CH2), 31.98 (CH2), 32.16 (CH2), 51.97 (CH3),
52.43 (CH2), 54.86 (CH), 127.32 (CH), 127.87 (CH), 128.33 (CH), 128.57 (CH),
29
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