Synthesis of piperazinones, piperazines, tetrahydropyrazines, and dihydropyrazinones from polymer-supported acyclic intermediates via N-Alkyl- and N-acyliminiums

Article abstract of DOI:10.1002/ejoc.201200591

Trisubstituted piperazinones, piperazines, tetrahydropyrazines, and dihydropyrazinones were prepared in a one-step procedure from easily accessible polymer-supported acyclic precursors containing either a masked aldehyde or ketone group. Acid-mediated unmasking of the aldehyde triggered cyclic iminium formation followed by reduction with triethylsilane present in the cleavage cocktail. The effect of the substituent at the iminium-forming nitrogen was evaluated: whereas complete conversion to the target compounds was observed with N-alkyl, aryl, and phenylsulfonamido derivatives, the N-acyl compound suffered from a partial reduction of the aldehyde to an alcohol. Similarly, ketones readily provided cyclic iminiums with N-alkyl compounds, whereas their cyclization with N-acyl precursors proceeded unwillingly. Interestingly, cleavage of the resin-bound acyclic precursor at 60 °C in the presence of triethylsilane resulted in the decomposition of the amide bond and formation of a lactone. An analogous synthetic route was also successfully used for the preparation of piperazines and tested as an alternative route for the synthesis of diazepanones. Straightforward solid-phase synthesis afforded linear precursors for formation of cyclic N-alkyl and N-acyliminiums. Exposure of acyclic resin-bound intermediates to TFA yielded trisubstituted dihydropyrazinones and tetrahydropyrazines, whereas treatment of the same intermediates with a TES-containing cleavage cocktail afforded piperazines and piperazinones. Copyright

Full text of DOI:10.1002/ejoc.201200591

Job/Unit: O20591
/KAP1
Date: 23-07-12 16:13:02
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201200591
Synthesis of Piperazinones, Piperazines, Tetrahydropyrazines, and
Dihydropyrazinones from Polymer-Supported Acyclic Intermediates via
N-Alkyl- and N-Acyliminiums
[a,b]
[a]
[a,b]
Lucie Brulíková,[a,b] Boyuan Wu, and Viktor Krchnák*
ˇ
ˇ
Barbora Vanková,
Keywords: Piperazinones / Cyclization / Piperazines / Solid-phase synthesis / Iminiums / Heterocycles
Trisubstituted piperazinones, piperazines, tetrahydropyr- tives, the N-acyl compound suffered from a partial reduction
azines, and dihydropyrazinones were prepared in a one-step
procedure from easily accessible polymer-supported acyclic
precursors containing either a masked aldehyde or ketone
group. Acid-mediated unmasking of the aldehyde triggered
cyclic iminium formation followed by reduction with trieth-
ylsilane present in the cleavage cocktail. The effect of the
substituent at the iminium-forming nitrogen was evaluated:
whereas complete conversion to the target compounds was
observed with N-alkyl, aryl, and phenylsulfonamido deriva-
of the aldehyde to an alcohol. Similarly, ketones readily pro-
vided cyclic iminiums with N-alkyl compounds, whereas
their cyclization with N-acyl precursors proceeded unwill-
ingly. Interestingly, cleavage of the resin-bound acyclic pre-
cursor at 60 °C in the presence of triethylsilane resulted in
the decomposition of the amide bond and formation of a lact-
one. An analogous synthetic route was also successfully used
for the preparation of piperazines and tested as an alterna-
tive route for the synthesis of diazepanones.
Introduction
Piperazines and piperazinones are frequently occurring
pharmacophores present in numerous currently used drugs
and a variety of chemical routes have been devised for their
preparation in a structurally diverse form (for in depth re-
view cf. e.g.[1]). One frequently applied route for piper-
azinones 3 syntheses is based on formation of 3,4-dihy-
dropyrazin-2(1H)-ones 2 (Scheme 1) from 2-amino-N-(2,2-
dimethoxyethyl)acetamides 1 through the agency of cyclic
iminium intermediates, followed by hydrogenation, typically
using a Pd catalyst.[2–4] Reduction of 3,4-dihydropyrazin-
Scheme 1. Reported syntheses of piperazinones.
We developed a solid-phase synthesis of linear precursors
for formation of cyclic N-alkyl and N-acyliminiums. Expo-
sure of the acyclic resin-bound intermediates to TFA
yielded trisubstituted dihydropyrazinones and tetra-
hydropyrazines, whereas treatment of the same intermedi-
ates with the TES-containing cleavage cocktail afforded
piperazines and piperazinones. This scenario represents an
example of scaffold hopping[12] as it enables the preparation
of topologically different scaffolds decorated with the same
R groups from identical precursors based on the selection
of resin-cleaving reaction conditions.
[4]
2(1H)-ones with triethylsilane (TES)[5] and NaCNBH3
has also been reported. Iminium chemistry has been re-
viewed in several excellent papers.[6–9] Alternative routes
from the analogous acyclic precursors by C–N bond forma-
tion include cyclization of mesylates 5 with the amide nitro-
gen[10] and Mitsunobu alkylation between the amide and
alcohol functions of precursor 6.[11] Amine – alcohol cycli-
zation has also been reported.[2]
[a] Department of Chemistry and Biochemistry, 251 Nieuwland
Science Center, University of Notre Dame,
Notre Dame, Indiana 46556, USA
Results and Discussion
Fax: +1-574-631-6652
E-mail: vkrchnak@nd.edu
The objective of this work was to demonstrate the ability
of structurally different acyclic precursors to form cyclic
iminiums and to reduce them with TES. We prepared model
compounds designed to form cyclic N-alkyl and N-acyl-
[b] Department of Organic Chemistry, Institute of Molecular and
Translational Medicine, Faculty of Science, Palacky University,
17. listopadu 12, 77146 Olomouc, Czech Republic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200591.
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B. Vanˇková, L. Brulíková, B. Wu, V. Krchnˇák
FULL PAPER
iminiums from secondary amines and amides. Cyclic imin-
iums were obtained by the reaction with internal carbonyl
compounds, aldehydes, and ketones. This section is divided
into three main parts. The first evaluates the ability of vari-
ous aldehydes and ketones to form piperazinones from N-
acyliminiums. The second part discloses the results ob-
tained with N-alkyliminiums. The last part of this section
briefly discusses application of the synthetic strategy to di-
azepanones.
Linear precursors for N-acyl and N-alkyliminiums were
prepared from simple commercially available building
blocks in the solid phase. Cyclic iminium intermediates
were formed from an aldehyde or ketone and amide or
amine. Among the various methods for iminium ion synthe-
sis, the condensation of secondary amides/amines with alde-
hydes/ketones is regarded as one of the most versa-
tile.[6,13–15] All polymer-supported acyclic precursors were
synthesized using standard solid-phase chemistry[16–21] and
individual synthetic steps will be portrayed for each particu-
lar reaction sequence.
Scheme 2. Solid-phase synthesis of model compounds 11. Reagents
and conditions: (i) 50% piperidine/DMF (v/v), 15 min; (ii) bromo-
acetic acid, DIC, DIEA, DCM, room temp., 1 h; (iii) 2,2-dimeth-
oxy-ethylamine, DIEA, DMF, room temp., 2 h; (iv) Fmoc-amino
acid, DIC, THF, 16 h; (v) benzenesulfonyl chlorides, lutidine,
DCM, room temp., 16 h; or 1-fluoro-2-nitrobenzenes, DIEA,
DMSO, room temp. for 4,5-dichloro-1-fluoro-2-nitrobenzene,
50 °C for 1-fluoro-2-nitrobenzene, 16 h; or carboxylic acid, DIC,
N-hydroxybenzotriazole (HOBt), DMF/DCM (1:1), 16 h; (vi) 10%
TES, 50% TFA, 40% DCM, 1 h.
atives afforded crude reaction mixtures containing different
ratios of three components: non-reduced 3,4-dihydropyr-
azin-2(1H)-one 10, target piperazinone 11, and amino
alcohol 12, formed by TES-mediated reduction of the alde-
hyde (Table 1). Modification of the reaction conditions (re-
action time, TES concentration, temperature) did not im-
prove the purity of target N-acylated compounds 11.
First, we focus on the construction of acyclic resin-
bound intermediates that can form N-acyliminiums with al-
dehydes and ketones; secondly, we disclose our results with
N-alkyliminium-forming intermediates.
N-Acyliminiums: Synthesis of Piperazinones
Table 1. Product distribution after 1 h treatment with TES/TFA
cleavage cocktail.[a]
Aldehyde-Containing Precursors
Entry R1
R2
R3
Composition of mixture [%]
In order to assess the scope and limitations of TFA cleav-
age and TES-mediated reduction of cyclic N-acyliminiums
we prepared a series of model resin-bound compounds 9
attached to the Rink resin[22] (Scheme 2) using well-docu-
mented chemistry (specific protocols are included in the ex-
perimental section). Resin-bound acyclic intermediates 9
were exposed to 50% TFA in DCM. 3,4-Dihydropyrazin-
2(1H)-ones 10 were cleanly formed in the absence of TES
in the cleavage cocktail. Since this route was well documen-
ted,[23] we did not focus on the isolation and characteriza-
tion of target 3,4-dihydropyrazin-2(1H)-ones 10.
10
11
12
1
2
3
4
5
6
H
H
H
H
H
H
H
H
CH3
H
H
H
benzoyl
Fmoc
Fmoc
Fmoc-Pro
Tos-Pro
Fmoc-Gly
30
10
23
40
66
68
40
68
58
52
24
23
30
22
11
Ͻ1
Ͻ1
Ͻ1
[a] Distribution of components in crude preparation was estimated
from LC traces with detection at λ = 220 nm.
Table 2 lists model compounds prepared for all three
Resin-bound acyclic intermediates 9 were then exposed types of N4-substituted target compounds. Replacement of
to 50% TFA in DCM containing 10% TES. Whereas all Gly with Ala [compound 11(1,2,1)] did not influence the
tested sulfonamides, N-alkyl, and N-aryl derivatives pro- purity, nor did synthesis on BAL linker[24] after reductive
vided target products 11, reactions of acyl and Fmoc deriv- amination with n-propylamine. To demonstrate the versatil-
Table 2. Synthesized piperazinones 11.
Entry
Product
R1
R2
R3
Purity [%][a]
MS [M + H]+
Yield [%]
1
2
3
4
5
6
7
8
9
11(1,1,1)
11(1,1,2)
11(1,1,3)
11(1,1,4)
11(1,1,5)
11(1,2,1)
11(2,1,1)
11(3,1,4)
11(3,1,6)
11(3,1,7)
–CH2-CONH2
–CH2-CONH2
–CH2-CONH2
–CH2-CONH2
–CH2-CONH2
H
H
H
H
H
Me
H
H
H
H
Tos
–CH2-CO-Ph
–(CH2)2-Pht
2-NO2-4-CF3-Ph
4,5-diCl-2-NO2-Ph
Tos
95
89
84
91
93
87
73
73
66
77
312
276
331
347
347, 349
326
454
389
385
321
81
66
47
71
67
76
53
32
62
29
–CH2-CONH2
–CH2-CO-βAla-Ala-NH2
–CH2-CONH-nPr
–CH2-CONH-nPr
–CH2-CONH-nPr
Tos
2-NO2-4-CF3-Ph
2-Nos
10
2-NO2-Ph
[a] Approximate purity estimated from LC traces with detection at λ = 220 nm.
2
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Nitrogen Heterocycles from Polymer-Supported Acyclic Intermediates
ity of the substitution pattern we prepared compound pendent on the R2 substituent. The ethyl precursors decom-
11(1,1,2) from resin 9(1,1,6) by alkylation with phenacyl posed significantly faster than phenyl or trifluoromethyl-
bromide and compound 11(1,1,3) from the same resin by phenyl-substituted derivatives.
Mitsunobu alkylation using N-(2-hydroxyethyl)phthal-
The TES/TFA-mediated transformation yielded unexpec-
imide.[25] The 2-Nos group was removed before cycliza- ted results. Treatment of acyclic substrates 17 with TES-
tion.[26] To confirm the applicability of the TES-mediated containing cleavage cocktail at 60 °C for 15–30 h afforded
reduction for the introduction of a piperazinone ring as a crude reaction mixtures composed of several components
peptide backbone constraint we prepared compound with two major products; the first corresponded to non-
11(2,1,1).
reduced 3,4-dihydro-1H-pyrazin-2-ones 20 and the second
corresponded to lactones 19, formed by TES-mediated re-
duction of the ketone to the alcohol and subsequent cycliza-
tion. The relative ratios of products 19 and 20 were highly
dependent on the R1 group. Although the trifluoromethyl-
phenyl-substituted derivative afforded a crude mixture of
non-reduced cyclic 20(1) and acyclic product 21(1) in a ratio
of 2:1 (both compounds were isolated and fully charac-
terized), the phenyl- and ethyl-modified precursors yielded
a mixture with minor 3,4-dihydro-1H-pyrazin-2-one 20, as
determined from LC traces (Table 3). The structures of acy-
clic methyl esters 21 were confirmed by 2D NMR spectro-
scopic experiments (COSY, gHMBC, gHSQC). Analogous
formation of lactone from carboxamide has been re-
ported.[28–32] Attempts to isolate lactones 19 were unsuc-
Ketone-Containing Precursors
The efficient formation of piperazinones by TES-medi-
ated reduction of cyclic N-acyliminiums prepared from al-
dehydes and amides prompted us to evaluate the applica-
tion of this transformation to N-acyliminiums prepared
using ketone-based intermediates, given that ketones are
known to be substantially less prone to formation of acyl-
iminiums.[13] Accordingly, we then synthesized resin bound
model compounds 17 attached to Wang resin[27] by a prop-
ylenediamine linker (Scheme 3).
Table 3. Synthesized acyclic compounds 21.
Entry
Com-
pound
R1
Ratio 20/
MS [M +
Na]+
Yield [%]
45
21[a]
1
4-CF3-
Ph
21(1)
1:2
485
2
3
21(2)
21(3)
Ph
Et
1:4
1:4
417
369
42
52
[a] Relative ratio estimated from LC traces with detection at λ =
220 nm.
Scheme 3. Synthesis of model compounds 21. Reagents and condi-
tions: (i) CDI, pyridine, DCM, room temp., 3 h, then 3-amino-1-
propanol, DCM, room temp., 2 h; (ii) phthalimide, PPh3, DIAD,
DMF, room temp., 16 h; (iii) hydrazine monohydrate, methanol/
THF (1:1), room temp., 4 h; (iv) Fmoc-Gly-OH, HOBt, DIC,
DMF/DCM (1:1), room temp., 2 h; (v) 50% piperidine/DMF (v/v),
room temp., 15 min; (vi) 4-nitrobenzenesulfonyl chloride (4-Nos-
Cl), lutidine, DCM, room temp., 16 h; (vii) bromoketone, DIEA,
DMF, room temp., 16 h; (viii) 10% TES, 50% TFA, 40% DCM,
room temp., 0.5–16 h; (ix) 10% TES, 50% TFA, 40% DCM, 60 °C,
15–30 h; (x) methanol, room temp., 16 h.
We first assessed the acid-mediated formation of cyclic
N-alkyliminiums from 17. The acyclic precursors 17 were
treated with TFA under the standard conditions (room
temp., 30 min) and yielded only the acyclic compound 18,
identified from LC/MS traces. Exposure to TFA at 60 °C
yielded the expected 3,4-dihydro-1H-pyrazin-2-ones 20, and
compound 20(4,1) was isolated and fully characterized. A
further increase in temperature to 80 °C and extension of
the reaction time from 1 h to 12 h resulted in decomposition
of the compounds; LC traces revealed complex mixtures
Scheme 4. Synthesis of acyclic hydroxy derivatives. Reagents and
conditions: (i) 50% piperidine/DMF (v/v), room temp., 15 min; ii)
4-Nos-Cl, lutidine, DCM, room temp., 16 h; (iii) methanol or eth-
anol, PPh3, DIAD, THF, room temp., 16 h; (iv) 2-mercaptoethanol,
DBU, DMF, room temp., 5 min; (v) Fmoc-Gly-OH, HOBt, DIC,
DMF/DCM (1:1), room temp., 16 h; (vi) bromoketone, DIEA,
DMF, room temp., 16 h; (vii) 10% TES, 50% TFA, 40% DCM,
60 °C, 22 h; (viii) methanol, room temp., 16 h; (ix) acetonitrile,
lacking a major product. The decomposition of 20 was de- 10 mm aqueous ammonium acetate, room temp., 16 h.
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B. Vanˇková, L. Brulíková, B. Wu, V. Krchnˇák
FULL PAPER
cessful due to decomposition of crude product in methanol,
the solvent used for dissolving crude product leading up to
purification.
Because the exposure of acyclic precursors 17 to the
TFA/TES cleavage cocktail caused reduction of the ketone
to the alcohol, and unexpected cleavage of the amide bond,
we evaluated the potential effect of the carboxamide N-sub-
stituent on the reaction outcome. We synthesized acyclic
precursors 26 attached to the Rink linker with N-methyl, N-
ethyl, and also N-H substituents (Scheme 4). TES-assisted
cyclization of all three precursors 26 at 60 °C afforded lact-
one 19 which underwent alcoholysis in methanol to give
methyl ester 21. To prevent methanolysis, we extracted the
crude product after cleavage from the resin into acetonitrile,
and LC/MS revealed the presence of 19. However, at-
tempted HPLC purification of this lactone using acetoni-
trile/water caused hydrolysis; following this procedure the
reaction products within the mixture were distributed as
80% of hydroxy acid 27 and 20% of lactone 19 as deter-
mined by LC.
Scheme 5. Synthesis of piperazines. Reagents and conditions: (i)
CDI, pyridine, DCM, room temp., 3 h, then diethylenetriamine,
DCM, room temp., 16 h; (ii) N-hydroxyphthalimide, DMF, room
temp., 16 h; (iii) Boc2O, pyridine, DCM, room temp., 2 h; (iv) hy-
drazine monohydrate, methanol/THF (1:1), room temp., 4 h; (v) 4-
Nos-Cl, lutidine, DCM, room temp., 16 h; (vi) bromoketone,
DIEA, DMF, room temp., 16 h; (vii) 10% TES, 50% TFA, 40%
DCM, 4 h to 16 h, (viii) 50% TFA, 50% DCM, room temp., 1 h.
of this segment of the acyclic precursor. Now, we synthe-
sized this segment by a stepwise assembly that enhanced
diversification. In addition, we also varied the type of linker
and attachment to resin in order to prepare compounds
with various functional groups on the R1 substituent
N-Alkyliminiums: Synthesis of Piperazines and
Tetrahydropyrazines
Unsuccessful synthesis of piperazinones using ketones in-
stead of aldehydes for cyclic N-acyliminium formation
prompted us to prepare N-alkyliminiums and explore their
reduction to piperazines, although piperazinones can also
be reduced to piperazines by DMS.[2] Since synthesis of
tetrahydropyrazines through the agency of cyclic N-alkyl-
iminiums has not been reported, we describe the synthesis
and full characterization of 2-substituted-1,2,3,4-tetra-
hydropyrazines. To prepare the acyclic precursor, we ap-
plied a synthetic route used recently for the preparation of
2-(2-amino/hydroxyethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]-
?>indazol-2-iums[33] (Scheme 5). Resin-bound acyclic pre-
Scheme 6. Preparation of resin-bound amines. Reagents and condi-
cursors 31 were treated with TFA to yield tetrahydropyr- tions: (i) trichloroacetonitrile, DCM, 0 °C, 30 min, then DBU,
DCM, room temp., 1 h; (ii) 2-(Fmoc-amino)ethanol, anhydrous
azines 33. TFA cleavage in the presence of TES yielded tar-
get piperazines 32. The cyclization and subsequent re-
THF, BF3·Et2O, room temp., 30 min; (iii) 50% piperidine/DMF
(v/v), room temp., 15 min; (iv) Fmoc-β-Ala-OH, HOBt, DIC,
duction proceeded smoothly although the reaction time had
DCM/DMF (1:1), room temp., 16 h; (v) 3-amino-1-propanol, 10%
to be extended relative to the N-acyliminium case in order
to achieve optimal transformation to the target compounds
(Table 4).
Encouraged by these results, we expanded the chemistry
to diversify substituents on the heterocycle. Previous syn-
AcOH in DMF, room temp., 16 h, then NaBH(OAc)3, 10%AcOH
in DMF, room temp., 8 h; (vi) 4-Nos-Cl, lutidine, DCM, room
temp., 16 h; (vii) phthalimide, PPh3, DIAD, anhydrous THF, room
temp., 16 h; (viii) 2-mercaptoethanol, DBU, DMF, room temp.,
5 min; (ix) p-toluenesulfonyl chloride, lutidine, DCM, room temp.,
16 h; (x) hydrazine monohydrate, THF/methanol (1:1, v/v), room
theses using diethylenetriamine did not allow modification temp., 16 h.
Table 4. Synthesized piperazines 32.
Entry
Product
R1–H
R2
Time [h]
Purity [%][a]
MS [M + H]+
Yield [%]
1
2
3
4
5
6
7
32(1,2)
32(1,4)
32(1,5)
32(2,1)
32(2,3)
32(2,5)
32(3,5)
–(CH2)2-NH2
–(CH2)2-NH2
–(CH2)2-NH2
–(CH2)2-OH
–(CH2)2-OH
–(CH2)2-OH
Ph
5
16
4
16
20
17
48
89
86
77
91
81
87
86
391
421
416
460
344
417
444
73
63
57
23
56
27
61
4-Me-Ph
4-CN-Ph
4-CF3-Ph
Et
4-CN-Ph
4-CN-Ph
–(CH2)2-CONH2
[a] Approximate purity estimated from LC traces with detection at λ = 220 nm.
4
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Nitrogen Heterocycles from Polymer-Supported Acyclic Intermediates
Table 5. Synthesized tetrahydropyrazines 33.
Entry
Product
R1–H
R2
Purity[%][a]
MS [M + H]+
Yield [%]
1
2
3
4
5
6
33(1,5)
33(1,6)
33(1,7)
33(2,6)
33(4,1)
33(4,2)
–(CH2)2-NH2
–(CH2)2-NH2
–(CH2)2-NH2
–(CH2)2-OH
–(CH2)3-NH-Tos
–(CH2)3-NH-Tos
4-CN-Ph
4-Me-Ph
4-Cl-Ph
4-Me-Ph
4-CF3-Ph
Ph
88
92
87
84
91
83
414
403
423
404
625
557
79
74
83
67
35
25
[a] Approximate purity estimated from LC traces with detection at λ = 220 nm.
(amine, amide, sulfonamide, alcohol). To obtain alcohols, fully in 20 h. Although no electron withdrawing group was
we immobilized 2-(Fmoc-amino)ethanol to Wang resin present on the aliphatic bromoketone, the lack of an elec-
[resin 34(1)].[34,35] Amides were prepared by acylation of tron donating group (in this case the benzene ring) in the
Rink amide resin with Fmoc-β-Ala-OH [resin 34(2)] aliphatic bromoketone potentially aided such a process.
whereas sulfonamides were synthesized on BAL resin using
3-aminopropanol and subsequently converted to resin- cyclic tetrahydropyrazines 33 (Table 5). Surprisingly, these
bound amines 34(3) (Scheme 6).
pyrazines 33 substituted with p-toluenesulfonyl moiety (R1)
The cleavage of acyclic derivatives 41 using TFA afforded
Resin bound amines 34 were subjected to a reaction se- exhibited significantly lower stability when compared to de-
quence analogous to Scheme 7. Target piperazines 32 were rivatives with amine, amide or alcohol modification.
obtained by TFA cleavage in the presence of TES. The Furthermore, the fast decomposition of all prepared tetra-
model compounds’ reduction capacity in the cleavage cock- hydropyrazines substituted with the 2-Nos moiety (R3) was
tail with TES relied heavily on the presence of electron observed during any attempt to isolate the pure product
withdrawing groups on the aromatic ring of the bromo- without any dependence on the R2 substituent (specifically
ketones. Specifically, we first alkylated the primary amine derivatives with R2 = trifluoromethylphenyl, phenyl, and
group with bromoacetophenone, and there was no trace of ethyl groups). On the other hand, 4-Nos crude target prod-
reduction even after 48 h [unlike the N-aminopropyl com- ucts displayed noticeably improved stability. Therefore, we
pound 32(1,2)]. However, when electron withdrawing isolated and fully characterized derivatives 33(4,2) and
groups, in this case trifluoromethyl or cyano groups, were 33(4,1).
present on bromoketones with an aromatic ring, the com-
pound was reduced successfully after 17 h. Although such
was the case for both model compound sets with –OH
and –CONH2 end groups, compound 32(3,5) with its car-
Ring Expansion – Synthesis of Diazepanones
The synthetic route described in Scheme 2 can also be
applied to the synthesis of seven-membered ring di-
azepanones. The use of Fmoc-β-Ala-OH instead of α-
amino acids yielded resin-bound compound 42, replacing
2,2-dimethoxy-ethylamine with 3,3-diethoxypropylamine
yielded compound 43 (Scheme 8). Resin-bound acyclic pre-
cursors 42 and 44 were treated with the TES-containing
cleavage cocktail to afford 1,4-diazepan-5-ones 43 and 1,4-
diazepan-2-ones 45 (Table 6). The purity and yield of target
compounds was expectedly lower relative to those of the
six-membered ring forming reactions. The major impurity
corresponded to the non-reduced olefin, analogous to com-
pound 10; we have not tried to optimize the reaction condi-
tions. Despite the presence of olefin, these synthetic routes
are still useful for practical syntheses, and optimized proto-
cols will be reported in due time.
boxamide took 48 h to be reduced. Finally, we prepared
model compound 32(2,3) with an aliphatic bromoketone, 1-
bromobutan-2-one, and the reduction proceeded success-
Scheme 7. Stepwise assembly of the acyclic precursors. Reagents
and conditions: (i) 4-Nos-Cl, lutidine, DCM, room temp., 16 h; (ii)
N-(2-hydroxyethyl)phthalimide, PPh3, DIAD, anhydrous THF,
room temp., 16 h; (iii) 2-mercaptoethanol, DBU, DMF, room
temp., 5 min, then Boc2O, DCM, room temp., 2 h; (iv) hydrazine
monohydrate, methanol/THF (1:1) room temp., 16 h, then 4-Nos-
Cl, lutidine, DCM, room temp., 16 h; (v) bromoketones, DIEA,
DMF, room temp., 16 h; (vi) 10% TES, 50% TFA, 40% DCM,
16 h to 48 h; (vii) 50% TFA, 50% DCM, 1 h.
Scheme 8. Access to diazepanones. For reagents and conditions cf.
Scheme 2.
Eur. J. Org. Chem. 0000, 0–0
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B. Vanˇková, L. Brulíková, B. Wu, V. Krchnˇák
FULL PAPER
Table 6. 1,4-Diazepan-5-ones 43 and 1,4-diazepan-2-ones 45.
Entry
Product
R1–H
R2
Purity [%][a]
MS [M + H]+
Yield [%]
1
2
3
4
43(1,1)
43(1,8)
45(3,6)
45(3,7)
–CH2-CONH2
–CH2-CONH2
–CH2-CONH-nPr
–CH2-CONH-nPr
Tos
Fmoc-
2-Nos
61
64
47
57
326
394
399
335
44
NI
14
35
2-NO2-Ph
[a] Relative amount in crude product based on LC traces with detection at λ = 220 nm; NI, not isolated.
Arylation with 1-Fluoro-2-nitrobenzenes (Resins 9–2): The Fmoc
protecting group of resin 8 (ca. 250 mg) was removed as described
above. The resin was washed 3ϫ with DMSO. A solution of 1-
fluoro-2-nitrobenzenes (0.5 m, 1 mmol) and DIEA (1 mmol,
174 μL) in DMSO (2 mL) was added to the resin and the resin
slurry was agitated at 50 °C (for unsubstituted o-fluoronitro-
benzene) or room temp. (for 4,5-dichloro-1-fluoro-2-nitrobenzenes)
for 16 h. The resin was washed 3ϫ with DMSO and 5ϫ with
DCM.
Conclusions
Straightforward solid-phase synthesis afforded linear
precursors for the formation of cyclic N-alkyl and N-acyl-
iminiums. Exposure of acyclic resin-bound intermediates to
TFA yielded trisubstituted dihydropyrazinones and tetra-
hydropyrazines, whereas treatment of the same intermedi-
ates with the TES-containing cleavage cocktail afforded pip-
erazines and piperazinones. N-Alkyl, N-aryl, and N-benz-
enesulfonyl derivatives were obtained in high purity, but N-
acyl derivatives suffered from incomplete reduction of dihy-
dropyrazinones and partial reduction of the aldehyde to the
alcohol. The TES-mediated approach is also amenable to
synthesis of diazepanones.
Acylation with Fmoc-Amino Acids or Carboxylic Acids [Resins 9–3,
16, 24, 34(2)]: The Fmoc protecting group of resins 8, 15, 23, 7(1)
(ca. 250 mg) was removed as described above. The resin was washed
3ϫ with DCM. Fmoc-amino acids (0.4 mmol) were dissolved in
DMF (1 mL) and HOBt (0.4 mmol, 61 mg), DIC (0.4 mmol,
63 μL) and DCM (1 mL) were added and the solution was added
to the resin. After 16 h reaction at room temp., the resin was
washed 3ϫ with DMF and 3ϫ with DCM.
Experimental Section
Reaction of Wang Resin with CDI and 3-Amino-1-propanol (Resins
14) or Diethylenetriamine (Resins 28): Wang resin (Advanced
ChemTech, 1 mmol/g, 1 g) was washed 3ϫ with DCM. A solution
of CDI (810 mg, 5 mmol) and pyridine (400 μL, 5 mmol) in DCM
(10 mL) was added and the resin slurry was agitated at room temp.
for 2 h. The resin was washed 3ϫ with DCM and a solution of 3-
amino-1-propanol or diethylenetriamine (5 mmol) in DCM
(10 mL) was added. Resin slurry was agitated at room temp. for
16, washed 5ϫ with DCM.
Synthesis of Acetals: Acylation with Bromoacetic Acid, Reaction
with 2,2-Dimethoxyethylamine or 3,3-Diethoxypropylamine and
Acylation with Fmoc-Amino Acids (Resins 8)
Rink amide resin 7(1) (ca. 1 g, loading 0.66 mmol/g) was washed
3ϫ with DCM. The Fmoc protecting group was removed by
15 min exposure to 50% piperidine in DMF and then the resin was
washed 3ϫ with DMF and 3ϫ with DCM.
Resins 7 were washed 3ϫ with DCM. A solution of bromoacetic
acid (0.5 m, 5 mmol, 700 mg) in DCM (10 mL) was prepared in a
polypropylene reaction vessels and DIC (2.5 mmol, 387 μL) was
added. After 5 min N,NЈ-diisopropylurea (DIU) was filtered off,
DIEA (2.5 mmol, 436 μL) was added and solution was added to
resin and reacted for 1 h. The resin was washed 5ϫ with DCM
and 3ϫ with DMF.
Mitsunobu Reaction with Phthalimide (Resins 15,37) or N-(2-
Hydroxyethyl)phthalimide (Resins 29, 39): Resins 14, 36, 28, 24
(ca. 1 g) were washed 3ϫ with anhydrous THF. Solutions of
phthalimide (2.5 mmol, 368 mg) or N-(2-hydroxyethyl)phthalimide
(2.5 mmol, 478 mg) and PPh3 (2.5 mmol, 655 mg) in anhydrous
THF (10 mL) were added. The resin was kept in a freezer for
30 min and then reacted with DIAD (2.5 mmol, 480 μL) at room
temp. for 16 h. The resin was washed 3ϫ with THF and 5ϫ with
DCM.
A solution of 2,2-dimethoxy-ethylamine (10 mmol, 1.09 mL) or
3,3-diethoxy-propylamine (10 mmol, 1.62 mL) and DIEA
(10 mmol, 1.74 mL) in DMF (10 mL) were added to the resin, and
the reaction slurry was then agitated for 2 h. The resin was washed
3ϫ with DMF, 3ϫ with DCM, and then 3ϫ with THF.
Mitsunobu Reaction with Methanol or Ethanol (Resins 23): Resins
22 (ca. 250 mg) were washed 3ϫ with anhydrous THF. A solution
of methanol (0.625 mmol, 25 μL) or ethanol (0.625 mmol, 37 μL)
and PPh3 (0.625 mmol, 164 mg) in anhydrous THF (2.5 mL) was
added. The resin was kept in a freezer for 30 min and then reacted
with DIAD (0.625 mmol, 123 μL) at room temp. for 16 h. The resin
was washed 3ϫ with THF and 5ϫ with DCM.
A solution of Fmoc-amino acid (Fmoc-Gly-OH: 10 mmol, 2.97 g
or Fmoc-Ala-OH: 10 mmol, 3.11 g) and DIC (5 mmol, 774 μL) in
THF (10 mL) were added to resin, and the reaction slurry was agi-
tated at room temp. for 16 h. The resin was washed 3ϫ with THF
and 3ϫ with DCM.
Removal of Pht Group [Resins 15, 30, 34(3), 40]: Resin 14, 29, 38,
39 (ca. 1 g) was washed 3ϫ with THF and reacted with a solution
of hydrazine hydrate (2 mL) in methanol/THF (10 mL, 1:1) at room
temp. for 16 h. The resin was washed 3ϫ with methanol, 5ϫ with
DCM.
Sulfonylation with Benzenesulfonyl Chlorides (Resins 9–1, 16, 22, 30,
37, 39): Resins 8, 15, 7(1), 29, 36, 34 (ca. 250 mg) were washed 3ϫ
with DCM and 3ϫ with DMF. The Fmoc protecting group was
removed by 15 min exposure to 50% piperidine in DMF and then
the resin was washed 3ϫ with DMF and 3ϫ with DCM. A 0.5 m
solution of benzenesulfonyl chlorides (1 mmol) and 0.5 m lutidine
(1 mmol, 116 μL) in DCM (2 mL) was added to the resin and the
reaction slurry was agitated at room temp. for 16 h. The resin was
washed 5ϫ with DCM.
Alkylation with Bromoketones (Resins 17, 26, 31, 41): Resin 16, 25,
30, 40 (ca. 250 mg) was washed 3ϫ with DMF. A solution (0.5 m)
of bromoketones (1.25 mmol) and DIEA (1.25 mmol, 218 μL) in
DMF (2.5 mL) was added to the resin, and the reaction slurry was
6
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Nitrogen Heterocycles from Polymer-Supported Acyclic Intermediates
agitated at room temp. for 16 h. The resin was washed 3ϫ with
DMF and 5ϫ with DCM.
127.6, 125.2, 120.1, 115.2, 107.5, 65.7, 47.6, 46.6, 45.4, 42.0 ppm.
HRMS (ESI): calcd. for C2.3H23N4O5 [M + H]+ 435.1654; found
435.1663.
Removal of Nos Group (Resins 24, 30, 38): Resin 23, 29, 37 (ca. 1 g)
was washed 3ϫ with DMF and was treated with a solution of 2-
mercaptoethanol (0.6 m, 6 mmol, 420 μL) and DBU (0.2 m,
2 mmol, 300 μL) in DMF (10 mL) for 5 min.
2-[2-Oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-acetamide 11(1,1,1):
Yield 24 mg (81%) of amorphous powder. 1H NMR (600 MHz,
[D6]DMSO): δ = 7.70 (m, 2 H), 7.48 (m, 2 H), 7.36 (br. s., 1 H),
7.10 (br. s., 1 H), 3.81 (s, 2 H), 3.52 (s, 2 H), 3.35–3.38 (m, 2 H),
3.21–3.27 (m, 2 H), 2.42 (s, 3 H) ppm. 13C NMR (151 MHz, [D6]-
DMSO): δ = 169.3, 163.4, 144.2, 131.3, 130.1, 127.8, 48.6, 48.6,
46.9, 42.7, 21.1 ppm. HRMS (ESI): calcd. for C13H18N3O4S [M +
H]+ 312.1013; found 312.1037.
Reaction with Boc2O (Resins 29, 40): Resin 28, 39 (ca. 1 g) was
washed with 3ϫ with DCM and was treated with a solution of
Boc2O (5 mmol, 1.1 g) in DCM (10 mL) at room temp. for 2 h. The
resin was then washed 5ϫ with DCM.
Reaction of Wang Resin with Trichloroacetonitrile and 2-(Fmoc-
amino)ethanol [Resins 34(1)]: Wang resin (1 g) was suspended in
solution of trichloroacetonitrile (1.5 mL) in anhydrous DCM
(10 mL) and kept for 30 min in freezer. Then, a solution of DBU
(100 μL) in anhydrous DCM (2 mL) was added and the resin slurry
was kept at room temp. for 1 h. The resin was washed 3ϫ with
anhydrous DCM and 3ϫ with anhydrous THF. A solution of 2-
(Fmoc-amino)ethanol (3 mmol, 849 mg) in anhydrous THF
(10 mL) was added to the resin, followed by dropwise addition of
a solution of BF3·Et2O (63 μL). The resin was reacted at room
temp. for 30 min and washed 3ϫ with THF, 3ϫ with methanol
then 5ϫ with DCM.
2-[2-Oxo-4-(2-oxo-2-phenyl-ethyl)-piperazin-1-yl]-acetamide
11(1,1,2): Yield 13.7 mg (66%) of amorphous powder. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.97 (dd, J = 8.4, 1.3 Hz, 2 H), 7.60–
7.68 (m, 1 H), 7.53 (t, J = 7.8 Hz, 2 H), 7.38 (br. s., 1 H), 7.05 (br.
s., 1 H), 4.04 (s, 2 H), 3.87 (s, 2 H), 3.27–3.33 (m, 2 H), 3.22 (s, 2
H), 2.81–2.88 (m, 2 H) ppm. 13C NMR (151 MHz, [D6]DMSO): δ
= 196.6, 169.7, 166.3, 135.7, 133.4, 128.7, 128.0, 61.8, 56.4, 48.9,
48.1, 47.1 ppm. HRMS (FAB): calcd. for C14H18N3O3 [M + H]+
276.1339; found 276.1343.
2-{4-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2-oxo-piper-
azin-1-yl}acetamide 11(1,1,3): Yield 6.9 mg (47%) of amorphous
powder. 1H NMR (600 MHz, [D6]DMSO): δ = 7.86–7.90 (m, 2 H),
7.82–7.86 (m, 2 H), 7.33 (br. s., 1 H), 7.02 (br. s., 1 H), 3.82 (s, 2
H), 3.72 (t, J = 6.3 Hz, 2 H), 3.20–3.25 (m, 2 H), 3.08 (s, 2 H),
2.69–2.75 (m, 2 H), 2.61 (t, J = 6.3 Hz, 2 H) ppm. 13C NMR
(151 MHz, [D6]DMSO): δ = 169.6, 167.8, 166.2, 134.5, 131.6,
123.1, 56.7, 54.1, 48.6, 48.0, 47.1, 39.8, 34.7 ppm. HRMS (FAB):
calcd. for C16H19N4O4 331.1379; found 331.1401.
Reductive Amination with 3-Amino-1-propanol (Resins 36): BAL
resin 35 (ca. 1 g) was washed 3ϫ with DCM and 3ϫ with dry
DMF. A solution of dry DMF (9 mL), AcOH (1 mL), and 3-
amino-1-propanol (380 μL, 5 mmol) was added. The resin slurry
was agitated at room temp. 17 h. Then sodium triacetoxyborohyd-
ride (1.056 g, 5 mmol) was added, agitated for 5 h, a second portion
of sodium triacetoxyborohydride (1.056 g, 5 mmol) was added and
agitated for 3 h. The resin was washed 3ϫ with AcOH (5%) in
DMF then 3ϫ with DMF neutralized with piperidine (5%) in
DMF, then 5ϫ with DMF and finally 3ϫ with DCM.
2-(4-(2-Nitro-4-(trifluoromethyl)phenyl)-2-oxopiperazin-1-yl)-
acetamide 11(1,1,4): Yield 37.3 mg (71%) of amorphous powder.
1H NMR (600 MHz, [D6]DMSO): δ = 8.18 (d, J = 2.0 Hz, 1 H),
7.86 (dd, J = 9.1, 2.0 Hz, 1 H), 7.48 (d, J = 9.1 Hz, 1 H), 7.45 (s,
1 H), 7.13 (s, 1 H), 3.96 (s, 2 H), 3.81 (s, 2 H), 3.51–3.56 (m, 2 H),
3.46–3.50 (m, 2 H) ppm. 13C NMR (151 MHz, [D6]DMSO): δ =
169.5, 165.0, 145.6, 138.4, 130.1, 123.8–124.2 (m), 123.6 (q, J =
270.9 Hz), 120.3, 119.2 (q, J = 33.7 Hz), 52.9, 48.7, 47.4, 46.2 ppm.
HRMS (FAB): calcd. for C13H14F3N4O4 347.0967; found 347.0962.
Reaction with p-Toluenesulfonyl Chloride (Resins 38): Resin 37
(ca. 1 g) was washed 3ϫ with DCM. A solution of p-toluenesulf-
onyl chloride (572 mg, 3.0 mmol) and lutidine (382 μL, 3.3 mmol)
in DCM (10 mL) was added. The resin slurry was agitated at room
temp. for 22 h. The resin was washed 5ϫ with DCM.
Cleavage from Resin and Reduction (Compounds 11, 21, 32, 43, and
45): Resin 9, 41, 42, or 44 (ca. 200 mg) was treated with a solution
of TFA, TES, and DCM (2 mL, 5:1:4) for 1–48 h. Resin 17
(ca. 250 mg) was treated with a solution of TFA, TES, and DCM
(2 mL, 5:1:4) for 15–30 h at 60 °C. The cleavage cocktail was col-
lected, and the resin was washed 3ϫ with TFA (50%) in DCM.
The combined extracts were concentrated by a stream of nitrogen,
and the crude products were purified by reverse phase HPLC.
2-(4-(4,5-Dichloro-2-nitrophenyl)-2-oxopiperazin-1-yl)acetamide
11(1,1,5): Yield 34.6 mg (67%) of amorphous powder. 1H NMR
(600 MHz, [D6]DMSO): δ = 8.19 (s, 1 H), 7.62 (s, 1 H), 7.44 (s, 1
H), 7.12 (s, 1 H), 3.94 (s, 2 H), 3.76 (s, 2 H), 3.42–3.46 (m, 2 H),
3.38–3.42 (m, 2 H) ppm. 13C NMR (151 MHz, [D6]DMSO): δ =
169.5, 165.1, 142.7, 139.4, 136.6, 127.4, 122.3, 122.1, 53.2, 48.5,
48.1, 46.5 ppm. HRMS (FAB): calcd. for C12H13Cl2N4O4 347.0327;
found 347.0308.
Cleavage from Resin with TFA (Compounds 33): Resin 31
(ca. 250 mg) was treated with a solution of TFA/DCM (2 mL, 1:1)
for 1 h. The cleavage cocktail was collected, and the resin was
washed 3ϫ with TFA (50%) in DCM. The combined extracts were
concentrated by a stream of nitrogen, and the crude products were
purified by reverse phase HPLC.
2-[3-Methyl-2-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-acetamide
11(1,2,1): Yield 23.4 mg (76%) of amorphous powder. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.73 (m, 2 H), 7.42 (m, 2 H), 7.31 (br.
s., 1 H), 7.05 (br. s., 1 H), 4.13–4.22 (m, 1 H), 3.80 (d, J = 16.5 Hz,
1 H), 3.70 (d, J = 16.5 Hz, 1 H), 3.64 (dt, J = 13.9, 3.2 Hz, 1 H),
3.49 (ddd, J = 13.9, 9.6, 4.4 Hz, 1 H), 3.17–3.28 (m, 2 H), 2.39 (s,
3 H), 1.31 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (151 MHz, [D6]-
DMSO): δ = 169.2, 167.3, 143.7, 136.4, 130.1, 126.9, 53.7, 48.8,
46.8, 38.8, 21.0, 18.0 ppm. HRMS (ESI): calcd. for C14H20N3O4S
[M + H]+ 326.1169; found 326.1191.
Analytical Data of Individual Compounds: Piperazinones
9H-Fluoren-9-yl-methyl [2-(4-Carbamoylmethyl-3-oxo-3,4-dihydro-
2H-pyrazin-1-yl)-2-oxoethyl]-carbamate 10(1,1,8): Yield 3.7 mg
1
(14%) of amorphous powder. H NMR (600 MHz, [D6]DMSO): δ
= 7.90 (m, 2 H), 7.73 (m, 2 H), 7.58 (t, J = 6.2 Hz, 1 H), 7.47 (s, 2-(3-{2-[2-Oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-acetyl-
1 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.31–7.36 (m, 2 H), 7.14 (s, 1 H),
amino}-propionylamino)propionamide 11(2,1,1): Yield 18.1 mg
(53%) of amorphous powder. H NMR (600 MHz, [D6]DMSO): δ
1
6.46–6.50 (m, 1 H), 5.86–5.91 (m, 1 H), 4.28–4.32 (m, 3 H), 4.20
(s, 2 H), 4.05 (s, 2 H), 3.96 (d, J = 6.2 Hz, 2 H) ppm. 13C NMR = 7.97 (d, J = 7.6 Hz, 1 H), 7.93 (t, J = 5.7 Hz, 1 H), 7.70 (m, 2
(75 MHz, [D6]DMSO): δ = 168.9, 165.0, 163.0, 156.6, 143.8, 140.7,
H), 7.49 (m, 2 H), 7.28 (br. s., 1 H), 6.95 (br. s., 1 H), 4.17 (quin,
Eur. J. Org. Chem. 0000, 0–0
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/KAP1
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Pages: 11
B. Vanˇková, L. Brulíková, B. Wu, V. Krchnˇák
(300 MHz, [D6]DMSO): δ = 8.32–8.37 (m, 2 H), 8.03–8.08 (m, 2
FULL PAPER
J = 7.3 Hz, 1 H), 3.84–3.90 (m, 1 H), 3.79–3.84 (m, 1 H), 3.52 (s,
2 H), 3.33–3.37 (m, 2 H), 3.17–3.27 (m, 4 H), 2.42 (s, 3 H), 2.18– H), 7.21–7.36 (m, 6 H), 5.60 (br. s., 1 H), 4.72 (dd, J = 8.6, 3.9 Hz,
2.33 (m, 2 H), 1.16 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (151 MHz,
[D6]DMSO): δ = 174.4, 170.0, 167.1, 163.5, 144.3, 131.4, 130.1,
1 H), 4.36 (d, J = 18.5 Hz, 1 H), 4.19 (d, J = 18.5 Hz, 1 H), 3.54
(s, 3 H) ppm, one proton overlapped with water. 13C NMR
127.8, 48.7, 48.6, 47.9, 46.9, 42.8, 35.3, 35.1, 21.1, 18.3 ppm. (75 MHz, [D6]DMSO): δ = 169.2, 149.7, 145.1, 142.6, 128.6, 128.2,
HRMS (ESI): calcd. for C1.9H28N5O6S [M + H]+ 454.1755; found 127.4, 126.0, 124.4, 71.8, 55.1, 51.9, 49.2 ppm. HRMS (ESI): calcd.
454.1732.
for C17H18N2O7SNa [M + Na]+ 417.0727; found 417.0731.
2-[4-(2-Nitro-4-trifluoromethyl-phenyl)-2-oxo-piperazin-1-yl]-N-
propyl-acetamide 11(3,1,4): Yield 8.0 mg (32%) of amorphous pow-
der. H NMR (600 MHz, [D6]DMSO): δ = 8.19 (d, J = 1.8 Hz, 1
H), 7.96 (t, J = 5.4 Hz, 1 H), 7.88 (dd, J = 9.0, 1.8 Hz, 1 H), 7.47
(d, J = 9.0 Hz, 1 H), 3.98 (s, 2 H), 3.82 (s, 2 H), 3.50 (bd, J =
Methyl-[(2-Hydroxybutyl)-(4-nitrobenzenesulfonyl)-amino]acetate
21(3): Yield 12.3 mg (52 %) of amorphous powder. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.35–8.42 (m, 2 H), 8.05–8.12 (m, 2
H), 4.75 (d, J = 4.7 Hz, 1 H), 4.31 (d, J = 18.2 Hz, 1 H), 4.22 (d,
J = 18.2 Hz, 1 H), 3.54 (s, 3 H), 3.47 (br. s., 1 H), 3.28 (d, J =
1
5.3 Hz, 4 H), 3.02 (q, J = 6.7 Hz, 2 H), 1.41 (sxt, J = 7.3 Hz, 2 H), 3.6 Hz, 1 H), 3.05 (dd, J = 14.5, 7.9 Hz, 1 H), 1.15–1.46 (m, 2 H),
0.83 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 167.3, 165.0, 145.5, 138.5, 130.1, 124.0–124.4 (m), 123.7 (q, J =
270.9 Hz), 120.3, 119.2, (q, J = 33.7 Hz), 52.8, 48.7, 47.5, 46.3,
0.79–0.87 (m, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
169.2, 149.7, 145.0, 128.7, 124.4, 70.5, 53.4, 51.9, 49.3, 27.3,
9.8 ppm. HRMS (ESI): calcd. for C13H18N2O7SNa [M + Na]+
40.3, 22.4, 11.4 ppm. HRMS (ESI): calcd. for C16H19F3N4O4 [M 369.0727; found 369.0717.
+ H]+ 389.1416; found 389.1431.
Analytical Data of Individual Compounds: Piperazines
2-[4-(2-Nitro-benzenesulfonyl)-2-oxo-piperazin-1-yl]-N-propyl-
acetamide 11(3,1,6): Yield 21 mg (62%) of amorphous powder. H
2-[4-(4-Nitro-benzenesulfonyl)-2-phenyl-piperazin-1-yl]-ethylamine
32(1,2): Yield 34.2 mg (73 %) of amorphous powder. 1H NMR
(600 MHz, [D6]DMSO): δ = 8.42 (m, 2 H), 8.00 (m, 2 H), 7.32–
7.36 (m, 5 H), 7.28–7.31 (m, 1 H), 3.68 (dd, J = 11.4, 2.3 Hz, 1 H),
3.45 (ddd, J = 11.3, 2.8, 2.6 Hz, 1 H), 3.39 (dd, J = 10.3, 3.2 Hz,
1 H), 3.12–3.19 (m, 1 H), 2.58–2.67 (m, 1 H), 2.51–2.57 (m, 2 H),
2.22–2.33 (m, 2 H), 1.94–2.04 (m, 1 H), 1.76 (s, 3 H) ppm. 13C
NMR (151 MHz, [D6]DMSO): δ = 150.2, 140.4, 139.5, 129.2,
128.7, 128.0, 127.9, 124.8, 65.5, 53.3, 52.6, 50.3, 46.0, 36.9 ppm.
HRMS (ESI): calcd. for C18H23N4O4S [M + H]+ 391.1435; found
1
NMR (300 MHz, [D6]DMSO): δ = 8.10 (d, J = 7.5 Hz, 1 H), 8.00–
8.07 (m, 1 H), 7.84–7.99 (m, 3 H), 3.91 (s,2 H) 3.86 (s,2 H), 3.52–
3.60 (m, 2 H), 3.41 (t, J = 5.2 Hz, 2 H), 3.00 (q, J = 6.6 Hz, 2 H),
1.38 (sxt, J = 7.2 Hz, 2 H), 0.82 (t, J = 7.3 Hz, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 167.0, 163.4, 147.9, 135.3, 132.7,
130.7, 128.8, 124.5, 48.9, 48.1, 47.3, 42.6, 40.3, 22.4, 11.4 ppm.
HRMS (ESI): calcd. for C15H20N4O6S [M + H]+ 385.1155; found
385.1176.
2-[4-(2-Nitro-phenyl)-2-oxo-piperazin-1-yl]-N-propyl-acetamide 391.1442.
11(3,1,7): Yield 6 mg (29 %) of amorphous powder. 1H NMR
2-(2-(4-Methoxyphenyl)-4-(4-nitrophenylsulfonyl)piperazin-1-yl)-
(600 MHz, [D6]DMSO): δ = 7.96 (t, J = 5.4 Hz, 1 H), 7.85 (dd, J
= 8.2, 1.5 Hz, 1 H), 7.59–7.64 (m, 1 H), 7.38 (d, J = 7.6 Hz, 1 H),
7.14–7.18 (m, 1 H), 3.97 (s, 2 H), 3.71 (s, 2 H), 3.40–3.45 (m, 2 H),
3.29–3.36 (m, 2 H), 3.02 (q, J = 6.6 Hz, 2 H), 1.41 (sxt, J = 7.3 Hz,
2 H), 0.84 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (151 MHz, [D6]-
DMSO): δ = 167.4, 165.6, 143.2, 142.3, 134.0, 125.7, 122.2, 121.2,
53.9, 48.8, 48.6, 46.9, 40.4, 22.4, 11.4 ppm. HRMS (ESI): calcd. for
C15H20N4O4 [M + H]+ 321.1557; found 321.1557.
ethanaminium Acetate 32(1,4): Yield 21.1 mg (63%) of amorphous
powder. 1H NMR (600 MHz, [D6]DMSO): δ = 8.42 (m, 2 H), 7.99
(m, 2 H), 7.23 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 3.73
(s, 3 H), 3.67 (dd, J = 11.2, 2.3 Hz, 1 H), 3.41 (ddd, J = 11.2, 2.9,
2.6 Hz, 1 H), 3.32 (dd, J = 10.3, 3.2 Hz, 1 H), 3.09–3.14 (m, 1 H),
2.55–2.62 (m, 1 H), 2.47–2.53 (m, 2 H), 2.41 (dt, J = 12.8, 7.8 Hz,
1 H), 2.19–2.31 (m, 2 H), 1.92–1.99 (m, 1 H), 1.83 (s, 3 H) ppm.
13C NMR (151 MHz, [D6]DMSO): δ = 158.9, 150.2, 140.3, 131.4,
129.2, 129.0, 124.8, 114.1, 64.8, 55.1, 53.5, 52.7, 50.4, 46.0,
1-(3-Aminopropyl)-4-(4-nitrobenzenesulfonyl)-6-(4-trifluoromethyl-
phenyl)-3,4-dihydro-1H-pyrazin-2-one 20(4,1): Yield 6.3 mg (22%) 37.2 ppm. HRMS (FAB): calcd. for C19H25N4O5S [M + H]+
of amorphous powder. 1H NMR (300 MHz, [D6]DMSO): δ = 8.41–
8.47 (m, 2 H), 8.19–8.29 (m, 2 H), 7.83 (m, 2 H), 7.63 (m, 2 H),
7.56 (br. s., 2 H), 6.61 (s, 1 H), 4.17 (s, 2 H), 3.26 (t, J = 7.3 Hz, 2
H), 2.33–2.47 (m, 2 H), 1.11–1.28 (m, 2 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 162.6, 150.6, 141.1, 135.8, 130.6, 129.4,
128.9, 128.0, 125.66–125.70 (m), 125.0, 112.1, 48.4, 36.3, 25.6 ppm.
HRMS (ESI): calcd. for C20H20F3N4O4S [M + H]+ 485.1101;
found 485.1090.
421.1534; found 421.1540.
2-(4-(4-Nitrophenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)piperazin-
1-yl)ethanaminium acetate 32(1,5): Yield 20.7 mg (57%) of amorph-
1
ous powder. H NMR (600 MHz, [D6]DMSO): δ = 8.42 (m, 2 H),
8.01 (m, 2 H), 7.81 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H),
3.68 (dd, J = 11.4, 2.3 Hz, 1 H), 3.54 (dd, J = 10.1, 3.1 Hz, 1 H),
3.48 (ddd, J = 11.1, 2.9, 2.7 Hz, 1 H), 3.10–3.21 (m, 1 H), 2.64 (dt,
J = 12.4, 6.3 Hz, 1 H), 2.54 (dd, J = 11.4, 2.6 Hz, 2 H), 2.23–2.35
(m, 4 H), 1.99–2.05 (m, 1 H), 1.83 (s, 3 H) ppm. 13C NMR
(151 MHz, [D6]DMSO): δ = 150.2, 145.3, 140.3, 132.7, 129.3,
Methyl-[[2-Hydroxy-2-(4-trifluoromethylphenyl)-ethyl]-(4-nitro-
benzenesulfonyl)-amino]acetate 21(1): Yield 12.4 mg (45 %) of
1
amorphous powder. H NMR (600 MHz, [D6]DMSO): δ = 8.30– 129.2, 124.8, 118.7, 110.8, 64.8, 51.9, 50.0, 50.0, 45.8, 36.8 ppm.
8.34 (m, 2 H), 8.01–8.06 (m, 2 H), 7.64 (d, J = 8.1 Hz, 2 H), 7.52 HRMS (FAB): calcd. for C19H22N5O4S [M + H]+ 416.1387; found
(d, J = 8.1 Hz, 2 H), 5.79 (br. s., 1 H), 4.80–4.91 (m, 1 H), 4.37 (d, 416.1390.
J = 18.2 Hz, 1 H), 4.27 (d, J = 18.2 Hz, 1 H), 3.56 (s, 3 H), 3.50
2-(4-(4-Nitrophenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)piperazin-
(dd, J = 14.7, 3.8 Hz, 1 H), 3.39–3.44 (m, 1 H) ppm. 13C NMR
1-yl)ethanol 32(2,1): Yield 6.7 mg (23%) of amorphous powder. 1H
(75 MHz, [D6]DMSO): δ = 169.1, 149.6, 147.2, 145.0, 128.6, 126.9,
NMR (500 MHz,[D6]DMSO): δ = 8.41 (m, 2 H), 7.99 (m, 2 H),
125.00–125.03 (m), 124.9, 124.3, 124.3 (q, J = 271.6 Hz), 71.0, 54.8,
7.81 (d, J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 4.36 (t, J =
51.9, 49.2 ppm. HRMS (ESI): calcd. for C18H21F3N3O7S [M +
5.4 Hz, 1 H), 3.67 (dd, J = 2.2, 11.2 Hz, 1 H), 3.55 (dd, J = 3.0,
NH4]+ 480.1047; found 480.1027.
10.2 Hz, 1 H), 3.48 (dt, J = 2.6, 11.4 Hz, 1 H), 3.33–3.29 (m, 2 H),
Methyl-[(2-Hydroxy-2-phenylethyl)-(4-nitrobenzenesulfonyl)-amino]-
3.22–3.14 (m, 1 H), 2.47 (d, J = 2.0 Hz, 1 H), 2.39 (td, J = 2.7,
11.6 Hz, 1 H), 2.35–2.27 (m, 1 H), 2.22 (t, J = 10.9 Hz, 1 H), 2.02
acetate 21(2): Yield 8.0 mg (42%) of amorphous powder. 1H NMR
8
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Job/Unit: O20591
/KAP1
Date: 23-07-12 16:13:02
Pages: 11
Nitrogen Heterocycles from Polymer-Supported Acyclic Intermediates
(dt, J = 5.7, 12.9 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 150.2, 144.7, 140.4, 129.2, 128.9, 125.42–125.48 (m), 124.7,
64.7, 58.1, 55.6, 52.3, 50.9, 46.0 ppm. HRMS (FAB): calcd. for
C19H21F3N3O5S [M + H]+ 460.1149; found 460.1163.
2 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 150.8, 142.4,
135.4, 133.9, 133.3, 129.4, 129.4, 129.3, 125.6, 107.4, 49.6, 45.1,
40.5, 37.2 ppm. HRMS (FAB): calcd. for C18H20N4O4SCl
[M + H]+ 423.0888; found 423.0864.
2-(4-(4-Nitrophenylsulfonyl)-6-p-tolyl-3,4-dihydropyrazin-1(2H)-
yl)ethanol 33(2,6): Yield 22.5 mg (67%) of amorphous powder. H
2-(2-Ethyl-4-(4-nitrophenylsulfonyl)piperazin-1-yl)ethanol 32(2,3):
Yield 3.4 mg (56%) of amorphous powder. 1H NMR (300 MHz,
[D6]DMSO): δ = 8.44 (m, 2 H), 8.01 (m, 2 H), 3.38 (t, J = 6.2 Hz,
2 H), 3.10–2.95 (m, 2 H), 2.89–2.75 (m, 2 H), 2.69–2.52 (m, 2 H),
2.45 (d, J = 3.6 Hz, 2 H), 2.37–2.26 (m, 1 H), 1.57–1.37 (m, 2 H),
0.81 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 150.1, 140.6, 129.1, 124.7, 59.0, 58.7, 54.3, 48.6, 48.2, 45.3, 19.4,
9.8 ppm. HRMS (FAB): calcd. for C14H22N3O5S [M + H]+
344.1275; found 344.1300.
1
NMR (300 MHz, [D6]DMSO): δ = 8.41 (d, J = 8.8 Hz, 2 H), 8.03
(d, J = 8.8 Hz, 2 H), 7.3 (m, 2 H), 7.15 (m, 2 H), 6.10 (s, 1 H),
3.45–3.50 (m, 2 H), 3.30 (t, J = 6.0 Hz, 2 H), 2.65–2.71 (m, 2 H),
2.60 (t, J = 6.1 Hz, 2 H), 2.29 (s, 3 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 150.1, 141.7, 137.4, 135.3, 133.2, 129.1, 128.6,
127.0, 124.8, 103.2, 59.3, 54.0, 45.8, 41.2, 20.8 ppm. HRMS (FAB):
calcd. for C19H22N3O5S [M + H]+ 404.1275; found 404.1248.
4-Methyl-N-{3-[4-(4-nitrobenzenesulfonyl)-6-(4-trifluoromethyl-
phenyl)-3,4-dihydro-2H-pyrazin-1-yl]-propyl}benzenesulfonamide
33(4,1): Yield 11.0 mg (35 %) of amorphous powder. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.37–8.44 (m, 2 H), 8.03–8.11 (m, 2
H), 7.67 (d, J = 8.3 Hz, 2 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.58 (d, J
= 8.3 Hz, 2 H), 7.32–7.39 (m, 3 H), 6.39 (s, 1 H), 3.43 (br. s., 2 H),
2.51–2.61 (m, 4 H), 2.42 (t, J = 7.3 Hz, 2 H), 2.36 (s, 3 H), 1.38–
1.53 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 150.9,
143.3, 142.4, 141.0, 138.0, 134.2, 130.3, 129.3, 127.9, 127.2, 126.05–
126.10 (m), 125.6, 107.7, 50.2, 45.0, 41.2, 41.0, 28.0, 21.6 ppm.
HRMS (ESI): calcd. for C27H28F3N4O6S2 [M + H]+ 625.1397;
found 625.1405.
4-[1-(2-Hydroxyethy)-4-(4-nitrobenzenesulfonyl)-piperazin-2-yl]benzo-
nitrile 32(2,5): Yield 1.8 mg (27%) of amorphous powder. 1H NMR
(500 MHz,[D6]DMSO): δ = 8.41 (m, 2 H), 7.99 (m, 2 H), 7.81 (m,
2 H), 7.56 (m, 2 H), 4.36 (t, J = 5.4 Hz, 1 H), 3.67 (dd, J = 2.2,
11.2 Hz, 1 H), 3.55 (dd, J = 3.0, 10.2 Hz, 1 H), 3.48 (dt, J = 2.6,
11.4 Hz, 1 H), 3.33–3.29 (m, 2 H), 3.22–3.14 (m, 1 H), 2.47 (d, J
= 2.0 Hz, 0 H), 2.39 (td, J = 2.7, 11.6 Hz, 1 H), 2.35–2.27 (m, 1
H), 2.22 (t, J = 10.9 Hz, 1 H), 2.02 (dt, J = 5.7, 12.9 Hz, 1 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 150.2, 145.6, 140.4, 132.5,
129.2, 129.1, 124.8, 118.7, 110.7, 64.7, 58.1, 55.6, 52.0, 50.8,
46.0 ppm. HRMS (FAB): calcd. for C19H21N4O5S [M + H]+
417.1227; found 417.1242.
4-Methyl-N-{3-[4-(4-nitrobenzenesulfonyl)-6-phenyl-3,4-dihydro-
2H-pyrazin-1-yl]-propyl}benzenesulfonamide 33(4,2): Yield 9.6 mg
(25%) of amorphous powder. H NMR (300 MHz, [D6]DMSO): δ
3-[2-(4-Cyanophenyl)-4-(4-nitrobenzenesulfonyl)-piperazine-1-yl]-
propionamide 32(3,5): Yield 15 mg (61%) of amorphous powder.
1H NMR (500 MHz,[D6]DMSO): δ = 8.41 (d, J = 9.0 Hz, 2 H),
7.99 (d, J = 9.0 Hz, 2 H), 7.80 (d, J = 8.4 Hz, 2 H), 7.54 (d, J =
8.4 Hz, 2 H), 7.21 (br. s., 1 H), 6.68 (br. s., 1 H), 3.70 (dd, J = 2.0,
11.2 Hz, 1 H), 3.53–3.45 (m, 2 H), 3.15–3.10 (m, 1 H), 2.57–2.51
(m, 1 H), 2.48–2.44 (m, 1 H), 2.35–2.25 (m, 1 H), 2.21 (t, J =
10.7 Hz, 1 H), 2.09 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 172.7, 150.2, 145.2, 140.4, 132.5, 129.2, 129.0, 124.8, 118.6,
110.7, 64.5, 51.9, 49.8, 45.9, 32.0 ppm. HRMS (FAB): calcd. for
C20H22N5O5S [M + H]+ 444.1336; found 444.1360.
1
= 8.41 (d, J = 8.8 Hz, 2 H), 8.05 (d, J = 8.8 Hz, 2 H), 7.57 (d, J =
8.3 Hz, 2 H) 7.25–7.40 (m, 8 H), 6.16 (s, 1 H), 3.44–3.31 (m, 4 H,
overlapped with water), 2.53–2.59 (m, 2 H), 2.39–2.47 (m, 2 H),
2.37 (s, 3 H), 1.41 (quin, J = 7.3 Hz, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 150.8, 143.3, 142.4, 138.0, 137.0, 135.9, 130.3,
129.3, 128.8, 127.5, 127.2, 125.6, 105.2, 50.1, 45.2, 41.5, 28.2, 21.7,
12.5 ppm. HRMS (ESI): calcd. for C26H29N4O6S2 [M + H]+
557.1523; found 557.1519.
Analytical Data of Individual Compounds: Diazepanones
4-(1-(2-Aminoethyl)-4-(4-nitrophenylsulfonyl)-1,4,5,6-tetrahydro-
pyrazin-2-yl)benzonitrile 33(1,5): Yield 39.3 mg (79%) of amorph-
ous powder. 1H NMR (300 MHz, [D6]DMSO): δ = 8.42 (d, J =
8.8 Hz, 2 H), 8.12 (d, J = 8.8 Hz, 2 H), 7.81 (d, J = 8.3 Hz, 2 H),
7.73 (br. s., 2 H), 7.59 (d, J = 8.3 Hz, 2 H), 6.54 (s, 1 H), 3.43–3.54
(m, 2 H), 2.78–2.92 (m, 2 H), 2.56–2.70 (m, 4 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 150.2, 141.7, 140.7, 132.7, 132.5, 128.7,
127.4, 124.9, 118.8, 110.2, 109.1, 49.1, 44.2, 39.9, 36.5 ppm. HRMS
(FAB): calcd. for C19H20N5O4S [M + H]+ 414.1231; found
414.1208.
2-[7-Oxo-4-(toluene-4-sulfonyl)-[1,4]diazepan-1-yl]-acetamide
43(1,1): Yield 13.7 mg (44 %) of amorphous powder. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.63 (d, J = 8.2 Hz, 2 H), 7.44 (d, J
= 7.9 Hz, 2 H), 7.30 (s, 1 H), 6.98 (s, 1 H), 3.82 (s, 2 H), 3.48–3.55
(m, 2 H), 3.23 (ddd, J = 4.8, 2.3, 2.1 Hz, 2 H), 3.12–3.17 (m, 2 H),
2.62–2.69 (m, 2 H), 2.40 (s, 3 H) ppm. 13C NMR (151 MHz, [D6]-
DMSO): δ = 172.9, 170.3, 143.6, 133.8, 130.0, 127.2, 50.8, 49.5,
48.4, 43.3, 37.1, 21.0 ppm. HRMS (ESI): calcd. for C14H20N3O4S
[M + H]+ 326.1169; found 326.1173.
2-[6-(4-Methylphenyl)-4-(4-nitrobenzenesulfonyl)-3,4-dihydro-2H-pyr-
azin-1-yl]ethylamine 33(1,6): Yield 13.6 mg (74%) of amorphous
powder. 1H NMR (300 MHz, [D6]DMSO): δ = 8.42 (d, J = 8.9 Hz,
2 H), 8.10 (d, J = 8.9 Hz, 2 H), 7.67 (br. s., 2 H), 7.42 (s, 4 H), 6.33
(s, 1 H), 3.44–3.51 (m, 2 H), 3.38 (br. s., 4 H), 2.64 (br. s., 2 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 173.2, 150.8, 142.4, 140.5,
138.2, 136.0, 133.9, 129.9, 129.3, 127.6, 125.5, 104.5, 53.8, 45.7,
41.5, 22.4, 21.4 ppm, TFA salt peak at 39.6 overlapped with
DMSO. HRMS (FAB): calcd. for C19H23N4O4S [M + H]+
403.1440; found 403.1375.
2-[4-(2-Nitro-benzenesulfonyl)-2-oxo-[1,4]diazepan-1-yl]-N-propyl-
acetamide 45(3,6): Yield 3.6 mg (14%) of amorphous powder. 1H
NMR (600 MHz, [D6]DMSO): δ = 8.00 (dd, J = 7.9, 1.2 Hz, 1 H),
7.98 (dd, J = 7.9, 1.2 Hz, 1 H), 7.91 (td, J = 7.6, 1.2 Hz, 1 H), 7.85
(dt, J = 7.9, 1.2 Hz, 1 H), 7.81 (t, J = 5.6 Hz, 1 H), 4.15 (s, 2 H),
3.85 (s, 2 H), 3.45–3.52 (m, 4 H), 3.00 (q, J = 6.7 Hz, 2 H), 1.80–
1.87 (m, 2 H), 1.39 (sxt, J = 7.3 Hz, 2 H), 0.83 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (151 MHz, [D6]DMSO): δ = 169.51, 167.7,
147.6, 134.8, 132.6, 130.9, 130.0, 124.4, 52.1, 51.0, 49.0, 48.4, 40.3,
28.1, 22.4, 11.4 ppm. HRMS (ESI): calcd. for C16H23N4O6S [M +
H]+ 399.1336; found 399.1333.
2-[6-(4-Chlorophenyl)-4-(4-nitrobenzenesulfonyl)-3,4-dihydro-2H-
pyrazin-1-yl]ethylamine 33(1,7): Yield 42.7 mg (83%) of amorphous
powder. 1H NMR (300 MHz, [D6]DMSO): δ = 8.42 (d, J = 8.9 Hz,
2 H), 8.10 (d, J = 8.9 Hz, 2 H), 7.67 (d, J = 6.9 Hz, 2 H), 7.42 (s,
4 H), 6.33 (s, 1 H), 3.46 (br. s., 2 H), 3.38 (br. s., 4 H), 2.64 (br. s.,
2-[4-(2-Nitrophenyl)-2-oxo-[1,4]diazepan-1-yl]-N-propyl-acetamide
45(3,7): Yield 7.4 mg (35 %) of amorphous powder. 1H NMR
(600 MHz, [D6]DMSO): δ = 7.80 (t, J = 5.6 Hz, 1 H), 7.76 (dd, J
= 8.1, 1.5 Hz, 1 H), 7.51 (t, J = 8.5 Hz, 1 H), 7.18 (d, J = 8.1 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20591
/KAP1
Date: 23-07-12 16:13:02
Pages: 11
B. Vanˇková, L. Brulíková, B. Wu, V. Krchnˇák
FULL PAPER
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1 H), 6.97 (m, 1 H), 4.02 (s, 2 H), 3.92 (s, 2 H), 3.37–3.42 (s, 2 H),
3.16 (t, J = 5.9 Hz, 2 H), 3.01 (q, J = 6.7 Hz, 2 H), 1.99 (m, 2 H),
1.39 (sxt, J = 7.3 Hz, 2 H), 0.83 (t, J = 7.3 Hz, 3 H) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 171.2, 167.8, 144.5, 133.9, 126.1,
120.3, 119.5, 56.6, 55.7, 53.0, 51.1, 48.3, 40.3, 27.8, 22.4, 11.4 ppm.
HRMS (ESI): calcd. for C16H23N4O4 [M + H]+ 335.1699; found
335.1714.
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intermediates and final products.
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This research was supported by the Department of Chemistry and
Biochemistry, University of Notre Dame, the Ministry of Educa-
tion, Youth and Sport of the Czech Republic (ME09057), and by
the European Social Fund project CZ.1.07/2.3.00/20.0009. We
gratefully appreciate the use of the NMR spectroscopy facility at
the University of Notre Dame.
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Received: May 5, 2012
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20591
/KAP1
Date: 23-07-12 16:13:02
Pages: 11
Nitrogen Heterocycles from Polymer-Supported Acyclic Intermediates
Solid-Phase Heterocycle Synthesis
ˇ
Straightforward solid-phase synthesis af-
forded linear precursors for formation of
cyclic N-alkyl and N-acyliminiums. Expo-
sure of acyclic resin-bound intermediates
to TFA yielded trisubstituted dihydropyr-
azinones and tetrahydropyrazines, whereas
treatment of the same intermediates with a
TES-containing cleavage cocktail afforded
piperazines and piperazinones.
B. Vanková, L. Brulíková, B. Wu,
V. Krchnˇák,* ................................... 1–11
Synthesis of Piperazinones, Piperazines,
Tetrahydropyrazines, and Dihydropyr-
azinones from Polymer-Supported Acyclic
Intermediates via N-Alkyl- and N-Acyl-
iminiums
Keywords: Piperazinones / Cyclization /
Piperazines
/
Solid-phase synthesis
/
Iminiums / Heterocycles
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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