Preparation of new 1,4-diazocanes as scaffolds for combinatorial chemistry

Article abstract of DOI:10.1002/ejoc.201101645

Hexahydro-2-oxo-1,4-diazocin-6-carboxylic acid constitutes a conformationally rigid, crown-shaped scaffold. An orthogonally protected (Boc at N-4 and methyl ester at 6-CO₂H) representative was prepared by ring expansion of a 3-pyrrolidone-derived 1,4-diketone with MeNH₂. After deprotection, this building block was further diversified by reductive aminations and amidations and by sulfonamide and urea formation. Furthermore, the 6-CO₂H function was transformed into a 6-NHCbz group in one step by carboxamide degradation in the presence of BnOH. An example of a cyclic tripeptoidic structure was synthesized by amidation with N-Boc-β-alanine and glycine methyl ester. Structural features of the eight-membered heterocycle were established by single-crystal X-ray structure analysis of a 4-bromoaniline derivative.

Full text of DOI:10.1002/ejoc.201101645

FULL PAPER
DOI: 10.1002/ejoc.201101645
Preparation of New 1,4-Diazocanes as Scaffolds for Combinatorial Chemistry
Miriam Penning[a] and Jens Christoffers*[a]
Keywords: Combinatorial chemistry / Nitrogen heterocycles / Amides / Building blocks
Hexahydro-2-oxo-1,4-diazocin-6-carboxylic acid constitutes
a conformationally rigid, crown-shaped scaffold. An orthogo-
nally protected (Boc at N-4 and methyl ester at 6-CO2H) rep-
resentative was prepared by ring expansion of a 3-pyrrol-
idone-derived 1,4-diketone with MeNH2. After deprotection,
this building block was further diversified by reductive amin-
ations and amidations and by sulfonamide and urea forma-
tion. Furthermore, the 6-CO2H function was transformed into
a 6-NHCbz group in one step by carboxamide degradation
in the presence of BnOH. An example of a cyclic tripeptoidic
structure was synthesized by amidation with N-Boc-β-ala-
nine and glycine methyl ester. Structural features of the
eight-membered heterocycle were established by single-
crystal X-ray structure analysis of a 4-bromoaniline deriva-
tive.
Introduction
Benzodiazocines are higher homologues of the famous
benzodiazepine motif[1] and are therefore well precedented
in the literature.[2] In contrast, the monocyclic diazocane
ring system has rarely been mentioned in the recent litera-
ture. In one case, 1,4-diazocane derivatives were prepared
by ring-closing metathesis and were then used as scaffolds
for combinatorial library synthesis.[3] Nucleophilic ring
opening of aziridines also provides synthetic access to 1,4-
diazocane building blocks.[4] Several cyclic peptides con-
taining 1,4-diazocane moieties can also be found in the lit-
erature, either as natural products[5] or as artificial peptide
loops mimicking bioactive conformations or local folding
of peptides and proteins.[6]
Scheme 1. Preparation of a model library of eight-membered-ring
lactams 4 from 1,4-diketones 1 and primary amines RA–NH2 and
RC–NH2.
We have recently discovered a bismuth-catalyzed [with
Bi(NO3)3·5H2O as precatalyst] transformation of 1,4-di-
ketones 1 (Scheme 1) with primary amines furnishing eight-
Furthermore, we have also converted tetrahydrothio-
membered ring lactams – hexahydroazocinones 2 – with po- phene derivatives 5 (X = S, Scheme 2) in corresponding bis-
tential as new scaffolds for combinatorial chemistry.[7] This muth-catalyzed ring-expansion reactions to form eight-
transformation was consequently used for the preparation membered ring lactams 7, each containing an additional
of a library of more than thousand amides 4 with three sulfur heteroatom.[10] These lactams 7 have meanwhile been
points of diversification (RA, RB, and RC).[8] Aromatic resi- used for the preparation of a combinatorial library con-
due RB originated from the starting material 1. After ring sisting of more than one hundred thiazocinones. Unlike in
expansion, the ester moieties were saponified and amidated the case of these sulfur heterocycles, we had previously
with another set of primary amines RC–NH2 to give prod-
ucts 4. A mechanistic explanation for the ring-expanding
transformation involves nucleophilic attack of the amine on
both carbonyl groups of the 1,4-diketone moiety with for-
mation of the bicyclic intermediate 3, as proposed for the
Paal–Knorr pyrrole synthesis.[9]
[a] Institut für Reine und Angewandte Chemie, Carl von Ossietzky-
Universität Oldenburg,
Scheme 2. Synthesis of hexahydro-1,4-thiazocin-2-ones 7 and -di-
azocin-2-ones 8 from tetrahydrothiophene 5 and pyrrolidine deriva-
tive 6.
26111 Oldenburg, Germany
Fax: +49-441-798-3873
E-mail: jens.christoffers@uni-oldenburg.de
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M. Penning, J. Christoffers
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failed to obtain good yields of the corresponding 1,4-oxaz-
ocin-3-ones (X = O) and 1,4-diazocin-2-ones (X = N–R).
Here we wish to report on the utilization of N-tert-butoxy-
carbonyl-protected pyrrolidine 6 as starting material for the
synthesis of such 1,4-diazocin-2-ones 8.
Results and Discussion
Pyrrolidone derivative 6 was prepared by conjugate ad-
dition of N-Boc-glycine methyl ester[11] (9, Scheme 3) to
methyl acrylate (10), followed by Dieckmann condensation
as reported by us recently (90% yield).[12] Alkylation with
phenacyl bromide was achieved by a standard protocol[10]
and furnished β-oxo ester 6, containing a 1,4-diketone mo-
tif, in good yield (73%).
The bismuth-catalyzed ring-expansion reaction was first
optimized with MeNH2 (conditions A in Scheme 3). In con-
trast to our previous experience with this reaction,[7,8] no
large excess of the primary amine was needed. The conver-
sion at 100 °C in THF required a tightly closed reaction Reagents and conditions A: R–NH2 (1.2 equiv.), Bi(NO3)3·5H2O
vial and was complete within 6 h. The reaction was scaled
Scheme 3. Preparation of hexahydro-1,4-diazocin-2-ones 8a–8e.
(0.1 equiv.), THF, 6 h, 100 °C. Conditions B: R–NH2 (1.2 equiv.),
THF, 6 h, 100 °C.
up to several grams and product 8a was obtained in 59%
yield. When BnNH2 was used under the same reaction con-
ditions, the product 8b contained several impurities, which
The use of 2-ethoxyethylamine under reaction condi-
made multiple chromatographic purification necessary. The tions A did not provide product 8e at all. In order to obtain
yield was therefore significantly lower (21%). When glycine a sample of compound 8e we again investigated several al-
tert-butyl ester and β-alanine tert-butyl ester[12] were used ternative sets of reaction conditions. To our surprise, com-
as starting materials, the corresponding products 8c and 8d pound 8e was formed under reaction conditions without
were also very hard to purify and the yields were also not the bismuth catalyst (conditions B, see Scheme 3), although
satisfactory (27% and 10%, respectively).
the yield was very low. When conditions B were applied to
Scheme 4. Deprotection and diversification at N-4. Reagents and conditions: a) TFA, CH2Cl2, 16 h, 23 °C; b) N-Boc-β-Ala, DCC, cat.
DMAP, HOBt, CH2Cl2, 3 d, 40 °C; c) MesSO2Cl, pyridine, CH2Cl2, 4 h, 23 °C; d) PhNCO, toluene, 1 h, 100 °C; e) 1. RCHO (1 equiv.),
MeOH, 1 h, 0 °C; 2. ZnCl2 (0.5 equiv.), NaCNBH3 (1 equiv.), MeOH, 5 h, 23 °C. Mes = 2,4,6-Me3C6H2.
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1,4-Diazocanes as Scaffolds for Combinatorial Chemistry
the preparation of 8a, the product 8a was also formed, in
61% yield, about the same as in the presence of the bismuth
catalysis. For preparations of products 8b–8d under condi-
tions B, the yields still remained unsatisfactory (17–22%
range). From this study we conclude: 1) that eight-mem-
bered lactam formation from pyrrolidone derivative 6 took
place even without the bismuth catalyst, although in some
cases the yields remain lower than with the catalyst (corre-
sponding control experiments without BiIII salts had been
performed in our earlier investigations, but we had never
before observed such reactivity in the absence of Bi catalyst,
so the pyrrolidone derivative 6 seems to be unique), and
2) that only methylamine seems to be suited for ring-expan-
sion reaction with pyrrolidone 6. Other (i.e., larger) amines
gave low yields not preparatively useful in terms of further
transformations of the products.
To explore the versatility of our new scaffold 8, we set
out to address the amino function N-4 and the carboxylate
at 6-CO2H of compound 8a synthetically. First of all, the
N-Boc group was removed with TFA to give secondary
amine 13 in almost quantitative yield (94%, Scheme 4).
Amidation of N-Boc-β-alanine[14] with amine 13 was ac-
complished with the aid of DCC and HOBt and catalytic
amounts of DMAP to furnish the carboxamide 12 (66%).
Sulfonamide formation was accomplished with MesSO2Cl
(Mes = 2,4,6-Me3C6H2) and pyridine to furnish compound
14 (69%). Conversion with PhNCO gave urea derivative 15
in 70% yield. A benzyl or an isobutyl group were installed
by reductive amination with PhCHO or isobutanal in the
presence of ZnCl2 and NaCNBH3 as reductant.[15] Com-
pounds 16a and 16b were isolated in 67% and 66% yields,
respectively.
Ester saponification of compound 8a at 6-CO2Me pro-
ceeded readily with NaOH in EtOH/water to yield carbox-
ylic acid 17 in 75% yield (Scheme 5). Two different amid-
ations of compound 17 were performed with DCC and
HOBt and catalytic amounts of DMAP. Amide 18 was ob-
tained (74%) from glycine methyl ester.[16] With para-
bromoaniline, product 20 was formed in 67% yield. Com-
Scheme 5. Deprotection and diversification at 6-CO2H. Reagents
and conditions: a) NaOH, H2O, EtOH, 20 min, 23 °C;
b) GlyOMe·HCl, NEt3, DCC, cat. DMAP, HOBt, CH2Cl2, 3 d,
40 °C; c) 4-BrC6H4NH2, DCC, cat. DMAP, HOBt, CH2Cl2, 3 d,
40 °C; d) 1. pyridine (1.8 equiv.), Boc2O (1.5 equiv.), dioxane, 0.5 h,
23 °C; 2. (NH4)2CO3 (2.8 equiv.), 17 h, 23 °C; e) PhI(OAc)2, KOH
(2.5 equiv.), for 21a: MeOH, CH2Cl2, 15 min, 0 °C, then 17 h,
23 °C; for 21b: BnOH, 16 h, 70 °C.
pound 20, with bromine as heavy atom, showed good crys- PhI(OAc)2 was fruitful.[19] In the presence of MeOH,
tallinity and suitable single crystals were obtained and in- methyl carbamate 21a was formed (55% yield). Gratify-
vestigated.[17] Figure 1 shows the structure in the solid state. ingly, with use of BnOH instead of MeOH, the Cbz-pro-
The eight-membered ring is in a folded, crown-shaped con- tected 6-amino derivative 21b was directly obtained in 54%
formation. The enamine C=C double bond and the lactam yield. An elevated temperature was required in this case,
N–C–O plane are twisted (dihedral angle C7,C8,N1,4-C = which was mainly due to limited solubility of the starting
117.3°). Furthermore, the two exocyclic carbonyl groups are material 19 in BnOH at 23 °C. Such a direct transformation
nearly perpendicular (dihedral angle 4-C,N4,6-C,O4 = of a carboxyamide into a Cbz-protected amine was reported
112.7°). Their separation [d(4-C,6-C)] is 467.8 pm.
very recently.[20] Literature reports on such a useful in-
Our intention was to prepare the 6-amino derivative of terconversion are presumably very rare at present because
the diazocanone scaffold by amide degradation of the carb- BnOH is not the optimal solvent for a Hofmann degrada-
oxylate function. The parent unsubstituted amide 19 was tion. This notwithstanding, compound 21b possesses two
prepared in 77% yield by activation of acid 17 with orthogonal amine protective groups (Boc at N-4 and Cbz
Boc2O[18] and conversion of the mixed anhydride with at 6-N).
hartshorn salt. Several degradation methods were investi-
Further investigations directed towards the preparation
gated but turned out to be unsuccessful, presumably be- of tripeptoidic structure 24 (Scheme 6) and starting either
cause the nucleophilic enamine moiety of compound 19 is with dipeptide 12 (Scheme 4) or 18 (Scheme 5) were per-
too reactive under oxidative or electrophilic conditions. Fi- formed. The ester and the carbamate groups of compounds
nally a variant of the Hofmann degradation with use of 12 and 18 were removed with either NaOH or TFA to give
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M. Penning, J. Christoffers
FULL PAPER
Figure 1. ORTEP representation of the structure of compound 20
in the solid state.
carboxylic acid 22 (54%) or the secondary amine 23 (95%,
Scheme 6), respectively. Amidation of acid 22 with glycine
methyl ester[16] was accomplished with the aid of DCC and
HOBt and catalytic amounts of DMAP to furnish the tri-
peptide mimetic 24 (51%) as a colorless crystalline material.
The overall yield of this four-step sequence starting from
compound 8a was 27%. Alternatively, the secondary amine
23 was coupled with N-Boc-β-alanine (66% yield) to give
the tripeptoide 24 (22% yield over four steps from com-
pound 8a). Compound 24 can be regarded as a cyclic β-
alanine derivative. Therefore, the 1,4-diazocine scaffold
such as in compound 24 represents a conformationally rigid
mimetic of cyclic β-peptide substructures.[21]
Scheme 6. Preparation of tripeptoide 24. Reagents and conditions:
a) NaOH, H2O, EtOH, 20 min, 23 °C; b) TFA, CH2Cl2, 16 h,
23 °C; c) DCC, cat. DMAP, HOBt, CH2Cl2, 3 d, 40 °C.
obviously cleaved under electrophilic reaction conditions.
Subsequently, the nucleophilic N-4 underwent transannular
attack at the enamine C-8 position with formation of a re-
action intermediate containing two annulated five-mem-
bered rings. This strained situation was relaxed by release
of the Me–N-1 with formation of an exocyclic amide. This
scenario could have been completed by oxidation of the di-
hydropyrrole to the aromatic product 26. Because trisubsti-
tuted pyrroles such as compound 26 are usually accessed
more easily, however, we did not follow this transformation
further.
To address the 6-CO2Me group of compound 8a further,
we set out to transform it into a carbaldehyde function. A
routine strategy for this functional group interconversion
would be reduction to a primary alcohol followed by Swern
oxidation. Whereas the reduction proceeded without any
problems (Scheme 7, 84% yield of alcohol 25), the only iso-
lable product of the subsequent Swern oxidation – 26 (65%
yield) – was unexpected. 1H and 13C NMR analysis, as well
as mass spectrometry, showed the following structural fea-
tures: the aldehyde function was formed as expected, but
the Boc group was cleaved and another C=C double bond
was introduced, presumably in conjugation with the alde-
4
hyde. The two olefinic protons revealed a J = 1.8 Hz cou-
pling, which matched our expectations. We were puzzled,
however, by a J = 4.8 Hz coupling of the Me–N–1 group
to the acidic N–H proton, which we thought to be at the
N-4 position in a diazocane ring. Fortunately, we were able
to obtain single crystals from this compound. An X-ray
structure analysis (Figure 2)[17] shed light on the consti-
tution of compound 26. As well as a normal Swern oxi-
Scheme 7. Formation of pyrrole derivative 26 by Swern oxidation
of primary alcohol 25. Reagents and conditions: a) NaBH4,
MeOH, 1 h, 0 °C, then 20 h, 23 °C; b) 1. (COCl)2 (1.1 equiv.),
DMSO (2.2 equiv.), 15 min, –60 °C; 2. NEt3 (5 equiv.), 5 min,
dation, yielding the aldehyde moiety, the Boc group was –60 °C, then 10 min, 23 °C.
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1,4-Diazocanes as Scaffolds for Combinatorial Chemistry
ester[13] was prepared by conjugate addition of BnNH2 to tert-butyl
acrylate (91% yield) and subsequent hydrogenolytic debenzylation
(76% yield). Both steps were performed under solvent-free condi-
tions, which was a significant improvement on the previously re-
ported protocols; the two procedures are given below.
N-Benzyl-β-alanine tert-Butyl Ester: Benzylamine (2.00 g,
18.7 mmol) was added to tert-butyl acrylate (1.60 g, 12.5 mmol)
and the resulting mixture was stirred for 23 h at ambient tempera-
ture. Subsequently, all volatile materials were removed in high vac-
uum and the residue was chromatographed (SiO2, hexane/EtOAc
1:2 + 1 vol-% NEt3, Rf = 0.08) to yield the title compound (2.66 g,
11.4 mmol, 91%) as
a
colorless liquid. 1H NMR (CDCl3,
500 MHz): δ = 1.48 (s, 9 H), 1.71 (br. s, 1 H), 2.49 (t, J = 6.4 Hz,
2 H), 2.90 (t, J = 6.4 Hz, 2 H), 3.84 (s, 2 H), 7.27–7.36 (m, 5
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 27.99 (3ϫCH3),
35.78 (CH2), 44.64 (CH2), 53.71 (CH2), 80.28 (C), 126.75 (CH),
127.95 (2ϫCH), 128.24 (2ϫCH), 140.16 (C), 172.02 (C) ppm. IR
Figure 2. ORTEP representation of the structure of compound 26
in the solid state.
(ATR): ν = 2978 (w), 2930 (w), 2826 (w), 1723 (s), 1366 (m), 1150
˜
(vs), 1122 (m), 734 (m), 697 (m) cm–1. C14H21NO2 (235.32).
β-Alanine tert-Butyl Ester: A catalytic amount of Pd (55 mg, 10
wt.-% on carbon black) was added to N-benzyl-β-alanine tert-butyl
ester (2.44 g, 10.4 mmol) and the mixture was stirred under hydro-
gen (1 atm, balloon) for 23 h. Subsequently, the mixture was dis-
tilled through a short column (bp. 33 °C at 50 mbar) to yield the
Conclusions
We have prepared an orthogonally protected (tert-butyl
carbamate at N-4 and methyl ester at 6-CO2H) hexahydro-
2-oxo-1,4-diazocin-6-carboxylic acid 8a by ring expansion
1
title compound (1.15 g, 7.91 mmol, 76%) as a colorless liquid. H
of 3-pyrrolidone-derived 1,4-diketone 6 with methylamine. NMR (CDCl3, 500 MHz): δ = 1.45 (s, 9 H), 1.52 (br. s, 2 H), 2.37
(t, J = 6.2 Hz, 2 H), 2.93 (t, J = 6.2 Hz, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 28.13 (3ϫCH3), 38.03 (CH2), 39.19 (CH2),
This building block represents a conformationally rigid
scaffold. Its structural features were established as a folded,
crown-shaped eight-membered heterocycle by single-crystal
X-ray structure analysis of 4-bromoaniline derivative 20.
After N-4 and 6-C deprotection, several examples of diver-
sifying reactions were developed, as were carboxamide,
80.52 (C), 172.09 (C) ppm. IR (ATR): ν = 3378 (w), 3311 (w), 2978
˜
(m), 2934 (w), 2878 (w), 1720 (vs), 1367 (s), 1246 (m), 1142 (vs),
843 (m) cm–1. C7H15NO2 (145.20).
1-tert-Butyl 3-Methyl 4-Oxo-3-(2-oxo-2-phenylethyl)pyrrolidin-1,3-
sulfonamide, and urea formation and reductive amination. dicarboxylate (6): K2CO3 (5.10 g, 36.9 mmol) and phenacyl brom-
ide (7.35 g, 36.9 mmol) were added successively to a solution of
compound 11 (8.55 g, 35.2 mmol) in acetone (35 mL). The re-
sulting mixture was stirred for 19 h at 40 °C and was then allowed
to cool to ambient temperature and diluted with H2O (50 mL). The
layers were separated and the aqueous layer was extracted with
tert-butyl methyl ether (MTBE, 3ϫ75 mL). The combined organic
layers were dried (MgSO4) and filtered, and the solvent was evapo-
A Hofmann-type degradation reaction in the presence of
benzyl alcohol directly transformed a carboxamide function
to afford Cbz-protected amine 21b. Furthermore, a tripept-
oidic structure 24 was synthesized by amidation with N-
Boc-β-alanine at N-4 and glycine methyl ester at 6-CO2H,
the latter representing a mimetic of a cyclic β-alanine deriv-
ative.
rated to give compound
6 (9.28 g, 25.7 mmol, 73%) after
chromatography (SiO2, hexane/EtOAc 2:1, Rf = 0.32) as a yellow
resin. A doubled set of broad signals is observed, due to E/Z iso-
mers (ratio ca. 1:1) at the carbamate C–N bond. 1H NMR
(500 MHz, CDCl3): δ = 1.49 (s, 9 H), 1.51 (s, 9 H), 3.59 (d, J =
11.9 Hz, 2 H), 3.67–3.72 (m, 1 H), 3.76 (s, 6 H), 3.85–3.91 (m, 3
H), 4.09–4.12 (m, 2 H), 4.17–4.23 (m, 2 H), 4.34 (d, J = 11.8 Hz,
1 H), 4.38 (d, J = 11.8 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 4 H), 7.60 (t,
J = 7.3 Hz, 2 H), 7.95 (d, J = 7.3 Hz, 4 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 28.28 (6ϫCH3), 42.44 (CH2), 42.66 (CH2),
51.85 (CH2), 52.42 (CH2), 52.45 (CH2), 53.07 (CH2), 53.27
(2ϫCH3), 56.44 (C), 57.55 (C), 80.41 (2ϫC), 128.07 (4ϫCH),
128.68 (4ϫCH), 133.86 (2ϫCH), 135.41 (2ϫC), 154.09 (C),
154.23 (C), 169.18 (C), 169.50 (C), 196.02 (2ϫC), 206.32 (C),
Experimental Section
General Methods: Preparative column chromatography was carried
out with Merck SiO2 (0.035–0.070 mm, type 60 A) and hexane,
EtOAc, CH2Cl2, or MeOH as eluents. TLC was performed with
Merck SiO2 F254 plates on aluminum sheets. 1H and 13C NMR
spectra were recorded with a Bruker Avance DRX 500 spectrome-
ter at 23 °C. Multiplicities in 13C NMR were determined with
DEPT experiments. EI MS, CI MS, and HRMS spectra were ob-
tained with a Finnigan MAT 95 spectrometer, ESI MS (HRMS)
spectra with a Waters Q-TOF Premier spectrometer. Elemental
analyses were measured with a Euro EA3000-CHNS instrument
from HEKAtech. IR spectra were recorded with a Bruker Ten-
sor 27 spectrometer fitted with a “GoldenGate” diamond-ATR
unit. The following starting materials were prepared by literature
procedures: N-Boc glycine methyl ester,[11] 1-tert-butyl 3-methyl 4-
oxopyrrolidine-1,3-dicarboxylate (11),[12] glycine methyl ester,[16] N-
Boc-β-alanine.[14] Glycine tert-butyl ester (Alfa Aesar) and all other
starting materials were commercially available. β-Alanine tert-butyl
207.06 (C) ppm. IR (ATR): ν = 2976 (w), 1769 (m), 1734 (m), 1681
˜
(s), 1399 (m), 1366 (m), 1220 (m), 1163 (s), 1123 (s), 755 (m), 689
(m) cm–1. MS (ESI): m/z (%) = 384 (100) [M + Na]+. HRMS (ESI)
calcd. 384.1423 (for C19H23NNaO6) [M + Na]+; found 384.1430.
C19H23NO6 (361.39).
4-tert-Butyl 6-Methyl (Z)-1-Methyl-2-oxo-8-phenyl-1,2,3,4,5,6-
hexahydro-1,4-diazocine-4,6-dicarboxylate
(8a):
Methylamine
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M. Penning, J. Christoffers
(8.30 mL of a 2 moldm–3 solution in THF) was added to a solution (50 mL), and H2O (50 mL). The organic layer was dried (MgSO4)
FULL PAPER
of compound 6 (5.00 g, 13.8 mmol) in THF (14 mL). The resulting
mixture was stirred for 6 h at 100 °C in a tightly closed reaction
vial. After the system had cooled to ambient temperature, the sol-
vents were evaporated and the residue was chromatographed (SiO2,
and filtered, and the solvents were evaporated. The residue was
chromatographed (SiO2, EtOAc, Rf = 0.43) to give product 12
(1.49 g, 3.35 mmol, 66%) as a colorless solid; m.p. 70 °C. A
doubled signal set is observed, due to E/Z isomers (ratio 1:0.22) at
the amide C–N bond. 1H NMR (500 MHz, CDCl3); major isomer:
δ = 1.38 (s, 9 H), 2.54 (dd, J = 9.8, 13.5 Hz, 1 H), 2.67–2.76 (m, 1
H), 2.89 (s, 3 H), 3.12 (dt, J = 1.4, J = 9.5 Hz, 1 H), 3.31–3.37 (m,
1 H), 3.38–3.46 (m, 1 H), 3.46–3.53 (m, 1 H), 3.76 (s, 3 H), 3.87
hexane/EtOAc 2:1, Rf
= 0.19) to give product 8a (1.28 g,
3.41 mmol, 61%) as a beige solid; m.p. 109 °C. A doubled set of
broad signals is observed, due to E/Z isomers (ratio 1:0.7) at the
carbamate C–N bond. 1H NMR (500 MHz, CDCl3); major isomer:
δ = 1.32 (s, 9 H), 2.92 (s, 3 H), 3.33–3.36 (m, 1 H), 3.43–3.49 (m, (d, J = 14.7 Hz, 1 H), 4.32 (d, J = 14.7 Hz, 1 H), 5.09 (d, J =
1 H), 3.79 (s, 3 H), 3.96–4.04 (m, 1 H), 4.25 (s, 2 H), 6.03 (d, J = 13.4 Hz, 1 H), 5.28 (br. s, 1 H), 6.05 (d, J = 9.4 Hz, 1 H), 7.32–
8.8 Hz, 1 H), 7.34–7.42 (m, 5 H) ppm; minor isomer: δ = 1.16 (s, 9
7.38 (m, 5 H) ppm; minor isomer: δ = 1.36 (s, 9 H), 2.37–2.44 (m,
H), 2.91 (s, 3 H), 3.54–3.60 (m, 2 H), 3.61–3.68 (m, 1 H), 3.79 (s, 1 H), 2.49–2.55 (m, 1 H), 2.87 (s, 3 H), 3.31–3.37 (m, 2 H), 3.38–
3 H), 3.96–4.04 (m, 1 H), 4.73 (d, J = 16.5 Hz, 1 H), 5.79 (d, J = 3.46 (m, 2 H), 3.79 (s, 3 H), 4.01–4.06 (m, 2 H), 4.66 (d, J =
6.3 Hz, 1 H), 7.34–7.42 (m, 5 H) ppm. 13C{1H} NMR (125 MHz,
CDCl3); major isomer: δ = 27.95 (3ϫCH3), 35.28 (CH3), 44.72
14.7 Hz, 1 H), 5.20 (br. s, 1 H), 5.80 (d, J = 9.6 Hz, 1 H), 7.32–7.38
(m, 5 H) ppm. 13C{1H} NMR (125 MHz, CDCl3); major isomer: δ
(CH), 46.00 (CH2), 49.94 (CH2), 52.41 (CH3), 81.06 (C), 119.59 = 28.31 (3ϫCH3), 33.75 (CH3), 33.87 (CH2), 36.24 (CH2), 44.10
(CH), 126.43 (2ϫCH), 128.85 (3ϫCH), 135.36 (C), 142.87 (C), (CH2), 44.99 (CH), 48.06 (CH2), 52.53 (CH3), 78.76 (C), 121.61
154.56 (C), 168.96 (C), 171.97 (C) ppm; minor isomer: δ = 27.95 (CH), 126.28 (2ϫCH), 128.99 (2ϫCH), 129.52 (CH), 134.95 (C),
(3ϫCH3), 36.17 (CH3), 43.98 (CH), 47.61 (CH2), 50.76 (CH2),
52.41 (CH3), 80.92 (C), 118.24 (CH), 126.68 (2ϫCH), 129.10
142.69 (C), 155.81 (C), 168.25 (C), 171.73 (C), 172.79 (C) ppm;
minor isomer: δ = 28.31 (3ϫCH3), 34.17 (CH2), 34.81 (CH3), 36.24
(3ϫCH), 136.01 (C), 143.83 (C), 154.56 (C), 168.96 (C), 171.97 (CH2), 44.51 (CH), 47.03 (CH2), 48.15 (CH2), 52.67 (CH3), 78.76
(C) ppm. IR (ATR): ν = 2977 (w), 1737 (m), 1694 (s), 1638 (s), (C), 118.58 (CH), 126.44 (2ϫCH), 128.86 (2ϫCH), 129.35 (CH),
1426 (m), 1366 (m), 1244 (s), 1160 (vs), 767 (s), 730 (m), 700 135.15 (C), 144.23 (C), 155.81 (C), 167.94 (C), 171.41 (C), 172.79
(m) cm–1. MS (EI, 70 eV): m/z (%) = 374 (10) [M]+, 274 (26), 261
(C) ppm. IR (ATR): ν = 3342 (w), 2931 (w), 1736 (m), 1708 (m),
˜
˜
(13), 217 (62), 204 (72), 188 (46), 118 (21), 84 (50), 57 (100). HRMS 1648 (s), 1434 (m), 1390 (m), 1365 (m), 1247 (m), 1166 (vs), 769
calcd. 374.1842 (for C20H26N2O5) [M]+; found 374.1846. (m) cm–1. MS (EI, 70 eV): m/z (%) = 445 (2) [M]+, 372 (19), 345
C20H26N2O5 (374.43): calcd. C 64.15, H 7.00, N 7.48; found C
63.73, H 7.32, N 7.09.
(23), 217 (100), 204 (88), 188 (52), 173 (35), 144 (19), 98 (19), 57
(65), 42 (37). HRMS calcd. 445.2213 (for C23H31N3O6) [M]+; found
445.2218. C23H31N3O6 (445.51).
Methyl (Z)-1-Methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-di-
azocine-6-carboxylate (13): TFA (2.7 mL, 35 mmol) was added to
a solution of compound 8a (432 mg, 1.15 mmol) in CH2Cl2
(2.5 mL). The resulting mixture was stirred for 16 h at ambient
temperature and was then diluted with H2O (20 mL) and saturated
aqueous NaHCO3 solution (ca. 50 mL) until pH 8 was reached.
The aqueous phase was extracted with CH2Cl2 (3ϫ50 mL). The
combined organic layers were dried (MgSO4), filtered, and concen-
trated to yield product 13 (297 mg, 1.08 mmol, 94%) as a brown
Methyl (Z)-4-(Mesitylsulfonyl)-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-
hexahydro-1,4-diazocine-6-carboxylate (14): Mesitylenesulfonyl
chloride (79 mg, 0.36 mmol) was added to a solution of amine 13
(0.10 g, 0.36 mmol) in a pyridine/CH2Cl2 mixture (1:1, 0.7 mL) and
the reaction mixture was stirred at ambient temperature for 4 h.
CH2Cl2 (10 mL) was added and the organic layer was washed with
saturated NaCl solution and water (10 mL each) and was then
dried (MgSO4) and filtered, and the solvents were evaporated. The
residue was chromatographed (SiO2, EtOAc, Rf = 0.72) to yield the
title product 14 (114 mg, 0.250 mmol, 69%) as a colorless solid;
1
solid; m.p. 107 °C. H NMR (500 MHz, CDCl3): δ = 1.88 (br. s, 1
H), 2.64 (dd, J = 9.4, 13.9 Hz, 1 H), 2.94 (s, 3 H), 3.02 (t, J =
9.3 Hz, 1 H), 3.35 (d, J = 13.5 Hz, 1 H), 3.45 (d, J = 13.9 Hz, 1
H), 3.61 (d, J = 13.5 Hz, 1 H), 3.75 (s, 3 H), 6.02 (d, J = 9.3 Hz, 1
H), 7.35–7.40 (m, 5 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ
= 33.42 (CH3), 48.22 (CH), 49.84 (CH2), 49.86 (CH2), 52.17 (CH3),
121.32 (CH), 126.19 (2ϫCH), 128.84 (2ϫCH), 129.10 (CH),
1
m.p. 199–200 °C. H NMR (500 MHz, CDCl3): δ = 2.32 (s, 3 H),
2.64 (s, 6 H), 2.87 (dd, J = 9.9, 12.7 Hz, 1 H), 2.91 (s, 3 H), 3.34
(t, J = 9.5 Hz, 1 H), 3.65 (d, J = 13.9 Hz, 1 H), 3.71 (s, 3 H), 4.11
(d, J = 12.8 Hz, 1 H), 4.23 (d, J = 13.9 Hz, 1 H), 5.93 (d, J =
9.6 Hz, 1 H), 6.99 (s, 2 H), 7.33–7.35 (m, 2 H), 7.38–7.41 (m, 3
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 20.96 (CH3),
22.66 (2ϫCH3), 33.80 (CH3), 44.13 (CH), 46.19 (CH2), 47.62
(CH2), 52.66 (CH3), 120.65 (CH), 126.33 (2ϫCH), 128.93
(2ϫCH), 129.53 (CH), 131.15 (C), 131.96 (2ϫCH), 134.53 (C),
140.76 (2ϫC), 143.03 (C), 143.44 (C), 167.75 (C), 171.50 (C) ppm.
135.06 (C), 142.00 (C), 172.09 (C), 172.70 (C) ppm. IR (ATR): ν =
˜
3314 (w), 2948 (w), 2910 (w), 1727 (s), 1632 (vs), 1435 (m), 1385
(m), 1303 (m), 1262 (m), 1192 (m), 1169 (s), 1088 (m), 881 (m), 769
(s), 696 (s) cm–1. MS (EI, 70 eV): m/z (%)
= 274 (38)
[M]+, 217 (59), 204 (100), 188 (51), 172 (46), 144 (94), 117 (56), 105
(45), 77 (38). HRMS calcd. 274.1317 (for C15H18N2O3) [M]+; found
274.1311. C15H18N2O3 (274.32).
IR (ATR): ν = 3033 (w), 2945 (w), 1732 (s), 1661 (s), 1311 (m),
˜
1259 (m), 1152 (s), 1049 (m), 856 (m), 770 (m), 656 (m) cm–1. MS
(EI, 70 eV): m/z (%) = 456 (5) [M]+, 399 (36), 273 (100), 204 (95),
119 (22), 42 (28). HRMS calcd. 456.1719 (for C24H28N2O5S) [M]+;
found 456.1714. C24H28N2O5S (456.55): calcd. C 63.14, H 6.18, N
6.14, S 7.02; found C 63.12, H 6.41, N 6.10, S 6.83.
Methyl (Z)-4-[(3-tert-Butoxycarbonylamino)propanoyl]-1-methyl-2-
oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-diazocine-6-carboxylate (12):
DCC (1.16 g, 5.61 mmol) and DMAP (32 mg, 0.26 mmol) were
added to a cooled (ice/water bath) solution of compound 13 (1.4 g,
5.1 mmol) in CH2Cl2 (15 mL). The resulting mixture was stirred
for 1 min at 23 °C, until a colorless precipitate had formed. N-Boc-
β-alanine (1.06 g, 5.61 mmol) and HOBt (861 mg, 88% purity,
5.61 mmol) were added to the reaction mixture, which was sub-
sequently heated to reflux for 3 d. After cooling to ambient tem-
perature, the mixture was washed successively with saturated aque-
ous NH4Cl solution (50 mL), saturated aqueous NaHCO3 solution
Methyl (Z)-1-Methyl-2-oxo-8-phenyl-4-(phenylcarbamoyl)-1,2,3,4,5,6-
hexahydro-1,4-diazocine-6-carboxylate (15): Phenyl isocyanate
(43 mg, 0.36 mmol) was added to a solution of amine 13 (0.10 g,
0.36 mmol) in abs. toluene (0.4 mL) under inert gas and the reac-
tion mixture was stirred at 100 °C for 1 h. After the system had
cooled to ambient temperature, CH2Cl2 (10 mL) was added and
1814
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1809–1818

1,4-Diazocanes as Scaffolds for Combinatorial Chemistry
the organic layer was washed with hydrochloric acid (2ϫ10 mL, 1
molar) and was then dried (MgSO4) and filtered, and the solvents
were evaporated. The crude product was chromatographed (SiO2,
hexane/EtOAc 2:1, Rf = 0.19) to yield urea 15 (99 mg, 0.25 mmol,
70%) as a colorless solid; m.p. 83 °C. 1H NMR (500 MHz, CDCl3):
δ = 2.66 (dd, J = 9.3, 13.7 Hz, 1 H), 3.02 (s, 3 H), 3.14 (t, J =
9.2 Hz, 1 H), 3.79 (s, 3 H), 3.90 (d, J = 14.8 Hz, 1 H), 4.38 (d, J =
14.9 Hz, 1 H), 5.05 (d, J = 13.6 Hz, 1 H), 6.17 (d, J = 9.3 Hz, 1
H), 7.03 (t, J = 7.4 Hz, 1 H), 7.26–7.32 (m, 2 H), 7.38–7.39 (m, 2
H), 7.43–7.47 (m, 5 H), 9.20 (s, 1 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 33.70 (CH3), 45.19 (CH2), 46.75 (CH),
48.01 (CH2), 52.57 (CH3), 119.63 (2ϫCH), 122.23 (CH), 122.70
(CH), 126.37 (2ϫCH), 128.72 (2ϫCH), 129.10 (2ϫCH), 129.68
(CH), 134.50 (C), 139.42 (C), 142.45 (C), 155.48 (C), 169.52 (C),
2868 (w), 2828 (w), 1732 (s), 1639 (s), 1386 (m), 1268 (m), 1229
(m), 1076 (m), 1033 (m), 1027 (m), 851 (m), 767 (s), 701 (m) cm–1.
MS (CI, isobutane): m/z (%) = 331 (100) [M + H]+. HRMS calcd.
331.2022 (for C19H27N2O3) [M
+
H]+; found 331.2028.
C19H26N2O3 (330.42): calcd. C 69.06, H 7.93, N 8.48; found C
68.67, H 8.30, N 8.30.
4-tert-Butyl (Z)-1-Methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-
diazocine-4,6-dicarboxylate (17): Soda lye (40 mL, 2 moldm–3) was
added to a solution of compound 8a (2.84 g, 7.58 mmol) in EtOH
(15 mL) and the resulting mixture was stirred for 20 min at ambient
temperature and then diluted with H2O (30 mL) and washed with
MTBE (2ϫ60 mL). The aqueous layer was acidified to pH 1 with
conc. hydrochloric acid (ca. 8 mL) and then extracted with MTBE
(3ϫ100 mL). The combined organic layers were dried (MgSO4)
and filtered, and the solvents were evaporated. The residue was
chromatographed [SiO2, CH2Cl2/MeOH 25:1, Rf(CH2Cl2/MeOH
10:1) = 0.11] to give product 17 (2.04 g, 5.67 mmol, 75%) as a col-
orless solid; m.p. 95 °C. A doubled set of broad signals is observed,
171.82 (C) ppm. IR (ATR): ν = 3306 (w), 3057 (w), 2952 (w), 1733
˜
(m), 1676 (m), 1635 (s), 1597 (s), 1550 (m), 1444 (m), 1402 (s), 1252
(m), 1197 (vs), 1069 (m), 754 (s), 694 (s) cm–1. MS (ESI): m/z (%)
= 416 (60) [M + Na]+. HRMS calcd. 416.1586 (for C22H23N3NaO4)
[M + Na]+; found 416.1583. C22H23N3O4 (393.44).
1
due to E/Z isomers (ratio 1:0.65) at the carbamate C–N bond. H
Methyl (Z)-4-Benzyl-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahy- NMR (500 MHz, CDCl3); major isomer: δ = 1.30 (s, 9 H), 2.95 (s,
dro-1,4-diazocine-6-carboxylate (16a): Benzaldehyde (19 mg,
0.18 mmol) was added to solution of amine 13 (50 mg,
3 H), 3.39–3.44 (m, 1 H), 3.50–3.57 (m, 1 H), 3.98–4.07 (m, 1 H),
4.26 (A part of an AB system, J = 16.1 Hz, 1 H), 4.32 (B part of
an AB system, J = 16.0 Hz, 1 H), 6.07 (d, J = 8.8 Hz, 1 H), 7.34–
7.42 (m, 5 H), 8.23 (br. s, 1 H) ppm; minor isomer: δ = 1.17 (s, 9
H), 2.93 (s, 3 H), 3.58–3.66 (m, 2 H), 3.69–3.78 (m, 1 H), 3.98–4.07
(m, 1 H), 4.75 (d, J = 16.8 Hz, 1 H), 5.82–5.88 (m, 1 H), 7.34–7.42
(m, 5 H), 8.23 (br. s, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3);
major isomer: δ = 27.85 (3ϫCH3), 23.56 (CH3), 44.40 (CH), 45.85
(CH2), 50.18 (CH2), 81.44 (C), 119.54 (CH), 126.33 (2ϫCH),
128.80 (3ϫCH), 135.05 (C), 142.68 (C), 154.67 (C), 169.37 (C),
174.84 (C) ppm; minor isomer: δ = 27.85 (3ϫCH3), 36.34 (CH3),
43.88 (CH), 47.44 (CH2), 50.56 (CH2), 81.07 (C), 118.59 (CH),
a
0.18 mmol) in MeOH (0.1 mL) and the mixture was stirred at 0 °C
for 1 h. ZnCl2 (12 mg, 0.090 mmol) and NaCNBH3 (11 mg,
0.18 mmol) in MeOH (0.1 mL) were then added at 0 °C and the
reaction mixture was stirred at ambient temperature for 3 h. Water
(5 mL) and EtOAc (5 mL) were added, the layers were separated,
and the aqueous phase was extracted with EtOAc (2ϫ5 mL). The
combined organic layers were dried (MgSO4) and filtered, and the
solvents were evaporated. After column chromatography (SiO2,
hexane/EtOAc 2:1, +1 vol.-% NEt3, Rf = 0.27), compound 16a
(44 mg, 0.12 mmol, 67%) was isolated as a yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 2.48 (dd, J = 8.8, 13.5 Hz, 1 H), 2.89 (s, 3 126.59 (2ϫCH), 129.07 (3ϫCH), 135.70 (C), 143.55 (C), 154.67
H), 3.18–3.21 (m, 2 H), 3.42 (d, J = 13.2 Hz, 1 H), 3.57 (d, J = (C), 169.60 (C), 174.84 (C) ppm. IR (ATR): ν = 2977 (w), 2932
˜
13.2 Hz, 1 H), 3.59 (d, J = 13.9 Hz, 1 H), 3.65 (s, 3 H), 4.11 (d, J (w), 1696 (s), 1638 (m), 1597 (m), 1427 (m), 1391 (m), 1366 (m),
= 13.9 Hz, 1 H), 5.98 (d, J = 9.3 Hz, 1 H), 7.17–7.20 (m, 1 H), 7.24–
1246 (m), 1159 (vs), 766 (s), 698 (m) cm–1. MS (EI, 70 eV): m/z (%)
7.27 (m, 2 H), 7.28–7.34 (m, 7 H) ppm. 13C{1H} NMR (125 MHz, = 360 (3) [M]+, 260 (11), 215 (7), 190 (24), 159 (10), 144 (7), 118
CDCl3): δ = 33.65 (CH3), 42.13 (CH), 52.25 (CH3), 54.39 (CH2), (13), 77 (5), 57 (100). HRMS calcd. 360.1685 (for C19H24N2O5)
55.38 (CH2), 57.37 (CH2), 122.11 (CH), 126.25 (2ϫCH), 127.19 [M]+; found 360.1679. C19H24N2O5 (360.40).
(CH), 128.23 (2ϫCH), 128.89 (2ϫCH), 129.08 (CH), 129.12
4-tert-Butyl
(Z)-6-{[(Methoxycarbonyl)methylamino]carbonyl}-1-
(2ϫCH), 135.35 (C), 138.36 (C), 141.66 (C), 168.91 (C), 173.08
methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-diazocine-4-carb-
oxylate (18): DCC (571 mg, 2.77 mmol), DMAP (17 mg,
0.14 mmol), Gly-OMe·HCl (383 mg, 3.05 mmol), NEt3 (309 mg,
3.05 mmol), HOBt (425 mg, 88% purity, 2.77 mmol), and com-
pound 17 (1.0 g, 2.8 mmol) were treated by the procedure given for
product 12 to give product 18 (888 mg, 2.06 mmol, 74%) as a color-
less solid after chromatography (SiO2, EtOAc, Rf = 0.31); m.p.
(C) ppm. IR (ATR): ν = 3062 (w), 3031 (w), 2953 (w), 2922 (w),
˜
2845 (w), 1734 (s), 1647 (s), 1450 (m), 1387 (m), 1204 (m), 1168
(m), 1073 (m), 770 (m), 735 (m), 700 (s) cm–1. MS (CI, isobutane):
m/z (%) = 365 (100) [M + H]+. HRMS calcd. 365.1865 (for
C22H25N2O3) [M + H]+; found 365.1855. C22H24N2O3 (364.44).
Methyl (Z)-4-Isobutyl-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahy-
dro-1,4-diazocine-6-carboxylate (16b): Amine 13 (50 mg, 76 °C. A doubled set of broad signals is observed, due to E/Z iso-
0.18 mmol), isobutanal (13 mg, 0.18 mmol), ZnCl2 (12 mg,
0.090 mmol), and NaCNBH3 (11 mg, 0.18 mmol) were treated by
the procedure given for compound 16a to give compound 16b
(39 mg, 0.12 mmol, 66%) after column chromatography (SiO2, hex-
mers (ratio 1:0.75) at the carbamate C–N bond. 1H NMR
(500 MHz, CDCl3); major isomer: δ = 1.36 (s, 9 H), 2.92 (s, 3 H),
3.16–3.23 (m, 1 H), 3.26–3.32 (m, 1 H), 3.48–3.57 (m, 1 H), 3.78
(s, 3 H), 4.02–4.17 (m, 3 H), 4.34 (d, J = 14.3 Hz, 1 H), 6.11–6.18
(m, 1 H), 6.82 (br. s, 1 H), 7.31–7.39 (m, 5 H) ppm; minor isomer:
ane/EtOAc 4:1, plus 1 vol.-% NEt3, Rf = 0.25) as a colorless solid;
1
m.p. 111 °C. H NMR (500 MHz, CDCl3): δ = 0.93 (dd, J = 6.6, δ = 1.17 (s, 9 H), 2.92 (s, 3 H), 3.48–3.57 (m, 1 H), 3.78 (s, 3 H),
11.2 Hz, 6 H), 1.91–1.99 (m, 1 H), 2.29 (dd, J = 6.6, 12.8 Hz, 1 H), 4.02–4.17 (m, 5 H), 4.56 (d, J = 16.0 Hz, 1 H), 5.91 (br. s, 1 H),
2.62–2.70 (m, 2 H), 2.92 (s, 3 H), 3.19 (t, J = 8.8 Hz, 1 H), 3.32 (d,
J = 13.5 Hz, 1 H), 3.40 (d, J = 13.4 Hz, 1 H), 3.51 (d, J = 13.4 Hz, (125 MHz, CDCl3); major isomer:
7.10 (br. s, 1 H), 7.31–7.39 (m, 5 H) ppm. 13C{1H} NMR
δ
= 24.85 (CH2), 27.81
1 H), 3.77 (s, 3 H), 6.05 (d, J = 9.4 Hz, 1 H), 7.34–7.41 (m, 5 (3ϫCH3), 36.07 (CH3), 41.17 (CH2), 44.91 (CH), 49.71 (CH2),
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 20.43 (CH3), 52.17 (CH3), 80.79 (C), 120.27 (CH), 126.51 (2ϫCH), 128.62
20.53 (CH3), 26.13 (CH), 33.64 (CH3), 42.51 (CH), 52.32 (CH3), (2ϫCH), 128.86 (CH), 135.66 (C), 142.69 (C), 154.73 (C), 169.25
55.02 (CH2), 56.37 (CH2), 60.75 (CH2), 122.21 (CH), 126.25 (C), 170.03 (C), 171.50 (C) ppm; minor isomer: δ = 25.48 (CH2),
(2ϫCH), 128.87 (2ϫCH), 128.99 (CH), 135.59 (C), 141.52 (C),
169.00 (C), 173.41 (C) ppm. IR (ATR): ν = 3057 (w), 2957 (w),
27.81 (3ϫCH3), 33.80 (CH2), 35.06 (CH3), 45.87 (CH), 48.21
(CH2), 52.17 (CH3), 80.79 (C), 121.18 (CH), 126.22 (2ϫCH),
˜
Eur. J. Org. Chem. 2012, 1809–1818
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1815

M. Penning, J. Christoffers
128.73 (2ϫCH), 128.86 (CH), 135.12 (C), 142.10 (C), 154.73 (C), (CH), 121.36 (2ϫCH), 126.55 (2ϫCH), 128.91 (2ϫCH), 129.15
FULL PAPER
169.25 (C), 170.03 (C), 171.50 (C) ppm. IR (ATR): ν = 3308 (w),
2977 (w), 2933 (w), 1750 (m), 1686 (s), 1643 (s), 1540 (m), 1427
(CH), 131.89 (2ϫCH), 135.52 (C), 137.65 (C), 142.61 (C), 154.99
(2ϫC), 169.56 (C), 170.44 (C) ppm. IR (ATR): ν = 3316 (w), 3276
˜
˜
(m), 1407 (m), 1366 (m), 1243 (m), 1202 (s), 1161 (vs), 888 (m), 856 (w), 2976 (w), 2934 (w), 1693 (s), 1641 (m), 1608 (m), 1538 (m),
(m), 768 (m), 700 (m) cm–1. MS (EI, 70 eV): m/z (%) = 431 (3)
1488 (m), 1428 (m), 1395 (s), 1366 (m), 1244 (s), 1159 (vs), 1073
[M]+, 274 (24), 215 (63), 172 (60), 118 (14), 57 (100), 42 (38). (m), 1009 (m), 911 (m), 857 (m), 825 (m), 766 (s), 730 (m), 697
HRMS calcd. 431.2056 (for C22H29N3O6) [M]+; found 431.2067. (s) cm–1. MS (EI, 70 eV): m/z (%) = 513 (5) [M]+, 412 (7), 343 (19),
C22H29N3O6 (431.48).
215 (100), 172 (86), 144 (20), 118 (16), 57 (87), 42 (25). HRMS
calcd. 513.1263 (for C25H28BrN3O4) [M]+; found 513.1276.
C25H28BrN3O4 (514.41).
tert-Butyl
(Z)-6-Carbamoyl-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-
hexahydro-1,4-diazocine-4-carboxylate (19): Pyridine (395 mg,
4.99 mmol) and Boc2O (910 mg, 4.16 mmol) were added to a solu-
tion of carboxylic acid 17 (1.0 g, 2.8 mmol) in dioxane (5.5 mL)
and the mixture was stirred at ambient temperature for 30 min.
tert-Butyl (Z)-6-(Methoxycarbonylamino)-1-methyl-2-oxo-8-phenyl-
1,2,3,4,5,6-hexahydro-1,4-diazocine-4-carboxylate (21a): Amide 19
(80 mg, 0.22 mmol) and PhI(OAc)2 (71 mg, 0.22 mmol) were added
(NH4)2CO3 (746 mg, 7.76 mmol) was then added and the reaction at 0 °C to a solution of KOH (31 mg, 0.55 mmol) in MeOH
mixture was stirred for 17 h at ambient temperature. Afterwards
water and MTBE (10 mL each) were added and stirring was contin-
ued for 10 min. The mixture was filtered and the residue was
washed with MTBE (3ϫ10 mL) and dried to yield amide 19
(768 mg, 2.14 mmol, 77%) as a colorless solid; m.p. 224 °C. A
(0.25 mL) and CH2Cl2 (0.2 mL) and the reaction mixture was
stirred for 15 min at this temperature and then for further 17 h at
ambient temperature. Water (5 mL) was added and the aqueous
phase was extracted with CH2Cl2 (3ϫ5 mL). The combined or-
ganic phases were dried (MgSO4) and filtered, and the solvents
were evaporated. After column chromatography (SiO2, hexane/
doubled set of broad signals is observed, due to the E/Z isomers
1
(ration ca. 1:1) at the carbamate C–N bond. H NMR (500 MHz, EtOAc 1:2, Rf = 0.29), carbamate 21a (47 mg, 0.12 mmol, 55%)
1
CDCl3): δ = 1.19 (s, 9 H), 1.34 (s, 9 H), 2.92 (s, 6 H), 3.18–3.28
(m, 1 H), 3.28–3.37 (m, 1 H), 3.45–3.58 (m, 2 H), 3.71–3.81 (m, 1
H), 4.03–4.17 (m, 3 H), 4.26–4.37 (m, 1 H), 4.45–4.56 (m, 1 H),
5.67–5.78 (m, 2 H), 5.91–6.01 (m, 1 H), 6.01–6.18 (m, 1 H), 6.52–
was isolated as a colorless solid; m.p. 68 °C. H NMR (500 MHz,
CDCl3); major conformer: δ = 1.21 (s, 9 H), 2.96 (s, 3 H), 3.37–
3.45 (m, 1 H), 3.56–3.60 (m, 1 H), 3.71 (s, 3 H), 4.01–4.10 (m, 1
H), 4.52–4.55 (m, 1 H), 4.60–4.69 (m, 2 H), 5.71 (d, J = 6.6 Hz, 1
6.65 (m, 1 H), 6.80–6.94 (m, 1 H), 7.31–7.40 (m, 10 H) ppm. H), 7.32–7.38 (m, 5 H) ppm; minor conformer: δ = 1.21 (s, 9 H),
13C{1H} NMR (125 MHz, CDCl3): δ = 27.95 (6ϫCH3), 35.06 2.93 (s, 3 H), 3.37–3.45 (m, 1 H), 3.56–3.60 (m, 1 H), 3.71 (s, 3 H),
(CH3), 35.95 (CH3), 44.69 (CH), 45.72 (CH), 47.11 (CH2), 48.28 4.01–4.10 (m, 1 H), 4.52–4.55 (m, 1 H), 4.87–4.96 (m, 1 H), 5.16–
(2ϫCH2), 49.76 (CH2), 80.99 (2ϫC), 120.40 (CH), 121.46 (CH), 5.23 (m, 1 H), 5.49 (m, 1 H), 7.32–7.38 (m, 5 H) ppm. 13C{1H}
126.28 (2ϫCH), 126.54 (2ϫCH), 128.78 (6ϫCH), 135.16 (C),
NMR (125 MHz, CDCl3); major conformer: δ = 27.88 (3ϫCH3),
135.67 (C), 142.23 (C), 142.85 (C), 154.80 (2ϫC), 169.36 (C), 35.71 (CH3), 49.06 (CH2), 50.26 (CH), 51.56 (CH2), 52.35 (CH3),
169.90 (C), 173.61 (2ϫC) ppm. IR (ATR): ν = 3383 (w), 3178 (w),
81.12 (C), 123.73 (CH), 126.21 (2ϫCH), 128.86 (2ϫCH), 128.95
˜
3066 (w), 2979 (w), 2926 (w), 1690 (vs), 1611 (s), 1433 (m), 1394
(CH), 135.18 (C), 140.94 (C), 154.92 (C), 156.35 (C), 168.83
(m), 1296 (m), 1245 (m), 1167 (m), 1151 (m), 764 (m), 696 (m) cm–1. (C) ppm; minor conformer: δ = 27.97 (3ϫCH3), 36.02 (CH3), 48.14
MS (ESI): m/z (%) = 382 (100) [M + Na]+. HRMS calcd. 382.1743
(for C19H25N3NaO4) [M + Na]+; found 382.1744. C19H25N3O4
(359.42): calcd. C 63.49, H 7.01, N 11.69; found C 63.67, H 7.31,
N 11.71.
(CH3), 49.86 (CH2), 49.95 (CH), 50.88 (CH2), 80.87 (C), 122.17
(CH), 126.65 (2ϫCH), 128.95 (CH), 129.03 (2ϫCH), 135.78 (C),
142.35 (C), 154.58 (C), 156.24 (C), 168.83 (C) ppm. IR (ATR): ν =
˜
3302 (w), 2977 (w), 2935 (w), 1694 (vs), 1641 (s), 1426 (m), 1366
(m), 1267 (m), 1239 (s), 1160 (vs), 1045 (m), 767 (s) cm–1. MS (ESI):
m/z (%) = 412 (100) [M + Na]+. HRMS calcd. 412.1848 (for
4-tert-Butyl (Z)-6-[(4-Bromophenyl)aminocarbonyl]-1-methyl-2-oxo-
8-phenyl-1,2,3,4,5,6-hexahydro-1,4-diazocine-4-carboxylate
(20):
C20H27N3NaO5) [M
(389.45).
+
Na]+; found 412.1858. C20H27N3O5
DCC (0.11 g, 0.55 mmol), DMAP (4 mg, 0.03 mmol), acid 17
(0.20 mg, 0.55 mmol), HOBt (84 mg, 88% purity, 0.55 mmol), and
4-bromoaniline (0.11 g, 0.61 mmol) were treated by the procedure
reported for product 12 to give product 20 (0.19 g, 0.37 mmol,
tert-Butyl (Z)-6-(Benzyloxycarbonylamino)-1-methyl-2-oxo-8-phen-
yl-1,2,3,4,5,6-hexahydro-1,4-diazocine-4-carboxylate (21b): Amide
67%) as a colorless solid after chromatography (SiO2, hexane/ 19 (0.10 g, 0.28 mmol) and PhI(OAc)2 (90 mg, 0.28 mmol) were
EtOAc 2:1, Rf = 0.14); m.p. 233 °C. Single crystals suitable for X- added to a solution of KOH (39 mg, 0.70 mmol) in BnOH (1.2 mL)
ray structure analysis were obtained by slow evaporation of a solu-
tion in EtOAc. A doubled set of broad signals is observed, due to
E/Z isomers (ratio 1:0.6) at the carbamate C–N bond. 1H NMR
(500 MHz, CDCl3); major isomer: δ = 1.17 (s, 9 H), 2.96 (s, 3 H),
3.41–3.51 (m, 1 H), 3.57–3.66 (m, 1 H), 3.67–3.74 (m, 1 H), 3.79–
3.87 (m, 1 H), 4.59 (d, J = 15.3 Hz, 1 H), 6.10 (br. s, 1 H), 7.34–
and the reaction mixture was stirred at 70 °C for 16 h. After the
system had cooled to ambient temperature, water and saturated
NaCl solution (5 mL each) were added and the aqueous phase was
extracted with MTBE (3ϫ5 mL). The combined organic layers
were dried (MgSO4) and filtered, and the solvents were evaporated.
The crude material was chromatographed (SiO2, hexane/EtOAc
7.42 (m, 5 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.52–7.63 (m, 2 H), 9.72 2:1, Rf = 0.19) to yield the title compound 21b (71 mg, 0.15 mmol,
(br. s, 1 H) ppm; minor isomer: δ = 1.30 (s, 9 H), 2.96 (s, 3 H),
3.26–3.38 (m, 1 H), 4.08–4.24 (m, 3 H), 4.34–4.44 (m, 1 H), 6.24
(br. s, 1 H), 7.34–7.42 (m, 5 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.52–
54%) as a colorless solid; m.p. 97 °C. A doubled set of broad sig-
nals is observed, due to the E/Z isomers (ratio 1:0.49) at the carb-
amate C–N-4 bond. 1H NMR (500 MHz, CDCl3); major con-
7.63 (m, 2 H), 9.29 (br. s, 1 H) ppm. 13C{1H} NMR (125 MHz, former: δ = 1.20 (s, 9 H), 2.96 (s, 3 H), 3.33–3.43 (m, 1 H), 3.57–
CDCl3); major isomer: δ = 24.92 (CH2), 27.97 (3ϫCH3), 33.92
3.61 (m, 1 H), 4.01–4.09 (m, 1 H), 4.52–4.70 (m, 2 H), 5.11–5.13
(CH3), 49.20 (CH), 49.90 (CH2), 81.38 (C), 116.72 (CH), 121.36 (m, 2 H), 5.70 (d, J = 6.1 Hz, 1 H), 7.33–7.37 (m, 11 H) ppm;
(2ϫCH), 126.55 (2ϫCH), 128.91 (2ϫCH), 129.15 (CH), 131.89
(2ϫCH), 135.52 (C), 137.65 (C), 142.61 (C), 154.99 (2ϫC), 169.56
(C), 170.44 (C) ppm; minor isomer: δ = 25.59 (CH2), 27.97
minor conformer: δ = 1.18 (s, 9 H), 2.73–2.81 (m, 2 H), 2.96 (s, 3
H), 4.52–4.70 (m, 1 H), 4.91–5.03 (m, 1 H), 5.11–5.13 (m, 1 H),
5.24–5.32 (m, 2 H), 5.44–5.50 (m, 1 H), 7.33–7.37 (m, 11 H) ppm.
(3ϫCH3), 33.92 (CH3), 49.20 (CH), 49.90 (CH2), 81.38 (C), 116.72 13C{1H} NMR (125 MHz, CDCl3); major conformer: δ = 27.86
1816
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1809–1818

1,4-Diazocanes as Scaffolds for Combinatorial Chemistry
(3ϫCH3), 35.67 (CH3), 49.09 (CH2), 50.28 (CH), 51.59 (CH2),
(%) = 331 (8) [M]+, 261 (18), 215 (60), 188 (23), 172 (100), 144 (24),
67.07 (CH2), 81.12 (C), 123.75 (CH), 126.18 (CH), 128.19 118 (13), 77 (8), 42 (27). HRMS calcd. 331.1532 (for C17H21N3O4);
(3ϫCH), 128.57 (2ϫCH), 128.85 (3ϫCH), 129.02 (CH), 135.14 found 331.1538 [M]+. C17H21N3O4 (331.37).
(C), 136.22 (C), 140.98 (C), 154.90 (C), 155.65 (C), 168.77 (C) ppm;
(Z)-4-[(3-tert-Butoxycarbonylamino)propanoyl]-N-[(methoxycarb-
minor conformer: δ = 27.86 (3ϫCH3), 36.06 (CH3), 48.18 (CH2),
onyl)methyl]-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-hexahydro-1,4-di-
49.76 (CH), 50.88 (CH2), 66.93 (CH2), 80.88 (C), 123.75 (CH),
azocine-6-carboxamide (24)
126.18 (CH), 126.39 (CH), 126.65 (CH), 128.19 (2ϫCH), 128.57
(2ϫCH), 128.85 (2ϫCH), 129.02 (CH), 135.27 (C), 135.78 (C),
From 22: DCC (221 mg, 1.07 mmol), DMAP (6 mg, 0.05 mmol),
carboxylic acid 22 (463 mg, 1.07 mmol), NEt3 (119 mg,
1.18 mmol), GlyOMe·HCl (148 mg, 1.18 mmol), and HOBt
(164 mg, 88% purity, 1.07 mmol) were treated by the procedure
reported for product 12 to give product 24 (0.31 g, 0.63 mmol,
67%) as a colorless solid after chromatography (SiO2, EtOAc, Rf
= 0.19); m.p. 182 °C.
142.42 (C), 154.53 (C), 155.52 (C), 168.77 (C) ppm. IR (ATR): ν =
˜
3304 (w), 2976 (w), 2933 (w), 1694 (vs), 1642 (m), 1426 (m), 1266
(m), 1237 (s), 1163 (s), 1142 (s), 1027 (m), 767 (s), 697 (s) cm–1.
MS (ESI): m/z (%) = 488 (100) [M + Na]+. HRMS calcd. 488.2161
(for C26H31N3NaO5) [M + Na]+; found 488.2150. C26H31N3O5
(465.54).
From 23: DCC (68 mg, 0.33 mmol), DMAP (2 mg, 0.02 mmol), N-
Boc-β-alanine (62 mg, 0.33 mmol), amine 23 (0.1 g, 0.3 mmol), and
HOBt (51 mg, 88% purity, 0.33 mmol) were converted by the pro-
cedure reported for product 12, to give product 24 (77 mg,
0.15 mmol, 51%) as a colorless solid after chromatography (SiO2,
EtOAc, Rf = 0.19). A doubled signal set is observed, due to E/Z
isomers (ratio 1:0.35) at the amide C–N-4 bond. 1H NMR
(500 MHz, CDCl3); major conformer: δ = 1.42 [s, 9 H, CH3(Boc)],
2.61 (dd, J = 9.4, 13.7 Hz, 1 H, 5-H), 2.73–2.81 [m, 1 H, 2-
CH(Gly)], 2.94 (s, 3 H, 1-CH3), 3.01 (t, J = 8.8 Hz, 1 H, 6-H),
3.29–3.36 [m, 1 H, 2-CH(Ala)], 3.36–3.43 [m, 1 H, 2-CH(Ala)],
3.45–3.52 [m, 1 H, 2-CH(Gly)], 3.78 (s, 3 H, OCH3), 3.86 (d, J =
14.7 Hz, 1 H, 3-H), 4.06 [A part of an ABX system, JAB = 18.2,
JAX = 5.2 Hz, 1 H, 3-CH(Ala)], 4.14 [B part of an ABX system,
JAB = 18.2, JBX = 5.6 Hz, 1 H, 3-CH(Ala)], 4.38 (d, J = 14.6 Hz,
1 H, 3-H), 5.00 (d, J = 13.6 Hz, 1 H, 5-H), 5.25–5.30 [m, 1 H,
NH(Gly)], 6.27 (d, J = 9.1 Hz, 1 H, 7-H), 6.55 [br. s, 1 H,
NH(Ala)], 7.34–7.42 (m, 5 H, C6H5) ppm; minor conformer: δ =
1.39 [s, 9 H, CH3(Boc)], 2.37–2.43 (m, 1 H), 2.64–2.70 (m, 1 H),
2.89 (s, 3 H, 1-CH3), 3.22 (dd, J = 9.9, 13.6 Hz, 1 H, 5-H), 3.29–
3.36 (m, 2 H), 3.36–3.43 (m, 2 H, 6-H), 3.45–3.52 (m, 1 H), 3.78
(s, 3 H, OCH3), 3.93–4.01 (m, 1 H, 3-H), 4.07–4.12 (m, 1 H, 5-H),
4.15–4.19 (m, 1 H), 4.76 (d, J = 14.6 Hz, 1 H, 3-H), 5.99 (d, J =
9.3 Hz, 1 H, 7-H), 7.14 (br. s, 1 H), 7.34–7.42 (m, 5 H, C6H5) ppm.
13C{1H} NMR (125 MHz, CDCl3); major conformer: δ = 24.92
[CH2, 2-C(Ala)], 28.42 [3ϫCH3, CH3(Boc)], 34.07 (CH3, 1-C),
36.36 [CH2, 2-C(Gly)], 41.38 [CH2, 3-C(Ala)], 45.97 (CH2, C5),
46.38 (CH, C6), 48.64 (CH2, C3), 52.45 (CH3, OCH3), 78.98 [C,
4°-C(Boc)], 122.76 (CH, C7), 126.33 (2ϫCH), 129.07 (2ϫCH),
129.49 (CH, para-CH), 134.82 (C, ipso-C), 142.06 (C, C8), 155.93
[C, C=O(Gly)], 156.77 [C, C=O(Boc)], 168.53 (C, C2), 170.04 (C, 4-
C), 171.16 (C, 6-C) ppm; minor conformer: δ = 25.61 (CH2), 28.42
[3ϫCH3, CH3(Boc)], 33.92 (CH2), 34.95 (CH3, 1-CH3), 41.26
(CH2), 45.88 (CH, C6), 47.08 (CH2, C3), 49.14 (CH3, OCH3), 49.31
(CH2, C5), 79.16 [C, 4°-C(Boc)], 120.05 (CH, C7), 126.51 (2ϫCH,
meta-C), 128.96 (2ϫCH, ortho-C), 129.37 (CH, para-C), 135.27 (C,
ipso-C), 143.75 (C, C8), 156.14 (C), 156.92 (C), 170.21 (C, 6-C),
(Z)-4-(3-tert-Butoxycarbonylamino)propanoyl-1-methyl-2-oxo-8-
phenyl-1,2,3,4,5,6-hexahydro-1,4-diazocine-6-carboxylic Acid (22):
Compound 12 (500 mg, 1.12 mmol) was converted with soda lye
(6 mL, 2 moldm–3) in EtOH (6 mL) by the procedure given for
product 17 to afford product 22 (0.26 g, 0.60 mmol, 54%) as a col-
orless solid after chromatography (SiO2, CH2Cl2/MeOH 15:2, Rf =
0.06); m.p. 124 °C. A doubled signal set is observed, due to E/Z
isomers (ratio 1:0.4) at the amide C–N bond. 1H NMR (500 MHz,
CDCl3); major isomer: δ = 1.43 (s, 9 H), 2.60–2.67 (m, 1 H), 2.75–
2.82 (m, 1 H), 2.96 (s, 3 H), 3.21 (t, J = 9.5 Hz, 1 H), 3.34–3.47
(m, 2 H), 3.47–3.55 (m, 1 H), 3.89 (d, J = 14.7 Hz, 1 H), 4.38 (d,
J = 14.5 Hz, 1 H), 5.16 (d, J = 13.6 Hz, 1 H), 5.34–5.37 (m, 1 H),
6.11 (d, J = 9.3 Hz, 1 H), 7.37–7.43 (m, 5 H), 10.37 (br. s, 1 H) ppm;
minor isomer: δ = 1.42 (s, 9 H), 2.60–2.67 (m, 2 H), 2.93 (s, 3 H),
3.15–3.18 (m, 1 H), 3.34–3.47 (m, 3 H), 3.91 (d, J = 14.0 Hz, 1 H),
4.25 (d, J = 12.6 Hz, 1 H), 4.87 (d, J = 14.2 Hz, 1 H), 5.54–5.57
(m, 1 H), 5.98 (d, J = 9.4 Hz, 1 H), 7.37–7.43 (m, 5 H), 10.37 (br.
s, 1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3); major isomer: δ
= 28.33 (3ϫCH3), 33.92 (CH3), 34.17 (CH2), 36.25 (CH2), 44.29
(CH2), 44.90 (CH), 48.19 (CH2), 79.16 (C), 122.06 (CH), 126.32
(2ϫCH), 128.66 (C), 129.02 (2ϫCH), 129.52 (CH), 134.52 (C),
142.51 (C), 156.10 (C), 168.36 (C), 173.21 (C) ppm; minor isomer:
δ = 28.30 (3ϫCH3), 33.92 (CH2), 34.76 (CH3), 36.03 (CH2), 44.29
(CH2), 44.68 (CH), 46.77 (CH2), 79.60 (C), 119.98 (CH), 126.46
(2ϫCH), 128.55 (C), 128.91 (2ϫCH), 129.35 (CH), 134.96 (C),
143.50 (C), 156.51 (C), 168.36 (C), 173.75 (C) ppm. IR (ATR): ν =
˜
3349 (w), 2977 (w), 2934 (w), 1710 (m), 1651 (s), 1505 (m), 1447
(m), 1392 (m), 1366 (m), 1249 (m), 1168 (vs), 1073 (m), 858 (m),
770 (m), 731 (m), 698 (m) cm–1. MS (EI, 70 eV): m/z (%) = 431 (2)
[M]+, 375 (30), 313 (20), 260 (23), 215 (29), 190 (100), 185 (46), 159
(40), 116 (48), 98 (19), 57 (64), 44 (45). HRMS calcd. 431.2056 (for
C22H29N3O6) [M]+; found 431.2049. C22H29N3O6 (431.48).
(Z)-N-[(Methoxycarbonyl)methyl]-1-methyl-2-oxo-8-phenyl-
1,2,3,4,5,6-hexahydro-1,4-diazocine-6-carboxamide (23): Com-
pound 18 (528 mg, 1.22 mmol) was converted with TFA (2.83 mL,
36.7 mmol) in CH2Cl2 (2.5 mL) by the procedure reported for
product 13, to give product 23 (383 mg, 1.16 mmol, 95%) as a col-
orless solid; m.p. 69 °C. 1H NMR (500 MHz, CDCl3): δ = 2.24 (br.
s, 1 H), 2.73 (dd, J = 9.2, 13.5 Hz, 1 H), 2.98 (s, 3 H), 3.13 (t, J =
9.0 Hz, 1 H), 3.37 (d, J = 13.3 Hz, 1 H), 3.42 (d, J = 13.3 Hz, 1
H), 3.65 (d, J = 13.3 Hz, 1 H), 3.75 (s, 3 H), 3.96 (dd, J = 4.9,
18.2 Hz, 1 H), 4.22 (dd, J = 6.1, 18.1 Hz, 1 H), 6.23 (d, J = 9.1 Hz,
1 H), 7.35–7.39 (m, 5 H), 7.70 (t, J = 5.4 Hz, 1 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 33.72 (CH3), 41.05 (CH2), 48.57
171.42 (C, C2), 173.36 (C) ppm. IR (ATR): ν = 3319 (w), 2977 (w),
˜
2936 (w), 1751 (w), 1711 (m), 1653 (s), 1521 (m), 1437 (m), 1391
(m), 1367 (m), 1247 (m), 1170 (s), 771 (m), 702 (m), 644 (m) cm–1.
MS (EI, 70 eV): m/z (%) = 502 (5) [M]+, 429 (21), 402 (38), 274
(37), 261 (56), 215 (100), 172 (90), 144 (23), 116 (25), 57 (33), 42
(22). HRMS calcd. 502.2427 (for C25H34N4O7); found 502.2442
[M]+. C25H34N4O7 (502.56).
(CH), 49.95 (CH2), 50.48 (CH2), 52.31 (CH3), 123.11 (CH), 126.22 tert-Butyl (Z)-6-Hydroxymethyl-1-methyl-2-oxo-8-phenyl-1,2,3,4,5,6-
(2ϫCH), 128.89 (2ϫCH), 129.07 (CH), 135.03 (C), 141.15 (C), hexahydro-1,4-diazocine-4-carboxylate (25): NaBH4 (228 mg,
170.48 (C), 172.71 (C), 172.76 (C) ppm. IR (ATR): ν = 3293 (w),
6.04 mmol) was added at 0 °C to a solution of ester 8a (1.13 g,
3.02 mmol) in MeOH (6 mL) and the mixture was stirred at this
temperature for 1 h and for an additional 20 h at ambient tempera-
˜
3059 (w), 2929 (w), 2854 (w), 1746 (m), 1630 (vs), 1543 (m), 1438
(m), 1385 (m), 1201 (s), 768 (s), 698 (m) cm–1. MS (EI, 70 eV): m/z
Eur. J. Org. Chem. 2012, 1809–1818
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1817

M. Penning, J. Christoffers
FULL PAPER
ture. The reaction was followed by thin layer chromatography and,
if necessary, further NaBH4 was added and stirring was continued
for 30 min. Water (20 mL) and hydrochloric acid (10 mL, 1 molar)
were added and the aqueous phase was extracted with EtOAc
(3ϫ15 mL). The combined organic layers were washed with satu-
rated NaHCO3 solution (30 mL) and then dried (MgSO4) and fil-
tered, and the solvents were evaporated. After column chromatog-
raphy (SiO2, EtOAc, Rf = 0.43), alcohol 25 (882 mg, 2.55 mmol,
84%) was isolated as a colorless solid; m.p. 57 °C. A doubled set
of broad signals is observed, due to the E/Z isomers (ratio 1:0.44)
Acknowledgments
We gratefully acknowledge support from Boehringer-Ingelheim, Bi-
berach. We are furthermore grateful to Wolfgang Saak and Detlev
Haase for X-ray crystallography and Dr. Herbert Frey for helping
us with this manuscript.
[1] Reviews: a) L. H. Sternbach, J. Med. Chem. 1979, 22, 1–7; b)
D. Hadjipavlou-Litina, C. Hansch, Chem. Rev. 1994, 94, 1483–
1505.
1
[2] Examples: a) N. D. Adhikary, P. Chattopadhyay, Eur. J. Org.
Chem. 2010, 1754–1762; b) B. Pettersson, A. Rydbeck, J.
Bergman, Org. Biomol. Chem. 2009, 7, 1184–1191; c) U. R.
Mach, N. E. Lewin, P. M. Blumberg, A. P. Kozikowski, Chem-
MedChem 2006, 1, 307–314; d) Y. Nakagawa, K. Irie, R. C.
Yanagita, H. Ohigashi, K.-i. Tsuda, J. Am. Chem. Soc. 2005,
127, 5746–5747; e) J. Sridhar, Z.-L. Wei, I. Nowak, N. E. Le-
win, J. A. Ayres, L. V. Pearce, P. M. Blumberg, A. P. Kozikow-
ski, J. Med. Chem. 2003, 46, 4196–4204; f) H. Yoshida, E. Shi-
rakawa, Y. Honda, T. Hiyama, Angew. Chem. 2002, 114, 3381–
3383; Angew. Chem. Int. Ed. 2002, 41, 3247–3249.
[3] N. Brown, G. Gao, M. Minatoya, B. Xie, D. VanderVelde,
G. H. Lushington, J.-P. H. Perchellet, E. M. Perchellet, K. R.
Crow, K. R. Buszek, J. Comb. Chem. 2008, 10, 628–631.
[4] F. Crestey, M. Witt, J. W. Jaroszewski, H. Franzyk, J. Org.
Chem. 2009, 74, 5652–5655.
[5] C. H. Kong, L. C. Chen, X. H. Xu, P. Wang, S. L. Wang, J.
Agric. Food Chem. 2008, 56, 11734–11739.
[6] a) J. F. Reichwein, B. Wels, J. A. W. Kruijtzer, C. Versluis,
R. M. J. Liskamp, Angew. Chem. 1999, 111, 3906–3910; Angew.
Chem. Int. Ed. 1999, 38, 3684–3687; b) T. Groth, M. Meldal,
J. Comb. Chem. 2001, 3, 45–63.
[7] M. Rössle, J. Christoffers, Synlett 2006, 106–108.
[8] a) R. Pflantz, P. Tielmann, M. Rössle, C. Hoenke, J. Christof-
fers, Eur. J. Org. Chem. 2007, 3227–3238; b) Review: J.
Christoffers, Catal. Today 2011, 159, 96–99.
at the carbamate C–N bond. H NMR (500 MHz, CDCl3); major
isomer: δ = 2.32 (s, 9 H), 2.62–2.75 (m, 2 H), 2.90 (s, 3 H), 3.74 (A
part of an ABX system, J = 6.1, J = 10.7 Hz, 1 H), 3.79 (B part
of an ABX system, J = 5.8, J = 10.6 Hz, 1 H), 3.82–3.87 (m, 1 H),
4.13 (A part of an AB system, J = 15.4 Hz, 1 H), 4.27 (B part of
an AB system, J = 15.1 Hz, 1 H), 5.76 (d, J = 8.5 Hz, 1 H), 7.28–
7.36 (m, 5 H) ppm; minor isomer: δ = 1.21 (s, 9 H), 2.90 (s, 3 H),
2.97–3.04 (m, 2 H), 3.08–3.17 (m, 1 H), 3.60–3.68 (m, 1 H), 3.82–
3.87 (m, 1 H), 4.11–4.16 (m, 1 H), 4.38–4.45 (m, 1 H), 5.53–5.57
(m, 1 H), 7.28–7.36 (m, 5 H) ppm; the OH proton was not ob-
served. 13C{1H} NMR (125 MHz, CDCl3); major conformer: δ =
27.99 (3ϫCH3), 34.88 (CH3), 41.35 (CH), 45.59 (CH2), 49.72
(CH2), 64.02 (CH2), 80.84 (C), 123.86 (CH), 126.09 (2ϫCH),
126.42 (CH), 128.75 (2ϫCH), 135.58 (C), 142.44 (C), 155.05 (C),
169.24 (C) ppm; minor conformer: δ = 27.99 (3ϫCH3), 35.55
(CH3), 40.98 (CH), 47.04 (CH2), 49.72 (CH2), 64.02 (CH2), 80.38
(C), 122.71 (CH), 126.09 (2ϫCH), 126.42 (CH), 128.75 (2ϫCH),
136.06 (C), 143.33 (C), 155.05 (C), 169.72 (C) ppm. IR (ATR): ν =
˜
3415 (w, br), 2977 (w), 2931 (w), 2881 (w), 1690 (s), 1669 (s), 1643
(s), 1428 (m), 1367 (m), 1246 (m), 1164 (s), 1083 (m), 768 (s), 701
(m) cm–1. MS (ESI): m/z (%) = 369 (100) [M + Na]+. HRMS calcd.
369.1790 (for C19H26N2NaO4) [M
C19H26N2O4 (346.42).
+
Na]+; found 369.1797.
[9] M. Rössle, T. Werner, A. Baro, W. Frey, J. Christoffers, Angew.
Chem. 2004, 116, 6709–6711; Angew. Chem. Int. Ed. 2004, 43,
6547–6549.
2-(4-Formyl-2-phenylpyrrol-1-yl)-N-methylacetamide (26): DMSO
(29 mg, 0.37 mmol) was added at –60 °C under an inert atmosphere
to a solution of oxalyl chloride (24 mg, 0.19 mmol) in abs. CH2Cl2
(0.9 mL) and the reaction mixture was stirred for 10 min at this
temperature. A solution of alcohol 25 (58 mg, 0.17 mmol) in abs.
CH2Cl2 (0.3 mL) was then added and stirring was continued for
15 min at –60 °C. NEt3 (86 mg, 0.85 mmol) was added and the mix-
ture was stirred for 5 min at –60 °C and then for 10 min at ambient
temperature. Water (5 mL) was added and the aqueous phase was
extracted with CH2Cl2 (3ϫ5 mL). The combined organic layers
were washed with saturated NaCl solution, aqueous H2SO4 (1%),
water, and saturated NaHCO3 solution (10 mL each) and then
dried (MgSO4) and filtered, and the solvents were evaporated. The
residue was chromatographed (CH2Cl2/MeOH 10:1, Rf = 0.31) to
yield the title compound 26 (26 mg, 0.11 mmol, 65%) as a yellow
[10] R. Pflantz, J. Sluiter, M. Kricˇka, W. Saak, C. Hoenke, J.
Christoffers, Eur. J. Org. Chem. 2009, 5431–5436.
[11] J. Basˇ, S. Recˇnik, J. Svete, S. Golicˇ-Grdadolnik, B. Stanovnik,
ARKIVOC (Gainesville, FL, U.S.) 2001, 2, 61–68.
[12] J. Christoffers, J. Sluiter, J. Schmidt, Synthesis 2011, 895–900.
[13] C. Schmuck, T. Rehm, L. Geiger, M. Schäfer, J. Org. Chem.
2007, 72, 6162–6170.
[14] J. A. McCubbin, M. L. Maddess, M. Lautens, Org. Lett. 2006,
8, 2993–2996 (Supporting Information).
[15] S. Kim, C. H. Oh, J. S. Ko, K. H. Ahn, Y. J. Kim, J. Org. Chem.
1985, 50, 1927–1932.
[16] J. Li, Y. Sha, Molecules 2008, 13, 1111–1119.
[17] CCDC-812530 (for 20) and -853489 (for 26) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[18] S. Lauwagie, R. Millet, J. Pommery, P. Depreux, J.-P. Henich-
art, Heterocycles 2006, 68, 1149–1162.
[19] R. M. Moriarty, C. J. Chany II, R. K. Vaid, O. Prakash, S. M.
Tuladhar, J. Org. Chem. 1993, 58, 2478–2482.
[20] D. P. Walker, S. E. Heasley, A. MacInnes, T. Anjeh, H.-F. Lu,
Y. M. Fobian, J. T. Collins, M. L. Vazquez, M. K. Mao, Synlett
2011, 2959–2962.
1
solid; m.p. 199 °C. H NMR (500 MHz, CDCl3): δ = 2.78 (d, J =
4.8 Hz, 3 H), 4.59 (s, 2 H), 5.42 (br. s, 1 H), 6.69 (d, J = 1.8 Hz, 1
H), 7.27–7.29 (m, 2 H), 7.37–7.42 (m, 4 H), 9.79 (s, 1 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 26.42 (CH3), 51.21 (CH2),
108.52 (CH), 127.16 (C), 128.74 (CH), 128.94 (2ϫCH), 129.01
(2ϫCH), 130.53 (CH), 130.62 (C), 137.44 (C), 167.70 (C), 185.22
(CH) ppm. IR (ATR): ν = 3285 (w), 3098 (w), 2818 (w), 1652 (s),
˜
1557 (m), 1481 (m), 1379 (m), 1174 (m), 1140 (s), 753 (s), 697 (s),
[21] P. G. Vasudev, S. Chatterjee, N. Shamala, P. Balaram, Chem.
Rev. 2011, 111, 657–687.
671 (m) cm–1. MS (ESI): m/z (%) = 265 [M + Na]+. HRMS calcd.
265.0953 (for C14H14N2NaO2) [M
C14H14N2O2 (242.27).
+
Na]+; found 265.0949.
Received: November 14, 2011
Published Online: February 3, 2012
1818
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Eur. J. Org. Chem. 2012, 1809–1818