Synthesis of annelated azaheterocycles containing a 5-carbamoylpyrazin-3- one fragment by a modification of the four-component Ugi reaction

Article abstract of DOI:10.1002/ejoc.200500522

A convenient synthesis of novel imidazole- and pyrrole-fused 1-oxo-1,2,3,4-tetrahydropyrazine heterocyclic structures by a novel modification of the four-component Ugi condensation is described. The usefulness and versatility of the developed approach for the synthesis of variously substituted compounds is demonstrated and the scope and limitations of the chemistry involved are discussed. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500522

FULL PAPER
Synthesis of Annelated Azaheterocycles Containing a 5-Carbamoylpyrazin-
3-one Fragment by a Modification of the Four-Component Ugi Reaction
Alexey P. Ilyin,[a] Vladimir V. Kobak,[a] Irina G. Dmitrieva,[a] Yulia N. Peregudova,[a]
Veronika A. Kustova,[a] Yulia S. Mishunina,[a] Sergey E. Tkachenko,[b] and
Alexandre V. Ivachtchenko*[b]
Keywords: Ugi condensation / Compound library / Combinatorial chemistry / Pyrazines
A convenient synthesis of novel imidazole- and pyrrole-fused
1-oxo-1,2,3,4-tetrahydropyrazine heterocyclic structures by a
novel modification of the four-component Ugi condensation
is described. The usefulness and versatility of the developed
approach for the synthesis of variously substituted com-
pounds is demonstrated and the scope and limitations of the
chemistry involved are discussed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
novel annelated heterocyclic systems containing the 5-car-
bamoylpyrazin-3-one fragment (Figure 1). Specifically, two
series of novel imidazo[1,5-a]pyrazin-8-ones (structure A)
and 6,7-dihydrofuro- and 6,7-dihydrothieno[2Ј,3Ј:4,5]pyr-
rolo[1,2-a]pyrazin-8(5H)-ones (structure B) were obtained.
Heteroaryl-fused pyrazin-3-one fragments are present in a
number of natural and synthetic physiologically active
agents. Among them are antineoplastic and antibacterial al-
kaloids longamide, longamide B (structures Ia,b) and phak-
ellstatins (IIa,b) isolated from marine organisms Agelas ge-
nus, Homaxinella sp. and Phakellia mauritiana,[4] antitrom-
botic agent III[5] and potential antiprotozoal drug IV[6]
(Figure 1). These examples have prompted us to explore
synthetic routes to the mentioned target molecular scaf-
folds, which can serve as a fertile source of bioactive mole-
cules.
Introduction
The four-component Ugi reaction (Ugi-4CR) between an
aldehyde, an amine, an isocyanide and a carboxylic acid
has emerged as a powerful tool for rapid identification and
optimization of lead compounds in drug discovery.[1] One
important modification of this reaction is the use of bifunc-
tional reagents. Thus, modified syntheses using bifunctional
keto acids (or formyl acids), amines and isonitriles as start-
ing materials have been reported.[2] For example, reaction
of ω-keto acids[2a] or aldehydes[2d] with the corresponding
isonitriles and amines led to β-lactams. A series of 2,3-dihy-
dro-1H-isoindol-3-ones was prepared from 2-formyl-[2f] or
2-acetylbenzoic acids.[2a] Using 1,8-naphthaldehydic acid, 2-
formylphenoxyacetic acid and 2Ј-formylphenoxy-2-benzoic
acid as the bifunctional reagents in Ugi coupling, a series
of rare six-, seven- and eight-membered heterocyclic rings
was obtained.[2f] Recently, Marcaccini et. al reported a syn-
thetic approach to novel S,N-heterocycles, starting from the
corresponding thiacarboxylic ω-keto- or ω-formyl ac-
ids.[2g,2h] Recent developments in the isocyanide-based
multicomponent synthesis of heterocycles are reviewed by
Zhu.[3]
Results
As first example of our approach, we describe the synthe-
sis of 6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one com-
pounds 6 (Scheme 1). A solution of the dicarboxylate 1 in
1,4-dioxane was treated with bromoacetone under phase-
transfer conditions, in the presence of K2CO3 and 18-
crown-6, to afford the keto diester 2 in 60% yield. The key
bifunctional keto acid 3 was then prepared using reaction
of 2 with 1.5% methanolic KOH at 20 °C for 72 h. LCMS
analysis of the crude reaction mixture revealed the presence
of the desired acid 3 (Ϸ 70%) as well as a small amount of
isomeric acid (Ϸ 5%) and the corresponding dicarboxylic
acid (Ϸ 25%). The observed difference in hydrolytic sta-
bility of the methyl carboxylate groups can be explained, in
our opinion, by nucleophilic attack of the oxygen atom in
enol form of compound 2 on the neighbouring carbonyl
As a further modification of this useful synthetic meth-
odology, we report an Ugi-type reaction of azaheterocyclic
reagents bearing a (2-oxoethylamino)acetic acid fragment
with isonitriles and primary amines. The reaction leads to
[a] Department of Organic Chemistry, Chemical Diversity Re-
search Institute,
114401 Khimki, Moscow Region, Russia
E-mail: api@chemdiv.com
[b] ChemDiv, Inc.,
11558 Sorrento Valley Rd., Suite 5, San Diego, California,
92121, USA
Fax: +1-858-794-4931
E-mail: av@chemdiv.com
4670
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500522
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Annelated Azaheterocycles by a Modification of the Four-Component Ugi Reaction
FULL PAPER
Figure 1. Structures obtained in this work.
Scheme 1. Synthesis of imidazo[1,5-a]pyrazin-8-ones 6a–r.
carbon atom. Such intermolecular interaction weakens the
ester bond of the 5-carboxylate group and thus allows its condensation, we additionally synthesized two small sets of
selective hydrolysis. The desired product 3 was isolated in 6,7-dihydrofuro- and 6,7-dihydrothieno[2Ј,3Ј:4,5]pyr-
50% yield. rolo[1,2-a]pyrazin-8(5H)-ones, which were not previously
To demonstrate the versatility of the developed Ugi-type
We have found that when keto acid 3 was treated with described (Scheme 2). Solutions of 4H-furo- and 4H-thi-
the isocyanide 4 and the primary amine 5 in methanol at eno[3,2-b]pyrrole derivatives 7a,b and 8a,b in 1,4-dioxane
40 °C, conversion into 6,7-dihydro-5H-imidazo[1,5-a]pyra- were alkylated with chloroacetone or bromoacetophenone
zin-8-ones 6a–r (Table 1) proceeded smoothly and without under phase-transfer conditions, in the presence of K2CO3
any indication of major side reactions (yields 65–85%). In and 18-crown-6, to afford the keto esters 9a–d and 10a–d
particular, in most cases there was no indication of attack in good yields (60–85%). The bifunctional reagents, 11a–d
upon the ester group, which can be used for introduction and 12a–d, were then prepared in 90–95% yields using mild
of additional complexity to the obtained scaffold.
alkali hydrolysis of 9a–d and 10a–d. The keto acids 11a–d
Eur. J. Org. Chem. 2005, 4670–4679
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A. V. Ivachtchenko et al.
Yield [%]
FULL PAPER
Table 1. Structures and yields of compounds 6a–r.
Compound
R1/reagent[a]
R2/reagent[a]
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
cyclopentyl/4a
cycloheptyl/4b
cycloheptyl/4b
cyclohexyl/4c
cyclohexyl/4c
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cyclopentyl/4a
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
3-chlorobenzyl/5{1}
cyclopropyl/5{2}
(2-thien-2-yl)ethyl/5{3}
4-methoxybenzyl/5{4}
Me/5{5}
69
75
71
78
85
65
65
78
72
65
76
70
80
66
70
79
65
69
3-methoxybenzyl/5{6}
2-ethoxybenzyl/5{7}
2-methylbenzyl/5{8}
3-methylbenzyl/5{9}
3-methoxypropyl/5{10}
iPr/5{11}
2-chlorobenzyl/5{12}
4-chlorobenzyl/5{13}
(4-chlorophenyl)ethyl/5{14}
phenylpropyl/5{15}
4-fluorobenzyl/5{16}
(cyclohex-1-en-1-yl)ethyl/5{17}
(4-ethoxyphenyl)ethyl/5{18}
[a] Number of the corresponding isocyanide or amine on Scheme 1.
Scheme 2. Synthesis of 6,7-dihydrofuro- and 6,7-dihydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazin-8(5H)-ones 13a–i and 14a–h.
and 12a–d were then treated with the isonitriles 4 and pri- cal assignments to be made to the individual compounds
mary amines 5 in methanol at 40 °C to yield two small li- through X-ray crystallography. For instance, the structure
braries of the desired products 13a–i and 14a–h (Table 2) of 13a was unambiguously established as N-cyclohexyl-7-
belonging to furo- and thieno-series, respectively (yield 25– isopropyl-6-methyl-8-oxo-5,6,7,8-tetrahydrofuro[2Ј,3Ј:4,5]pyr-
90%).
rolo[1,2-a]pyrazine-6-carboxamide by single-crystal X-ray
For imidazo[1,5-a]pyrazin-8-ones 6a–r, isolated yields in analysis (Figure 2). Single crystals of compounds suitable
the described reactions were often in excess of 60% and for X-ray analysis were grown from diethyl ether.
sometimes better than 80%. However, many 6,7-dihy-
drofuro- and 6,7-dihydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyra-
zin-8(5H)-ones (13a–i and 14a–h, respectively) were ob-
tained in low to moderate yields (25–50%), and this fact
Discussion
limits the applicability of the developed approach for these
The reported synthetic approaches to heteroaryl-fused
heterocyclic chemotypes. The reaction products 6a–r, 13a–i pyrazinones are typically tedious multistep procedures in-
and 14a–h usually precipitated from the reaction mixtures compatible with the high-throughput combinatorial proto-
after the reaction was cooled to room temperature. The pre- col.[7,8] In one reported example of a combinatorial ap-
cipitates could be recrystallized from diethyl ether or puri- proach to 6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-ones, as-
fied by flash column chromatography on silica gel. All com- sembly of the core heterocyclic moiety occurs at the sixth
pounds were obtained as racemic mixtures of enantiomers. step of the synthetic sequence.[9] The method developed in
The assignment of all structures was made on the basis this work dramatically reduces the number of synthetic
of 1H, 13C NMR and high-resolution mass-spectroscopy stages leading to the target molecular scaffold.
data; satisfactory analytical data were obtained for all syn-
The Ugi-4CR reaction developed in this work presum-
thesized compounds. In many cases, pure crystalline sub- ably follows the same course as the classical Ugi condensa-
stances could be obtained, thus allowing firm stereochemi- tion with an intermediate imine being attacked by the isocy-
4672
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4670–4679

Annelated Azaheterocycles by a Modification of the Four-Component Ugi Reaction
FULL PAPER
Table 2. Structures and yields of compounds 13a–i and 14a–h.
Compound
X
R1/reagent[a]
R2/reagent[a]
R3
R4
Yield [%]
13a
13b
13c
13d
13e
13f
13g
13h
13i
14a
14b
14c
14d
14e
14f
14g
14h
O
O
O
O
O
O
O
O
O
S
S
S
S
S
cyclohexyl/4c
cyclohexyl/4c
cyclohexyl/4c
cyclohexyl/4c
cyclooctyl/4d
3-methylbutyl/4e
iPr/5{11}
H
H
Me
Me
Me
H
H
Me
H
Et
H
H
Et
Et
H
Me
Ph
Ph
Me
Me
Me
Me
Ph
Ph
Me
Ph
Ph
Ph
43
28
27
63
66
40
48
36
27
90
34
25
28
63
65
40
39
3-fluorobenzyl/5{19}
3-fluorobenzyl/5{19}
(pyridin-3-yl)methyl/5{20}
(thien-2-yl)methyl/5{21}
2-methoxyethyl/5{22}
(tetrahydrofuran-2-yl)methyl/4f 4-chlorobenzyl/5{13}
cycloheptyl/4b
cycloheptyl/4b
cycloheptyl/4b
cyclohexyl/4c
cycloheptyl/4b
cycloheptyl/4b
4-methylcyclohexyl/4g
cyclopentyl/4a
2-methylcyclohexyl/4h
cyclohexyl/4c
Bn/5{23}
Pr/5{24}
2-furylmethyl/5{25}
3-bromobenzyl/5{26}
Pr 5{24}
Pr 5{24}
(pyrrolidin-1-yl)ethyl 5{27}
1-benzylpiperidin-4-yl 5{28}
3-fluorophenyl 5{29}
(1,3-benzodioxol-5-yl)methyl 5{30}
Me
Me
Me
Ph
S
S
S
H
Et
[a] Number of the corresponding isocyanide or amine on Scheme 3.
(Scheme 3). Thus, a representative methyl carboxylate 6e
was hydrolyzed under mild alkali conditions to smoothly
afford the acid 15 (yield 80%). The latter was then con-
verted into the amides 16a,b using N,NЈ-carbonyldiimid-
azole (CDI)-promoted coupling with two different amines.
The reaction proceeded in dimethylformamide via reactive
imidazolide intermediates which were used in the reaction
with amines without purification. Due to relatively mild re-
action conditions (75–80 °C, 8 h), easy separation pro-
cedures and high yields (80–85%), the described reaction
scheme can also be used in high-throughput combinatorial
format. The amide formation mediated by strong coupling
agents, such as SOCl2 or POCl3, was less successful in this
case: The desired products were obtained in 30–45% yields.
The synthesized compounds represent examples of β-
turn mimics[10,11] with an inherent potential for combinato-
rial exploration of functional diversity. Reverse β-turns are
common secondary structures in biologically active pep-
tides or proteins that often play an important role in their
interactions with receptors, enzymes, or antibodies. Such
peptide–protein or protein–protein interactions can be
Figure 2. ORTEP plot for compound 13a.
anide to give a nitrilium intermediate, which then undergoes mimicked by small molecules bearing similar structural fea-
intramolecular cyclization.[1] Similar conditions were suit- tures. Syntheses of a putative peptide β-turn mimetic based
able for the reaction of a range of different primary amines on piperazinone fragment were reported.[12]
and isonitriles with the keto acids 3, 11 and 12. With respect
to amine component, various aliphatic and aromatic pri-
mary amines, such as substituted anilines, benzylamines
and their heteroaryl analogs, linear and branched aliphatic
Conclusions
amines and nitrogen-containing compounds, were tolerated
In this work, we have shown that novel heteroaryl-fused
without any limitations. A restriction is the limited number pyrazinones can be efficiently prepared by a novel modifica-
of commercially or synthetically available isonitriles. In this tion of four-component Ugi reaction of heterocyclic bifunc-
work, we used eight different isonitriles 4a–h available from tional keto acids, isonitriles and amines. Considering the
commercial sources. The process does, however, appear to availability of initial reactants, convenient synthesis and iso-
be impeded by steric congestion, with the sterically hin- lation of products, this route provides a new valuable entry
dered substrates (for example, when R4 = phenyl) under- to novel heterocycle-fused analogs of biologically active py-
going slow and incomplete conversion to the final products. razinones. Compounds synthesized in this work constitute
The ester functionality can be used for introduction of interesting examples of conformationally rigid cyclic pepti-
additional complexity to the obtained heterocyclic scaffolds domimetics, which are the subject of increasing interest as
Eur. J. Org. Chem. 2005, 4670–4679
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A. V. Ivachtchenko et al.
FULL PAPER
Scheme 3. Introduction of additional complexity to 6e.
Methyl 2-Ethyl-4-(2-oxopropyl)-4H-thieno[3,2-b]pyrrole-5-carboxyl-
potential new small-molecule therapeutics. Biological test-
ing of the obtained compounds is currently in progress.
ate (10a): M. p. 111–112 °C. IR ν = 1675 (CO), 1715 (CO) cm–1.
˜
1H NMR: δ = 1.30–1.33 (t, J = 8.4 Hz, 3 H CH3), 2.10–2.13 (s, 3
H, CH3), 2.83–2.86 (q, J = 8.4 Hz, 2 H, CH2), 3.74–3.77 (s, 3 H,
CH3), 5.13–5.16 (s, 2 H, CH2), 6.78 (s, 1 H, ArH), 7.05 (s, 1 H,
ArH) ppm. HRMS: m/z 266.3321; calcd. 266.3342 [M+].
Experimental Section
1H and 13C NMR spectra were recorded with Bruker DPX-300
4-Methoxycarbonyl-1-(2-oxopropyl)-1H-imidazole-5-carboxylic
Acid (3): Aqueous solution of KOH (1.5%, 100 mL) was added to
a solution of the diester 2 (12.0 g, 50 mmol) in methanol (150 mL).
The reaction mixture was stirred at room temp. for 72 h, then con-
centrated under reduced pressure to remove methanol. Water
(150 mL) was added, and the mixture was acidified by addition of
1% aqueous HCl until pH 3 was reached. The formed precipitate
was filtered off, washed with water (3×150 mL) and dried with
Na2SO4. Recrystallization from ethanol gave pure 3 as a white solid
(5.66 g, 50%). 1H NMR: δ = 2.30 (s, 3 H, CH3), 3.57 (s, 3 H, CH3),
6.74 (s, 1 H, ArH), 9.86–10.14 (br. s, 1 H, OH) ppm. 13C NMR: δ
= 28.21, 49.08, 51.48, 134.22, 138.18, 145.88, 156.65, 166.36, 168.87
ppm. HRMS: m/z 226.2003; calcd. 226.1861 [M+].
1
spectrometer (300.13 MHz for H NMR and 75.46 for 13C NMR)
in [D6]DMSO using TMS as an internal standard. LCMS spectra
were recorded with PE SCIEX API 150EX liquid chromatograph
equipped with a UV detector (λmax 215 and 254 nm) and using a
C18 column (100×4 mm). Elution started with water and ended
with acetonitrile/water (95:5, v/v) and used a linear gradient at a
flow rate of 0.15 mL/min and an analysis cycle time of 25 min.
High-resolution mass spectra have been recorded using electrospray
ionization time-of-flight reflectron experiments (ESI-TOF) on Ag-
ilent ESI-TOF mass spectrometer. Samples were electrosprayed
into the TOF reflectron analyzer at an ESI voltage of 4000 V and
a flow rate of 200 microliters per minute. Melting points were mea-
sured with a Buchi B-520 melting point apparatus and were not
corrected. IR spectra were recorded with Specord M80 spectrome-
ter in KBr. All solvents and reagents were obtained from Acros
Organics, Aldrich or ChemDiv and used without purification.
General Procedure for Preparation of Keto Acids 11a–d and 12a–d:
A solution of NaOH (4.8 g, 120 mmol) in water (30 mL) was added
to a solution of keto ester 9a–d or 10a–d (100 mmol) in methanol
(100 mL). The reaction mixture was stirred at 70 °C for 6 h then
cooled to room temp., and concentrated under reduced pressure to
remove methanol. Water (10 mL) was added, and the mixture was
acidified by addition of 1% aqueous HCl until pH 3 was reached.
The formed precipitate was filtered off, washed with water
(3×50 mL) and dried with Na2SO4 to give 11a–d and 12a–d in
90–95% yield. Satisfactory analytical data were obtained for all
compounds, for example:
General Procedure for Preparation of Keto Esters 2, 9a–d or 10a–d:
A mixture of the dicarboxylate 1 or the carboxylates 7a,b and 8a,b
(100 mmol), α-halo ketone (100 mmol), K2CO3 (16.56 g,
120 mmol), and 18-crown-6 phase-transfer catalyst (200 mg) in 1,4-
dioxane (100 mL) was stirred at reflux for 7 h. The reaction mixture
was cooled, diluted with toluene and washed with water until the
extract was neutral, after which the organic layer was dried (anhy-
drous Na2SO4) and concentrated in vacuo. The desired product
was chromatographed on silica gel (eluent CH2Cl2) to afford the
corresponding keto ester 2, 9a–d or 10a–d in 60–85% yield. Satis-
factory analytical data were obtained for all the synthesized com-
pounds, for example:
4-(2-Oxopropyl)-4H-furo[3,2-b]pyrrole-5-carboxylic Acid (11c):
M. p. 168–169 °C. IR ν = 1640 (CO), 1725 (CO), 2200–3200 (OH)
˜
1
cm–1. H NMR: δ = 2.09 (s, 3 H, CH3), 5.11–5.14 (s, 2 H, CH2),
6.57 (d, J = 6.8 HZ, 1 H, ArH), 6.71 (s, 1 H, ArH), 7.55 (d, J =
6.8 Hz, 1 H, ArH), 11.94–11.98 (br. s, 1 H, OH) ppm. HRMS:
m/z 208.1951; calcd. 208.1932 [M+].
Dimethyl 1-(2-Oxopropyl)-1H-imidazole-4,5-dicarboxylate (2): 1H
NMR: δ = 2.25–2.31 (br. s, 3 H, CH3), 3.53 (s, 3 H, CH3), 3.71 (s,
3 H, CH3), 6.89 (s, 1 H, ArH) ppm. HRMS: m/z 240.2154; calcd.
240.2132 [M+].
4-(2-Oxopropyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic Acid (12d):
M. p. 168–169 °C. IR ν = 1680 (CO), 1720 (CO), 2800–3300 (OH)
˜
cm–1. 1H NMR: δ = 2.12 (s, 3 H, CH3), 524–5.26 (s, 2 H, CH2),
7.04 (d, J = 6.2 Hz, 1 H, ArH), 7.11 (s, 1 H, ArH), 7.31–7.33 (d, J
= 6.2 Hz, 1 H, ArH) ppm. HRMS: m/z 224.2551; calcd. 224.2566
[M+].
Methyl 2-Methyl-4-(2-oxopropyl)-4H-furo[3,2-b]pyrrole-5-carboxyl-
1
ate (9b): M. p. 95–97 °C. IR ν = 1670 (CO), 1720 (CO) cm–1. H
˜
NMR: δ = 2.12 (s, 3 H, CH3), 2.38–2.39 (br. s, 3 H, CH3), 3.74 (s,
3 H, CH3), 5.04–5.07 (br. s, 2 H, CH2), 6.19 (s, 1 H, ArH), 6.65 (s, General Procedure for the Synthesis of 6,7-Dihydro-5H-imidazo[1,5-
1 H, ArH) ppm. HRMS: m/z 236.2405; calcd. 236.24981 [M+].
a]pyrazin-8-ones 6a–r, 6,7-Dihydrofuro[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyr-
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Annelated Azaheterocycles by a Modification of the Four-Component Ugi Reaction
azin-8(5H)-ones 13a–i and 6,7-Dihydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2- Methyl 6-[(Cycloheptylamino)carbonyl]-7-(3-methoxybenzyl)-6-
FULL PAPER
a]pyrazin-8(5H)-ones 14a–h: The equimolar amounts of keto acid,
isocyanide, and amine were dissolved in methanol to a concentra-
tion of 1  in each component. The reaction mixture was stirred at
40 °C for 4–18 h. The reaction was followed by TLC (5% MeOH
in CH2Cl2). On completion, the reaction mixture was cooled to
room temp., the formed precipitate was filtered off and purified by
recrystallization from diethyl ether or by chromatography on silica
gel, eluting with a gradient of 0–10% MeOH in CH2Cl2.
methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
ate (6f): Yield 60%. 1H NMR: δ = 1.12–1.7 (m, 12 H, cyclohep-
tane), 1.56 (s, 3 H, CH3), 3.5–3.61 (m, 1 H, CH), 3.7 (s, 3 H, CH3),
3.8 (s, 3 H, CH3), 4.07 (d, J = 6.7 Hz, 1 H, CH2), 4.27 (d, J =
6.8 Hz, 1 H, CH2), 4.83 (d, J = 6.7 Hz, 1 H, CH2), 5.22 (d, J =
6.8 Hz, 1 H, CH2), 6.7 (d, J = 6.3 Hz, 1 H, NH), 6.84 (s+d, 2 H,
ArH), 7.24 (d+d, J = 7,6 Hz, 2 H, ArH), 7.62 (s, 1 H, ArH) ppm.
13C NMR: δ = 7.8, 9.01, 18.58, 21.03, 24.61, 25.02, 25.77, 27.41,
27.58, 2×33.85, 50.68, 52.02, 52.77, 64.99, 124.61, 133.64, 135.87,
157.88, 162.87, 169.16 ppm. HRMS: m/z found: 468.5527; calcd.
468.5576 [M+].
Methyl 7-(3-Chlorobenzyl)-6-[(cyclopentylamino)carbonyl]-6-
methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
1
ate (6a): Yield 69%. H NMR: δ = 1.13–1.81 (m, 8 H, cyclopen-
tane), 1.49 (s, 3 H, CH3), 3.81 (s, 3 H, CH3), 3.81–3.83 (m, 1 H,
Methyl 6-[(Cycloheptylamino)carbonyl]-7-(2-ethoxybenzyl)-6-
CH), 4.11 (d, J = 6.9 Hz, 1 H, CH2), 4.22 (d, J = 6.8 Hz, 1 H, methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
CH2), 4.9 (d, J = 6.9 Hz, 1 H, CH2), 5.27 (d, J = 6.8 Hz, 1 H,
ate (6g): Yield 65%. 1H NMR: δ = 1.2–1.8 (m, 12 H, cycloheptane),
CH2), 7.15 (m, 4 H, ArH), 7.41 (d, J = 6.0 Hz, 1 H, NH), 7.68 (s, 1.54 (s, 6 H, 2CH3), 3.5–3.61 (m, 1 H, CH), 3.71 (s, 3 H, CH3), 4.1
1 H, ArH) ppm. 13C NMR: δ = 20.33, 23.46, 23.92, 31.26, 31.82, (m, 3 H, CH, CH2), 4.4 (d, J = 6.8 Hz, 1 H, CH2), 4.90 (d, J =
45.58, 50.73, 51.13, 51.77, 64.80, 123.51, 125.30, 2×126.44, 129.98,
6.7 Hz, 1 H, CH2), 5.12 (d, J = 6.8 Hz, 1 H, CH2), 6.8 (d+d, J =
133.01, 134.18, 136.34, 142.27, 157.94, 162.80, 169.22 ppm. 7.8 Hz, 2 H, ArH), 7.13 (t, 2 H, ArH), 6.8 (d, J = 6.3 Hz, 1 H,
HRMS: m/z found: 444.1641; calcd. 444.9220 [M+].
NH), 7.24 (s, 1 H, ArH) ppm. 13C NMR: δ = 7.9, 9.11, 10.66,
18.55, 21.33, 24.01, 25.77, 26.12, 27.56, 28.43, 2 × 33.87, 51.03,
53.22, 54.27, 64.94, 124.67, 134.11, 134.89, 157.84, 162.85, 168.98
ppm. HRMS: m/z found: 482.5791; calcd. 482.5847 [M+].
Methyl 6-[(Cycloheptylamino)carbonyl]-7-cyclopropyl-6-methyl-8-
oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (6b):
Yield 75%. 1H NMR: δ = 0.7–0.88 (m, 4 H, cyclopropane), 1.2–
1.71 (m, 12 H, cycloheptane), 1.67 (s, 3 H, CH3), 2.46–2.55 (br. s,
1 H, CH), 3.58–3.7 (m, 1 H, CH), 3.8 (s, 3 H, CH3), 4.08 (d, J =
6.7 Hz, 1 H, CH2), 4.73 (d, J = 6.7 Hz, 1 H, CH2), 7.31 (br. s, 1
H, NH), 7.63 (s, 1 H, ArH) ppm. 13C NMR: δ = 7.8, 8.89, 20.32,
23.62, 23.97, 25.54, 26.32, 27.45, 27.85, 2 × 33.80, 50.62, 51.12,
51.59, 65.18, 124.65, 133.63, 135.84, 158.00, 162.81, 169.16 ppm.
HRMS: m/z found: 388.2184; calcd. 388.4706 [M+].
Methyl 6-[(Cycloheptylamino)carbonyl]-6-methyl-7-(2-methylbenz-
yl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate
(6h): Yield 78%. 1H NMR: δ = 1.27–1.66 (m, 12 H, cycloheptane),
1.50 (s, 3 H, CH3), 2.32 (s, 3 H, CH3), 3.58–3.67 (m, 1 H, CH), 3.8
(s, 3 H, CH3), 4.1 (d, J = 6.8 Hz, 1 H, CH2), 4.2 (d, J = 6.6 Hz, 1
H, CH2), 4.88 (d, J = 6.8 Hz, 1 H, CH2), 5.27 (d, J = 6.6 Hz, 1 H,
CH2), 7.0–7.21 (m, 4 H, ArH), 7.5 (d, J = 6.2 Hz, 1 H, NH), 7.7
(s, 1 H, ArH) ppm. 13C NMR: δ = 7.7, 10.11, 19.59, 22.13, 24.63,
25.72, 25.95, 27.54, 27.59, 2 × 33.76, 51.04, 52.54, 52.75, 65.04,
125.65, 133.61, 135.71, 157.32, 162.23, 168.21 ppm. HRMS: m/z
found: 452.5539; calcd. 452.5582 [M+].
Methyl 6-[(Cycloheptylamino)carbonyl]-6-methyl-8-oxo-7-(2-thien-
2-ylethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate
(6c): Yield 71%. 1H NMR: δ = 1.23–1.62 (m, 12 H, cycloheptane),
1.52 (s, 3 H, CH3), 3.11 (t, J = 4.4 Hz, CH2), 3.3–3.45 (m, 1 H,
CH), 3.6–3.72 (m, 1 H, CH), 3.81 (s, 3 H, CH3), 4.06 (d, J = 6.8 Hz, Methyl 6-[(Cycloheptylamino)carbonyl]-6-methyl-7-(3-methylbenz-
1 H, CH2), 4.76 (d, J = 6.8 Hz, 1 H, CH2), 6.85 (d, J = 7.2 Hz, 1 yl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate
1
H, ArH), 6.9 (d+d, J = 7.4 Hz, 1 H, ArH), 7.15 (d, J = 7.2 Hz, 1 (6i): Yield 72%. H NMR: δ = 1.2–1.61 (m, 12 H, cycloheptane),
H, ArH), 7.51 (d, J = 6.2 Hz, 1 H, NH), 7.62 (s, 1 H, ArH) ppm. 1.51 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 3.51–3.65 (m, 1 H, CH), 3.8
13C NMR: δ = 19.72, 2×23.46, 27.13, 27.77, 28.82, 33.18, 33.81, (s, 3 H, CH3), 4.06 (d, J = 6.8 Hz, 1 H, CH2), 4.25 (d, J = 6.8 Hz,
44.43, 50.10, 50.83, 51.69, 64.10, 123.01, 123.55, 124.83, 126.62, 1 H, CH2), 4.84 (d, J = 6.8 Hz, 1 H, CH2), 5.27 (d, J = 6.8 Hz, 1
134.04, 135.89, 140.80, 156.77, 162.51, 168.26 ppm. HRMS: m/z
H, CH2), 7.0 (d, J = 6.0 Hz, 1 H, NH), 7.08–7.2 (m, 4 H, ArH),
7.67 (s, 1 H, ArH) ppm. 13C NMR: δ = 7.8, 9.65, 20.32, 22.19,
24.43, 24.21, 25.91, 27.58, 28.34, 2 × 33.26, 52.14, 52.99, 53.43,
65.14, 124.21, 134.22, 135.73, 157.31, 164.32, 168.28 ppm. HRMS:
m/z found: 452.5538; calcd. 452.5582 [M+].
found: 458.2061; calcd. 458.5840 [M+].
Methyl 6-[(Cyclohexylamino)carbonyl]-7-(4-methoxybenzyl)-6-
methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
ate (6d): Yield 78%. 1H NMR: δ = 1.0–1.68 (m, 10 H, cyclohexane),
1.5 (s, 3 H, CH3), 3.39–3.42 (m, 1 H, CH), 3.7 (s, 3 H, CH3), 3.8 Methyl 6-[(Cycloheptylamino)carbonyl]-7-(3-methoxypropyl)-6-
(s, 3 H, CH3), 4.05 (d, J = 6.8 Hz, 1 H, CH2), 4.28 (d, J = 6.6 Hz,
1 H, CH2), 4.87 (d, J = 6.8 Hz, 1 H, CH2), 5.21 (d, J = 6.6 Hz, 1
methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
ate (6j): Yield 65%. 1H NMR: δ = 1.2–1.71 (m, 12 H, cyclohep-
H, CH2), 6.8 (d, J = 7.8 Hz, 2 H, ArH), 7.12 (t, J = 7.0 Hz, 2 H, tane), 1.52 (s, 3 H, CH3), 1.8–2.0 (m, 2 H, CH2), 3.22 (s, 3 H, CH3),
ArH), 7.22 (br. s, 1 H, NH), 7.62 (s, 1 H, ArH) ppm. 13C NMR: δ
= 7.8, 8.89, 20.32, 23.62, 23.67, 25.54, 27.45, 27.55, 2×33.80, 50.62,
51.12, 51.50, 65.18, 124.65, 133.63, 135.84, 158.00, 162.81, 169.16
ppm. HRMS: m/z found: 454.5260; calcd. 454.5305 [M+].
3.3–3.5 (m, 3 H, CH2), 3.5–3.67 (m, 2 H, CH, CH2), 3.8 (s, 3 H,
CH3), 4.08 (d, J = 6.8 Hz, 1 H, CH2), 4.78 (d, J = 6.8 Hz, 1 H,
CH2), 7.44 (d, J = 5.8 Hz, 1 H, NH), 7.6 (s, 1 H, ArH) ppm. 13C
NMR: δ = 8.1, 9.64, 23.11, 24.65, 25.11, 26.03, 27.78, 29.33,
3×33.72, 37.65, 52.44, 52.65, 53.48, 58.76, 65.15, 71.43, 158.01,
164.36, 168.76 ppm. HRMS: m/z 420.5095; calcd. 420.5130 [M+].
Methyl 6-[(Cyclohexylamino)carbonyl]-6,7-dimethyl-8-oxo-5,6,7,8-
1
tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (6e): Yield 85%. H
NMR: δ = 1.1–1.83 (m, 10 H, cyclohexane), 1.53 (s, 3 H, CH3),
Methyl 6-[(Cyclopentylamino)carbonyl]-7-isopropyl-6-methyl-8-oxo-
3.05 (s, 1 H, CH3), 3.46–3.51 (m, 1 H, CH), 3.80 (s, 3 H, CH3), 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (6k): Yield
1
4.11 (d, J = 6.8 Hz, 1 H, CH2), 4.71 (d, J = 6.8 Hz, 1 H, CH2),
76%. H NMR: δ = 1.12–2.0 (m, 8 H, cyclopentane), 1.4 (s, 3 H,
7.52 (d, J = 6.2 Hz, 1 H, NH), 7.61 (s, 1 H, ArH) ppm. 13C NMR: CH3), 1.5 (s, 3 H, CH3), 1.6 (s, 3 H, CH3), 3.12–3.3 (m, 1 H, CH),
δ = 21.01, 23.65, 24.63, 25.59, 27.48, 27.44, 2×34.10, 51.60, 52.14,
52.98, 65.43, 125.64, 134.69, 135.98, 159.03, 162.89, 168.66 ppm.
HRMS: m/z found: 348.4015; calcd. 348.4052 [M+].
3.8 (s, 3 H, CH3), 3.9–4.02 (m, 1 H, CH), 4.2 (d, J = 7.0 Hz, 1 H,
CH2), 4.5 (d, J = 7.0 Hz, 1 H, CH2), 7.58 (s, 4 H, ArH), 7.9 (d, J
= 6.2 Hz, 1 H, NH) ppm. 13C NMR: δ = 2×19.43, 23.43, 24.59,
Eur. J. Org. Chem. 2005, 4670–4679
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4675

A. V. Ivachtchenko et al.
FULL PAPER
32.01, 33.21, 45.58, 51.13, 52.43, 53.01, 64.81, 159.11, 163.99, (m, 2 H, CH2), 2.1–2.26 (m, 4 H, cyclohexene), 3.13–3.26 (m, 1 H,
169.66 ppm. HRMS: m/z 362.4287; calcd. 362.4323 [M+].
CH2), 3.6–3.8 (m, 2 H, CH, CH2), 3.8 (s, 3 H, CH3), 4.05 (d, J =
6.9 Hz, 1 H, CH2), 4.72 (d, J = 6.9 Hz, 1 H, CH2), 5.4 (s, 1 H,
CH), 7.37 (d, J = 6.2 Hz, 1 H, NH), 7.64 (s, 1 H, ArH) ppm. 13C
NMR: δ = 8.1, 9.64, 22.63, 23.11, 24.65, 25.11, 25.32, 26.13, 27.78,
28.43, 29.11, 29.76, 3× 33.32, 37.55, 52.49, 53.48, 58.76, 65.15,
71.43, 158.01, 164.36, 168.88 ppm. HRMS: m/z 456.5858; calcd.
456.5901 [M+].
Methyl 7-(2-Chlorobenzyl)-6-[(cycloheptylamino)carbonyl]-6-
methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
1
ate (6l): Yield 70%. H NMR: δ = 1.24–1.63 (m, 12 H, cyclohep-
tane), 1.5 (s, 3 H, CH3), 3.61–3.7 (m, 1 H, CH), 3.81 (s, 3 H, CH3),
4.2 (d, J = 6.9 Hz, 1 H, CH2), 4.29 (d, J = 6.8 Hz, 1 H, CH2), 4.94
(d, J = 6.9 Hz, 1 H, CH2), 5.33 (d, J = 6.8 Hz, 1 H, CH2), 7.12–
7.3 (m, 4 H, ArH), 7.44–7.53 (br. s, 1 H, NH), 7.7 (s, 1 H, ArH)
ppm. 13C NMR: δ = 7.9, 9.65, 22.19, 24.46, 24.28, 25.34, 27.57,
28.34, 2×33.28, 52.04, 52.91, 53.43, 65.19, 124.28, 134.43, 135.54,
158.21, 164.35, 168.88 ppm. HRMS: m/z 472.9711; calcd. 472.9761
[M+].
Methyl 6-[(Cycloheptylamino)carbonyl]-7-[2-(4-ethoxyphenyl)ethyl]-
6-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbox-
1
ylate (6r): Yield 69%. H NMR: δ = 1.3–1.65 (m, 12 H, cyclohep-
tane), 1.45 (t, J = 8.4 Hz, 3 H, CH3), 1.52 (s, 3 H, CH3), 2.8–3.0
(m, 2 H, CH2), 3.21–3.29 (m, 1 H, CH2), 3.59–3.71 (m, 1 H, CH),
3.86 (s, 3 H, CH3), 3.9–4.03 (m, 4 H, CH, CH2), 4.77 (d, J = 6.8 Hz,
1 H, CH2), 6.82 (d, J = 6.8 Hz, 2 H, ArH), 7.11 (d, J = 7.2 Hz, 2
H, ArH), 7.41 (br. s, 1 H, NH), 7.64 (s, 1 H, ArH) ppm. 13C NMR:
δ = 7.8, 9.88, 10.66, 18.59, 22.43, 24.11, 25.47, 26.11, 27.59, 28.55,
29.97, 2×32.88, 51.03, 53.22, 54.27, 64.55, 124.69, 134.76, 135.32,
156.87, 162.84, 168.35 ppm. HRMS: m/z 496.6071; calcd. 496.6118
[M+].
Methyl 7-(4-Chlorobenzyl)-6-[(cycloheptylamino)carbonyl]-6-
methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxyl-
1
ate (6m): Yield 80%. H NMR: δ = 1.21–1.75 (m, 12 H, cyclohep-
tane), 1.51 (s, 3 H, CH3), 3.53–3.7 (m, 1 H, CH), 3.85 (s, 3 H,
CH3), 4.1 (d, J = 6.7 Hz, 1 H, CH2), 4.21 (d, J = 6.8 Hz, 1 H,
CH2), 4.88 (d, J = 6.7 Hz, 1 H, CH2), 5.31 (d, J = 6.8 Hz, 1 H,
CH2), 7.21 (m, 4 H, ArH), 7.42 (d, J = 6.2 Hz, 1 H, NH), 7.69 (s,
1 H, ArH) ppm. 13C NMR: δ = 7.8, 10.34, 22.21, 25.21, 25.78,
25.99, 27.37, 29.01, 2×33.24, 52.15, 53.03, 54.63, 65.19, 124.28,
134.41, 135.22, 158.98, 164.21, 168.23 ppm. HRMS: m/z 472.9719;
calcd. 472.9761 [M+].
N-Cyclohexyl-7-isopropyl-6-methyl-8-oxo-5,6,7,8-tetrahydrofuro-
[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13a): Yield 43 %.
1H NMR: δ = 1.41 (s, 9 H, 3CH3), 1.0–2.0 (m, 10 H, cyclohexane),
3.1–3.21 (m, 1 H, CH), 3.54–3.71 (m, 1 H, CH), 4.01 (d, J = 7.0 Hz,
1 H, CH2), 4.43 (d, J = 7.0 Hz, 1 H, CH2), 6.51 (d, J = 6.8 Hz, 2
H, ArH), 7.50 (s, 1 H, ArH), 7.92 (d, J = 6.1 Hz, 1 H, NH) ppm.
13C NMR: δ = δ = 2 × 21.32, 23.43, 24.59, 32.31, 33.21, 45.32,
51.18, 52.43, 64.81, 116.32, 122.31, 143.54, 163.99, 169.66 ppm.
HRMS: m/z 357.1671; calcd. 357.4565 [M+].
Methyl 7-[2-(4-Chlorophenyl)ethyl]-6-[(cycloheptylamino)carbonyl]-
6-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbox-
ylate (6n): Yield 66%. 1H NMR: δ = 1.27–1.77 (m, 12 H, cyclohep-
tane), 1.51 (s, 3 H, CH3), 2.8–3.0 (t, J = 7.6 Hz, 1 H, CH2), 3.21–
3.3 (q, J = 7.6 Hz, 1 H, CH2), 3.57–3.72 (m, 1 H, CH), 3.8–3.85
(m, 1 H, CH), 3.85 (s, 3 H, CH3), 4.06 (d, J = 7.0 Hz, 1 H, CH2),
4.76 (d, J = 7.0 Hz, 1 H, CH2), 7.22 (m, 4 H, ArH), 7.42 (br. s, 1
H, NH), 7.67 (s, 1 H, ArH) ppm. 13C NMR: δ = 8.1, 9.87, 22.27,
25.28, 25.78, 26.13, 28.43, 28.59, 28,98, 2 × 33.25, 52.15, 53.13,
54.67, 65.24, 124.11, 133.85, 134.13, 157.48, 164.23, 169.43 ppm.
HRMS: m/z 486.9980; calcd. 487.0032 [M+].
N-Cyclohexyl-7-(3-fluorobenzyl)-8-oxo-6-phenyl-5,6,7,8-tetrahydro-
furo[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13b): Yield
1
28%. H NMR: δ = 0.8–1.7 (m, 10 H, cyclohexane), 3.4–3.6 (m, 1
H, CH), 3.7–3.8 (d, J = 6.9 Hz, 1 H, CH2), 4.7–4.8 (d, J = 6.9 Hz,
1 H, CH2), 5.0–5.17 (m, 2 H, CH2), 6.3–6.47 (m, 1 H, ArH), 6.5–
6.63 (m, 3 H, ArH), 6.7–6.81 (m, 1 H, ArH), 6.9–7.08 (m, 1 H,
ArH), 7.15–7.31 (m, 5 H, ArH), 7.45–7.58 (s+d, J = 6.0 Hz, 2 H,
ArH, NH) ppm. 13C NMR: δ = 7.9, 9.43, 24.33, 25.41, 25.99, 27.43,
28.72, 2×33.21, 53.21, 54.73, 64.32, 119.43, 122.32, 125.06, 126.76,
127.33, 133.65, 134.41, 135.22, 144.31, 164.87, 169.54 ppm.
HRMS: m/z 485.2181; calcd. 485.5632 [M+].
Methyl 6-[(Cycloheptylamino)carbonyl]-6-methyl-8-oxo-7-(3-phen-
ylpropyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate
(6o): Yield 70%. 1H NMR: δ = 1.25–1.76 (m, 12 H, cycloheptane),
1.53 (s, 3 H, CH3), 1.8–2.0 (m+m, 2 H, CH2), 2.62 (t, J = 7.4 Hz,
2 H, CH2), 3.18–3.28 (m, 1 H, CH2), 3.52–3.74 (m, 2 H, CH, CH2),
3.81 (s, 3 H, CH3), 4.02 (d, J = 6.8 Hz, 1 H, CH2), 4.72 (d, J =
6.8 Hz, 1 H, CH2), 7.1–7.27 (m, 5 H, ArH), 7.4 (d, J = 6.3 Hz, 1
H, NH), 7.63 (s, 1 H, ArH) ppm. 13C NMR: δ = 7.7, 9.21, 21.66,
24.12, 25.13, 25.54, 26.54, 27.42, 28.52, 298,12, 2×34.01, 52.35,
53.13, 54.62, 65.55, 124.87, 134.06, 134.98, 156.87, 164.04, 169.21
ppm. HRMS: m/z 466.5803; calcd. 466.5853 [M+].
N-Cyclohexyl-7-(3-fluorobenzyl)-2-methyl-8-oxo-6-phenyl-5,6,7,8-
tetrahydrofuro[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13c):
1
Yield 27%. H NMR: δ = 0.85–1.84 (m, 10 H, cyclohexane), 2.36
(s, 3 H, CH3), 3.51–3.58 (m, 1 H, CH), 3.8 (d, J = 6.8 Hz, 1 H,
CH2), 4.68 (d, J = 6.8 Hz,1 H, CH2), 4.87–5.11 (d+d, J = 6.9 Hz,
2 H, CH2), 6.1 (s, 1 H, ArH), 2.51 (s, 1 H, ArH), 6.51 (t, J =
6.7 Hz, 2 H, ArH), 6.7–6.8 (t, J = 6.7 Hz, 1 H, ArH), 7.0–7.1 (q,
J = 7.2 Hz, 1 H, ArH), 7.17–7.31 (m, 6 H, ArH) ppm. 13C NMR:
δ = 7.87, 13.43, 24.13, 25.54, 26.19, 27.43, 28.72, 2×34.08, 54.01,
54.73, 64.32, 120.21, 122.37, 125.45, 126.33, 127.21, 134.27, 134.99,
135.54, 144.32, 164.78, 168.36 ppm. HRMS: m/z 499.2181; calcd.
499.5903 [M+].
Methyl 6-[(Cycloheptylamino)carbonyl]-7-(4-fluorobenzyl)-6-methyl-
8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (6p):
Yield 79%. 1H NMR: δ = 1.22–1.7 (m, 12 H, cycloheptane), 1.5 (s,
3 H, CH3), 3.51–3.67 (m, 1 H, CH), 3.82 (s, 3 H, CH3), 4.08 (d, J
= 6.8 Hz, 1 H, CH2), 4.20 (d, J = 6.9 Hz, 1 H, CH2), 4.89 (d, J =
6.8 Hz, 1 H, CH2), 5.3 (d, J = 6.9 Hz, 1 H, CH2), 7.0 (dd, J =
7.6 Hz, 2 H, ArH), 7.28–7.39 [m(F), 2 H, ArH], 7.41 (d, J = 6.0 Hz,
1 H, NH), 7.68 (s, 1 H, ArH) ppm. 13C NMR: δ = 7.9, 9.43, 22.21,
24.33, 25.41, 25.99, 27.27, 28.77, 2 × 33.28, 53.21, 54.13, 54.98,
64.32, 125.06, 134.41, 135.22, 158.98, 165.11, 169.14 ppm. HRMS:
m/z 456.5170; calcd. 456.5215 [M+].
N-Cyclohexyl-2,6-dimethyl-8-oxo-7-(pyridin-3-ylmethyl)-5,6,7,8-
tetrahydrofuro[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13d):
1
Yield 63%. H NMR: δ = 0.8–1.65 (m, 10 H, cyclohexane), 1.4 (s,
3 H, CH3), 2.32–2.39 (s, 3 H, CH3), 3.31–3.42 (q, J = 7.4 Hz, 1 H,
CH), 3.9 (d, J = 6.7 Hz,1 H, CH2), 4.24 (d, J = 6.8 Hz, 1 H, CH2),
4.61 (d, J = 6.7 Hz,1 H, CH2), 5.16 (d, J = 6.8 Hz, 1 H, CH2), 6.1
(s, 1 H, ArH), 6.5 (s, 1 H, ArH), 7.1–7.3 (m, 2 H, ArH), 7.58–7.61
Methyl 6-[(Cycloheptylamino)carbonyl]-7-(2-cyclohex-1-en-1-yl-
ethyl)-6-methyl-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-car- (d, J = 6.4 Hz, 1 H, NH), 8.35 (s, 1 H, ArH), 8.49 (s, 1 H, ArH)
boxylate (6q): Yield 65%. 1H NMR: δ = 1.21–1.73 (m, 12 H, cyclo-
heptane), 1.21–1.73 (m, 4 H, cyclohexene), 1.53 (s, 3 H, CH3), 2.04
ppm. 13C NMR: δ = 7.9, 13.87, 23.49, 25.51, 33.02, 34.79, 45.65,
52.21, 54.31, 64.81, 116.32, 119.43, 120.65, 122.31, 124.06, 124.98,
4676
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Annelated Azaheterocycles by a Modification of the Four-Component Ugi Reaction
FULL PAPER
133.33, 144.14, 163.32, 169.61 ppm. HRMS: m/z 420.2230; calcd.
J = 7.9 Hz, 2 H, CH2), 3.47–3.51 (m, 1 H, CH), 4.0 (d, J = 6.7 Hz,
1 H, CH2), 4.7 (d, J = 6.9 Hz, 1 H, CH2), 4.55 (d, J = 6.7 Hz, 1
H, CH2), 4.82 (d, J = 6.9 Hz,1 H, CH2), 6.3 (d, J = 7.3 Hz, 2 H,
ArH), 6.6–6.71 (s, 2 H, ArH), 6.85 (s, 1 H, ArH), 7.35–7.41 (s, 1
H, NH) ppm. 13C NMR: δ = 7.8, 16.13, 20.31, 23.33, 24.82, 25.55,
27.20, 33.10, 34.33, 46.05, 54.26, 54.91, 64.54, 114.54, 119.43,
120.88, 122.31, 124.06, 124.98, 134.36, 164.31, 168.21 ppm.
HRMS: m/z 453.2157; calcd. 453.6081 [M+].
420.5158 [M+].
N-Cyclooctyl-2,6-dimethyl-8-oxo-7-(thien-2-ylmethyl)-5,6,7,8-tetra-
hydrofuro[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13e):
Yield 66%. 1H NMR: δ = 1.1–1.57 (m, 14 H, cyclooctane), 1.58 (s,
3 H, CH3), 2.4 (s, 3 H, CH3), 3.51–3.2 (m, 1 H, CH), 3.8 (d, J =
6.6 Hz,1 H, CH2), 4.55 (d, J = 6.9 Hz,1 H, CH2), 4.66 (d, J =
6.9 Hz,1 H, CH2), 5.07 (d, J = 6.9 Hz,1 H, CH2), 6.1 (s, 1 H, ArH),
6.49 (d, J = 7.3 Hz, 1 H, ArH), 6.53 (s, 1 H, ArH), 6.8 (t, J =
7.4 Hz, 1 H, ArH), 7.06 (d, J = 7.4 Hz, 1 H, ArH), 7.22 (d, J =
5.9 Hz, 1 H, NH) ppm. 13C NMR: δ = 7.9, 14.13, 23.43, 24.22,
25.59, 27.21, 33.12, 34.76, 46.05, 54.26, 54.91, 64.83, 116.33,
119.43, 120.65, 122.31, 124.06, 124.98, 133.33, 163.32, 168.43 ppm.
HRMS: m/z 453.2157; calcd. 453.6081 [M+].
7-(3-Bromobenzyl)-N-cyclohexyl-8-oxo-6-phenyl-5,6,7,8-tetrahydro-
thieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (14b): Yield
1
34%. H NMR: δ = 0.7–1.9 (m, 10 H, cyclohexane), 3.41–3.58 (m,
1 H, CH), 3.67–3.78 (d, J = 6.4 Hz, 1 H, CH2), 4.8–4.92 (d, J =
6.8 Hz, 1 H, CH2), 5.12–5.19 (d+d, J = 6.8 Hz, 1 H, CH2), 5.2–5.3
(d, J = 6.8 Hz, 1 H, CH2), 6.8–6.82 (d, J = 6.8 Hz, 1 H, ArH), 5.84
(s, 1 H, ArH), 6.87–7.1 (m, 3 H, ArH), 7.18–7.38 (m, 7 H, ArH),
7.52–7.61 (d, J = 6.2 Hz, 1 H, NH) ppm. 13C NMR: δ = 7.87,
24.13, 25.54, 26.19, 27.43, 28.72, 2 × 34.08, 54.01, 54.73, 64.32,
120.21, 122.37, 125.45, 126.33, 127.21, 134.27, 134.99, 135.54,
144.32, 164.78, 168.36 ppm. HRMS: m/z 562.1150; calcd. 562.5334
[M+].
7-(2-Methoxyethyl)-6-methyl-N-(3-methylbutyl)-8-oxo-5,6,7,8-tetra-
hydrofuro[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13f):
Yield 40%. 1H NMR: δ = 0.6 (s, 3 H, CH3), 0.8 (s, 3 H, CH3),1.11–
1.3 (m, 3 H, CH2), 2.9–3.1 (m, 2 H, CH2), 3.2 (s, 3 H, CH3), 3.5–
3.6 (m, 3 H, CH2), 1.7–1.81 (m, 1 H, CH), 3.9 (d, J = 7.0 Hz, 1 H,
CH2), 4.55 (d, J = 7.0 Hz, 1 H, CH2), 6.49 (d, J = 7.4 Hz, 2 H,
ArH), 7.4 (s, 2 H, ArH, NH) ppm. 13C NMR: δ = 19.11, 23.13,
24.59, 25.65, 32.31, 33.21, 45.30, 47.76, 51.18, 52.43, 54.58, 64.81,
122.31, 143.54, 154.65, 163.99, 169.64 ppm. HRMS: m/z 361.2079;
calcd. 361.4447 [M+].
N-Cycloheptyl-8-oxo-6-phenyl-7-propyl-5,6,7,8-tetrahydrothieno-
[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (14c): Yield 25 %.
1H NMR: δ = 0.56–0.7 (t, J = 8.4 Hz, 3 H, CH3), 1.1–1.8 (m, 14
H, cycloheptane, CH2), 2.6–2.75 (m, 1 H, CH2), 3.4–3.52 (m, 1 H,
CH2), 3.73–3.84 (m, 1 H, CH), 4.62–4.8 (d, J = 7.0 Hz, 1 H, CH2),
5.07–5.18 (d, J = 7.0 Hz, 1 H, CH2), 6.88 (s, 1 H, ArH), 7.9–8.0
(d, J = 7.4 Hz, 1 H, ArH), 7.1–7.19 (d, J = 5.9 Hz, 1 H, NH), 7.2–
7.28 (d, J = 7.2 Hz, 1 H, ArH), 7.38–7.53 (m, 5 H, ArH) ppm. 13C
NMR: δ = 7.89, 22.19, 24.17, 25.28, 26.44, 27.43, 27.41, 28.46,
29.49, 2×33.21, 54.59, 56.43, 64.65, 128.21, 134.04, 134.43, 136.43,
145.12, 166.32, 169.21 ppm. HRMS: m/z 449.2206; calcd. 449.6199
[M+].
7-(4-Chlorobenzyl)-6-methyl-8-oxo-N-(tetrahydrofuran-2-ylmethyl)-
5,6,7,8-tetrahydrofuro[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carbox-
amide (13g): Yield 48%. 1H NMR: δ = 1.0–1.7 (m, 6 H, tetra-
hydrofuran), 1.5 (s, 3 H, CH3), 3.0–3.2 (m, 1 H, CH), 3.5–3.7 (m,
1 H, CH2), 4.0–4.2 (m, 1 H, CH2), 4.66 (d, J = 6,8 Hz, 1 H, CH2),
5.5 (d, J = 6,8 Hz, 1 H, CH2), 6.55 (d, J = 7.2 Hz, 2 H, ArH),
7.09–7.36 (m, 4 H, ArH), 7.5 (s, 1 H, ArH), 7.7–7.9 (m, 1 H, NH)
ppm. 13C NMR: δ = 7.8, 14.27, 23.49, 33.12, 34.39, 53.11, 54.31,
64.81, 116.38, 119.43, 121.61, 122.31, 124.06, 124.44, 133.6, 134.54,
144.61, 163.38, 168.22 ppm. HRMS: m/z 441.1524; calcd. 441.9184
[M+].
N-Cycloheptyl-2-ethyl-8-oxo-6-phenyl-7-propyl-5,6,7,8-tetrahydro-
thieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (14d): Yield
1
28%. H NMR: δ = 0.58–0.70 (t, J = 5.5 Hz, 3 H, CH3), 1.15–1.7
(m, 14 H, cycloheptane, CH2), 1.25–1.28 (t, J = 8.6 Hz, 3 H, CH3),
2.6–2.8 (m, 1 H, CH2), 2.82–2.9 (q, J = 7.8 Hz, 2 H, CH2), 3.3–
3.52 (m, 1 H, CH2), 3.72–3.9 (m, 1 H, CH), 4.6–4.79 (d, J = 6.9 Hz,
1 H, CH2), 5.06–5.17 (d, J = 6.9 Hz, 1 H, CH2), 6.6 (s, 1 H, ArH),
6.8 (s, 1 H, ArH), 7.0–7.1 (d, J = 6.4 Hz, 1 H, NH), 7.3–7.5 (m, 5
H, ArH) ppm. 13C NMR: δ = 7.85, 20.32, 22.11, 25.07, 25.28,
26.48, 28.23, 28.98, 29.11, 29.49, 2 × 33.77, 54.51, 56.48, 64.15,
129.11, 134.77, 135.13, 136.43, 145.17, 165.72, 168.51 ppm.
HRMS: m/z 477.2528; calcd. 477.6741 [M+].
7-Benzyl-N-cycloheptyl-2-methyl-8-oxo-6-phenyl-5,6,7,8-tetrahydro-
furo[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13h): Yield
36%. H NMR: δ = 1.0–1.7 (m, 12 H, cycloheptane), 2.35 (s, 3 H,
1
CH3), 1.6–1.72 (m, 1 H, CH), 4.1 (d, J = 6.8 Hz, 1 H, CH2), 4.58
(d, J = 6.7 Hz, 1 H, CH2), 4.81 (d, J = 6.8 Hz, 1 H, CH2), 4.92 (d,
J = 6.7 Hz, 1 H, CH2), 6.1 (s, 1 H, ArH), 6.57 (s, 1 H, ArH), 6.8–
7.32 (m, 11 H, ArH, NH) ppm. 13C NMR: δ = 7.89, 13.41, 24.13,
25.54, 26.01, 26.19, 27.41, 28.43, 29.41, 2 × 33.58, 54.11, 55.21,
64.37, 121.43, 122.39, 124.33, 126.04, 127.21, 133.22, 134.55,
135.53, 144.39, 165.12, 168.87 ppm. HRMS: m/z 495.2592; calcd.
495.6270 [M+].
2-Ethyl-6-methyl-N-(4-methylcyclohexyl)-8-oxo-7-(2-pyrrolidin-
1-ylethyl)-5,6,7,8-tetrahydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-
6-carboxamide (14e): Yield 63%. 1H NMR: δ = 0.77–0.82 (t, J =
8.7 Hz, 3 H, CH3), 1.25–1.30 (t, J = 7.6 Hz, 3 H, CH3), 1.45 (br.
s, 3 H, CH3), 0.77–1.8 (m, 13 H, cyclohexane, pyrrolidine), 2.4–
2.62 (m, 2 H, CH2), 2.65–3.0 (m, 6 H, 3CH2), 3.3–3.52 (m, 2 H,
CH2), 3.8–4.0 (m, 2 H, 2CH), 4.7 (d, J = 6.8 Hz, 1 H, CH2), 6.68
(s, 1 H, ArH), 6.73 (s, 1 H, ArH), 7.8 (d, J = 6.6 Hz, 1 H, NH)
ppm. 13C NMR: δ = 19.11, 14.22, 20.54, 23.13, 24.59, 25.65, 26.74,
32.31, 34.51, 45.30, 47.75, 51.10, 52.43, 64.18, 122.37, 143.59,
153.61, 163.99, 168.24 ppm. HRMS: m/z 470.2795; calcd. 470.6824
[M+].
N-Cycloheptyl-8-oxo-6-phenyl-7-propyl-5,6,7,8-tetrahydrofuro-
[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide (13i): Yield 27%. 1H
NMR: δ = 0.59 (s, 3 H, CH3), 1.1–1.65 (m, 14 H, cycloheptane,
CH2), 2.58–2.7 (m, 1 H, CH), 3.38–3.5 (m, 1 H, CH2), 3.68–3.8 (m,
1 H, CH2), 4.55–4.73 (d, J = 7.0 Hz, 1 H, CH2), 4.83–5.04 (d, J =
7.0 Hz, 1 H, CH2), 6.37–6.6 (d, J = 7.4 Hz, 2 H, ArH), 7.1 (d, J =
7.2 Hz, 1 H, NH), 7.25–7.77 (m, 5 H, ArH), 7.45 (s, 1 H, ArH)
ppm. 13C NMR: δ = 7.87, 21.49, 24.13, 25.23, 26.61, 26.99, 27.41,
28.46, 29.49, 2×34.12, 54.58, 55.11, 64.65, 128.21, 134.76, 134.99,
136.43, 145.12, 164.07, 168.81 ppm. HRMS: m/z 433.2435; calcd.
433.5553 [M+].
7-(1-Benzylpiperidin-4-yl)-N-cyclopentyl-6-methyl-8-oxo-5,6,7,8-
tetrahydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide
1
N-Cycloheptyl-2-ethyl-7-(2-furylmethyl)-6-methyl-8-oxo-5,6,7,8-
(14f): Yield 65%. H NMR: δ = 1.4 (s, 3 H, CH3), 1.3–2.22 (m, 13
tetrahydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide H, cyclopentane, piperidine), 2.7–2.94 (m, 4 H, 2CH2), 3.3–3.5
(14a): Yield 90%. 1H NMR: δ = 1.2–1.5 (m, 12 H, cyclooctane),
1.21–1.25 (t, J = 8.4 Hz, 3 H, CH3), 1.6 (s, 3 H, CH3), 2.73–2.9 (q,
(d+d, J = 6.4 Hz, 2 H, CH2), 4.0–4.11 (q, J = 6.6 Hz, 1 H, CH),
4.13–4.2 (d, J = 7.0 Hz, 1 H, CH2), 1.4–1.5 (d, J = 7.0 Hz, 1 H,
Eur. J. Org. Chem. 2005, 4670–4679
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4677

A. V. Ivachtchenko et al.
FULL PAPER
CH2), 6.9 (s, 1 H, ArH), 6.93–7.0 (d, J = 7.4 Hz, 1 H, ArH), 7.15– 3 H, CH3), 2.91 (s, 3 H, CH3), 3.0–3.33 (m, 6 H, 3CH2), 3.4–3.54
7.21 (m, 6 H, ArH), 8.13 (d, J = 4.9 Hz, 1 H, NH) ppm. 13C NMR: (m, 1 H, CH), 3.8–3.91 (m, 2 H, CH2), 4.17 (d, J = 6.9 Hz, 1 H,
δ = 7.83, 22.11, 25.07, 25.29, 26.36, 28.27, 28.99, 30.43, 31.48, CH2), 4.72 (d, J = 6.9 Hz, 1 H, CH2), 6.75 (t, J = 6.8 Hz, 1 H,
2 × 34.15, 54.51, 56.48, 62.43, 119.54, 130.33, 134.77, 135.19, ArH), 6.88 (d, J = 7.4 Hz, 2 H, ArH), 7.22 (t, J = 7.0 Hz, 2 H,
138.42, 145.17, 165.78, 169.51 ppm. HRMS: m/z 490.2482; calcd.
ArH), 7.68 (d, J = 6.2 Hz, 1 H, NH), 7.71 (s, 1 H, ArH) ppm. 13C
NMR: δ = 19.92, 24.54, 24.64, 25.06, 28.09, 31.91, 45.73, 48.06,
48.51, 48.62, 50.19, 64.13, 2×115.86, 119.25, 119.61, 2×128.81,
128.91, 136.38, 137.52, 150.75, 158.17, 163.09, 168.64 ppm.
HRMS: m/z 478.2772; calcd. 478.5993 [M+].
490.6728 [M+].
7-(3-Fluorophenyl)-6-methyl-N-(2-methylcyclohexyl)-8-oxo-5,6,7,8-
tetrahydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-carboxamide
1
(14g): Yield 40%. H NMR: δ = 0.54 (s, 3 H, CH3), 1.28 (s, 3 H,
CH3), 0.8–1.79 (m, 8 H, cyclohexane), 3.0–3.18 (m, 2 H, 2CH),
4.32–4.4 (d, J = 6.5 Hz, 1 H, CH2), 5.0–5.07 (d, J = 6.9 Hz, 1 H,
CH2), 6.7–7.4 (m, 7 H, ArH), 7.57–7.7 (t, J = 6.2 Hz, 1 H, NH)
ppm. 13C NMR: δ = 7.86, 25.07, 25.28, 28.23, 28.98, 29.11, 29.49,
34.77, 54.51, 57.42, 64.15, 122.21, 133.20, 136.33, 137.73, 145.17,
166.22, 168.51 ppm. HRMS: m/z 439.1797; calcd. 439.5561 [M+].
N6-Cyclohexyl-N1-[2-(4-methoxyphenyl)ethyl]-6,7-dimethyl-8-oxo-
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1,6-dicarboxamide (16b):
Yield 80%. H NMR: δ = 1.1–1.35 (m, 5 H, cyclohexane), 1.58 (s,
1
3 H, CH3), 1.59–1.76 (m, 5 H, cyclohexane), 3.01 (s, 3 H, CH3),
3.45–3.57 (m, 1 H, CH), 4.25 (d, J = 6.8 Hz, 1 H, CH2), 4.4–4.52
(m, 2 H, CH2), 4.84–4.95 (m, 1 H, CH2), 6.8 (d, J = 6.8 Hz, 1 H,
ArH), 7.24 (d, J = 7.2 Hz, 1 H, ArH), 7.86 (s, 1 H, ArH), 7.92 (d,
J = 6.0 Hz, 1 H, NH), 10.86 (br. s, 1 H, NH) ppm. 13C NMR: δ =
19.79, 24.52, 24.63, 25.01, 29.03, 31.83, 31.92, 48.58, 50.07, 54.98,
64.04, 2×113.73, 121.17, 2×128.54, 131.14, 136.68, 138.05, 158.18,
159.96, 160.22, 168.19 ppm. HRMS: m/z 467.2445; calcd. 467.5729
[M+].
7-(1,3-Benzodioxol-5-ylmethyl)-N-cyclohexyl-2-ethyl-8-oxo-6-
phenyl-5,6,7,8-tetrahydrothieno[2Ј,3Ј:4,5]pyrrolo[1,2-a]pyrazine-6-
carboxamide (14h): Yield 39%. 1H NMR: δ = 1.28–1.32 (t, J =
8.6 Hz, 3 H, CH3), 0.8–1.7 (m, 10 H, cyclohexane), 2.8–3.0 (q, J =
6.6 Hz, 2 H, CH2), 3.4–3.53 (m, 1 H, CH), 3.9–4.07 (m, 1 H, CH),
4.67–4.8 (m, 1 H, CH), 4.6–4.77 (d, J = 6.9 Hz, 1 H, CH2), 5.05–
5.18 (d, J = 6.9 Hz, 1 H, CH2), 5.88 (d, J = 8.0 Hz, 2 H, CH2, 1,3-
benzodioxolyl), 6.12 (d, J = 8.0 Hz, 1 H, ArH, 1,3-benzodioxolyl),
6.46 (d, J = 8.0 Hz, 2 H, ArH, 1,3-benzodioxolyl), 6.65 (s, 1 H,
ArH), 6.88 (s, 1 H, ArH), 7.0–7.15 (m, 1 H, NH), 7.2–7.39 (m, 5
H, ArH) ppm. 13C NMR: δ = 7.71, 14.33, 24.01, 24.28, 25.99,
26.19, 27.43, 28.21, 2×34.18, 52.71, 54.01, 54.83, 66.12, 121.29,
122.37, 125.45, 126.33, 128.43, 134.27, 135.09, 136.34, 146.12,
164.77, 169.31 ppm. HRMS: m/z 555.2257; calcd. 555.7015 [M+].
Crystallographic Data for 13a: Tetragonal single crystal
[0.55×0.10×0.10 mm3, space group I41/a, unit cell constants a =
20.669(5) Å, b = 20.669(5) Å, c = 18.394(7) Å, α = 90°, β = 90°, γ
= 90°, V = 7859(4) Å3, Z = 16, Dx = 1.263 Mg/m3]. Cell parameters
were retrieved using SMART software and refined using SAINT
on all observed reflections. Data reduction was performed with
SAINT, and the structures were solved by the direct method using
the SHELXS-97 program incorporated in SHELXTL-PC V 5.10
and refined by the least-squares method on F2. The final R indices
are R1 = 0.0509, wR2 = 0.1221.
6-[(Cyclohexylamino)carbonyl]-6,7-dimethyl-8-oxo-5,6,7,8-tetra-
hydroimidazo[1,5-a]pyrazine-1-carboxylic Acid (15): To a solution
of ester 6e (696 mg, 2 mmol) in methanol (15 mL) was added a
2% aqueous solution of NaOH (10 mL). The reaction mixture was
stirred at 70 °C for 7 h, then cooled to room temp. and concen-
trated under reduced pressure to remove methanol. Water (15 mL)
was added, and the mixture was acidified by addition of 1% aque-
ous HCl until pH 3 was reached. The formed precipitate was fil-
tered off, washed with water (3×50 mL) and dried with Na2SO4 to
Acknowledgments
The authors would like thank Caroline T. Williams (Department
of Analytical Chemistry, ChemDiv, Inc.) for NMR spectroscopic
data. The authors also thank the Scribbs Center for Mass Spec-
trometry (La Jolla, California, USA) for HRMS spectroscopic
data.
1
give 15 as a white solid (536 mg, 80%). Yield 80%. H NMR: δ =
1.0–1.5 (m, 10 H, cyclohexane), 1.62 (s, 3 H, CH3), 3.03 (s, 3 H,
CH3), 3.41–3.58 (m, 1 H, CH), 4.3 (d, J = 6.8 Hz, 1 H, CH2), 4.8
(d, J = 6.8 Hz, 1 H, CH2), 7.88 (s, 1 H, ArH), 7.9 (d, J = 6.2 Hz,
1 H, NH), 14.63 (s, 1 H, OH) ppm. 13C NMR: δ = 19.46, 24.50,
24.61, 24.99, 29.10, 31.81, 31.89, 48.81, 50.03, 64.89, 123.22,
135.14, 137.98, 159.95, 161.25, 167.63 ppm. HRMS: m/z 334.1712;
calcd. 334.3781 [M+].
[1] a) I. Ugi, S. Lohberger, R. Karl, in: Comprehensive Organic
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General Procedure for Preparation of Amides 16a,b: 1,1Ј-Carbonyl-
diimidazole (178 mg, 1.1 mmol) was added portionwise to a solu-
tion of the acid 15 (334 mg, 1 mmol) in DMF (2 mL). The resulting
mixture was stirred at room temperature for 10 min and then at
80–90 °C for 3 h to accomplish the conversion of initial acid into
the corresponding imidazolide intermediate. The mixture was co-
oled to room temperature and DMF was added until the total vol-
ume was equal to 4 mL. A portion of this solution (2 mL) was
added to a solution of amine HNR3R4 (1 mmol) in dry DMF
(500 µL), and the reaction mixture was stirred at 75–80 °C for 8 h
and then cooled to room temperature. Water (2 mL) was added,
the formed precipitate was filtered off and recrystallized from di-
ethyl ether to afford pure carboxamide 16a or 16b.
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