Access to novel imidazo[1,5-a]pyrazine scaffolds by the combined use of a three-component reaction and a base-assisted intramolecular cyclization

Article abstract of DOI:10.1039/c4ob00676c

A novel and practical two-step approach to an intriguing class of imidazo[1,5-a]pyrazines with exocyclic CX (X = CH₂, O) bonds is described. The process utilizes a sequential three-component reaction of propargyl amine or aminoester, 1,2-diaza-1,3-dienes and isothiocyanates to furnish functionalized 2-thiohydantoins which are transformed into thiohydantoin-fused tetrahydropyrazines by subsequent regioselective base-promoted cyclization. This journal is

Full text of DOI:10.1039/c4ob00676c

Organic &
Biomolecular Chemistry
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Access to novel imidazo[1,5-a]pyrazine scaffolds
by the combined use of a three-component
reaction and a base-assisted intramolecular
cyclization†
Cite this: Org. Biomol. Chem., 2014,
12, 4610
Orazio A. Attanasi,a Gianfranco Favi,*a Gianluca Giorgi,b Roberta Majer,a
Francesca Romana Perrulli*a and Stefania Santeusanioa
A novel and practical two-step approach to an intriguing class of imidazo[1,5-a]pyrazines with exocyclic
CvX (X = CH2, O) bonds is described. The process utilizes a sequential three-component reaction of pro-
pargyl amine or aminoester, 1,2-diaza-1,3-dienes and isothiocyanates to furnish functionalized 2-thio-
hydantoins which are transformed into thiohydantoin-fused tetrahydropyrazines by subsequent
regioselective base-promoted cyclization.
Received 31st March 2014,
Accepted 29th April 2014
DOI: 10.1039/c4ob00676c
www.rsc.org/obc
Introduction
Among the known members of the azaindolizine family the
imidazo[1,5-a]pyrazine heterocyclic framework is a structural
unit found in several natural products, drugs, and drug candi-
dates. For example, the imidazo[1,5-a]pyrazine1 derived struc-
tures possess diverse pharmacological properties, such as
Factor Xa inhibitors,2 IGF-IR inhibitors,3 PDE10 inhibitors,4
mTORC1/2 inhibitors,5 ACK1 inhibitors,6 Smo antagonists,7
etc. They were also identified to act on a number of targets
including the CFR receptor,8 GABAA receptor,9 and melanocor-
tin receptor.10 Recently, the compound BMS-279700 was dis-
covered as a novel, potent, and orally active Lck inhibitor with
excellent in vivo anti-inflammatory activity11 (Fig. 1). Due to
the resemblance to drug-like molecules, bicyclic skeletons
with thiohydantoin and tetrahydropyrazine have a special
appeal. However, this heterobicyclic structure as a derivatiza-
tion of a new scaffold12 obtained from fusion of these two
important motifs is much less common. A thorough search of
the literature revealed only a single example of such a type of
imidazo[1,5-a]pyrazine (compound I, Fig. 1).13
Fig. 1 Selected examples of compounds containing imidazo[1,5-a]-
pyrazine skeletons.
discovery and optimization in medicinal chemistry. By virtue
of its inherent convergence, simplicity, efficiency, atom
economy, shortened reaction times, and complexity-generating
power, the MBFTs represent an attractive area in modern
organic chemistry. In conjunction with our efforts to explore
new multiple bond-forming reactions from 1,2-diaza-1,3-
dienes (DDs),16 herein we would like to report a new synthetic
strategy for the efficient construction of potentially biological
active bicyclic thiohydantoin-tetrahydropyrazine derivatives
using the MCRs/post-functionalization17 strategy. Recently, our
laboratory has developed a robust chemo- and regioselective
approach to 2-thiohydantoin or 2-iminothiazolidin-4-one
derivatives by sequential three-component reactions involving
the combination of a primary amine 1, a DD 2, and an isothio-
cyanate 3.18 The ready availability of numerous acyclic reagents
1–3 allows for the incorporation of various points of functional
diversity into the products 4. Aiming at expanding the scope of
In the field of multicomponent reactions (MCRs),14 sequen-
tial multiple bond-forming transformations (MBFTs)15 rep-
resent undoubtedly a well-suited tool for lead compound
aDepartment of Biomolecular Sciences, Section of Organic Chemistry and Organic
Natural Compounds, University of Urbino “Carlo Bo”, Via I Maggetti 24, 61029
Urbino, Italy. E-mail: gianfranco.favi@uniurb.it
bDepartment of Chemistry, University of Siena, Via Aldo Moro, 53100 Siena, Italy
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra. CCDC 1003262. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4ob00676c
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was added to furnish 2-thiohydantoin compound 4aa in 64%
yield (entry 1, Table 1). With the required precursor 4aa in
hand, NaH as a base was tested to attempt the base-mediated
activation of the hydrazonic nitrogen to induce the intramole-
cular cyclization.19 Surprisingly, the hydroamination/cycliza-
tion of 4aa-containing unactivated alkyne proceeded well in
ethanol at room temperature and the desired bicyclic product
5aa was obtained in 67% yield (entry 1, Table 1). Notably, only
5aa with an exocyclic C–C double bond formed via a 6-exo-dig
ring closing pathway was observed. Despite the importance
provided by the intramolecular amines–alkynes cyclization for
the construction of azaheterocycles,20–22 hydroamination reac-
tions of hydrazones are scarce and mostly limited to the for-
mation of five-membered rings. Analogously, reports of similar
hydroamination/cyclization to form six-membered N-hetero-
cycles having exocyclic olefin are rarely encountered in the lit-
erature.23 In fact, although an exocyclic olefin is preferentially
formed through the hydroamination/cyclization process, a
more stable endocyclic double bond is then obtained by a
spontaneous 1,3-hydrogen shift.24 In our case, the exclusive
formation of 5aa-exo isomer may lie in its rigid conformation,
which prevents at room temperature a possible isomerization
toward a more strained structure. Only upon reflux in ethanol
with the assistance of NaH 5aa was converted to 6aa-endo
isomer (68% yield) as a result of double bond isomerization
(Scheme 2).25
Scheme 1 Access to thiohydantoin-fused tetrahydropyrazines.
this 3CR, we envisaged that an intramolecular cyclization reac-
tion of a functionalized 2-thiohydantoin intermediate of type 4
with a propargylic or ester appendage on the N(1) position
would lead to an imidazo[1,5-a]pyrazine skeleton 5. The key
cyclization precursor 4 should be accessible from 1-propargyl-
amine 1a or aminoester 1b, DD 2, and isothiocyanate 3 via a
sequential one-pot reaction (see retrosynthetic analysis,
Scheme 1). Following this designed strategy, overall the trans-
formation should create four C–N bonds (a)–(d) and two new
fused heterocyclic rings. Such thiohydantoin-fused tetrahydro-
pyrazine scaffolds could have worth in the synthesis of novel
screening compounds with lead-like molecular properties.
Results and discussion
Based on these promising results, the scope of this novel
two-step synthesis of thiohydantoin-fused tetrahydropyrazines
was next examined with different DDs 2a–f and isothiocyanates
3a–e (Table 1).
In practice, diversely substituted 2-thiohydantoin inter-
mediates 4aa–ag (52–82% yield) were prepared earlier by a 3CR
We initiated an exploratory study preparing the 2-thiohydan-
toin structure as a 4aa bearing N-propargyl appendage that
was then subjected to cyclization via an intramolecular hydro-
amination. Thus, 1-propargylamine 1a was reacted with 2a in
CHCl3 at room temperature and, subsequently (after the quick
disappearance of the reagents, TLC check), isothiocyanate 3a
Table 1 Synthetic pathway to thiohydantoin-fused tetrahydropyrazine derivatives 5aa–ag
1-Propargyl-2-
thiohydantoin 4
Thiohydantoin-fused
tetrahydropyrazine 5
DD 2
Isothiocyanate 3
Entry
R
R1
R2
R3
Yielda (%)
Yieldb (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Et
Me
Et
CO2Et
Me
Me
Me
Me
Et
Et
Me
3a
3a
3a
3b
3c
3d
3e
Ph
Ph
Ph
4-MeO–Ph
Bn
4-Cl–Ph
Et
4aa
4ab
4ac
4ad
4ae
4af
64
55
57
60
63
82
52
5aa
5ab
5ac
5ad
5ae
5af
67
76
58
78
93
91
54
CO2Bn
CO2Me
CO2t-Bu
CO2t-Bu
CO2Bn
CO2Me
Et
Me
Me
Et
2c
4ag
5ag
a Yield of isolated pure product based on DD 1. b Yield of isolated pure product based on intermediate 4.
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Keeping the preparation of variously functionalized 2-thio-
hydantoin structures 4 in mind, we hypothesized that we
could expand the utility of a cyclization approach to the novel
thiohydantoin-fused tetrahydropyrazine nucleus by introduc-
tion of an acetate appendage on the N(1) position of 4. For this
purpose, the requisite cyclization precursor was readily syn-
thesized from glycine ethyl ester hydrochloride 1b, DD 2g and
isothiocyanate 3a in CHCl3 at room temperature and in the
presence of DIPEA. 2-Thiohydantoin compound 4ba was
obtained in 78% yield. Treatment of 4ba with DIPEA in CHCl3
effected cyclization (in practice a lactamization27) within 2 h at
reflux to afford the bicyclic product 5ba in 87% yield (entry 1,
Table 2). With the objective of promoting consecutive ring
annulation events in a single stroke, we next turned our atten-
tion toward a one-pot strategy. Capture of the pendant ester by
the in situ generated hydrazone nucleophile would afford a
thiohydantoin-fused tetrahydropyrazine 5ba having an exo-
cyclic CvO bond. Thus, when the formation of functionalized
2-thiohydantoin intermediate 4ba was complete (TLC check),
DIPEA was added to the reaction mixture, and after 4 h at
reflux, bicyclic compound 5ba was obtained in 77% overall
yield.28 Following the same one-pot protocol, combinations of
glycine ethyl ester hydrochloride 1b with different DDs 2b–e,g,h
and isothiocyanates 3a,b,d,f were next examined. The results
are reported in Table 2.
Scheme 2 Isomerization of 5aa to 6aa.
Fig. 2 ORTEP representation of 5ac.
and then converted into the corresponding methylidene thio-
hydantoin-fused tetrahydropyrazines 5aa–ag (54–93% yield).
The reactions were found to be equally effective with both
aliphatic and aromatic isothiocyanates even if ethyl isothiocya-
nate gave lower yields (Table 1, entry 7). Similarly, differently
substituted DDs (R1 = COX; X = OMe, OEt, OBn, Ot-Bu; R, R2 =
Me, Et) were found to be tolerated. All the thiohydantoin-fused
tetrahydropyrazines 5aa–ag synthesized were characterized by
their 1H NMR, 13C NMR and MS data and unambiguously con-
firmed by X-ray crystal structure analysis of 5ac (see the ORTEP
diagram, Fig. 2).26
The reactions proceeded with both aromatic isothio-
cyanates and differently substituted DDs (R1 = COX; X = OMe,
OEt, OBn, Ot-Bu, NHPh; R, R2 = Me, Et) to give a series of new
thiohydantoin-fused tetrahydropyrazines in yields ranging
from 55% to 78% (Table 2, entries 1–7). Our efforts to include
aliphatic isothiocyanates in this transformation have been
fruitful only when 3g was investigated (entry 8, Table 2).
Table 2 One-pot three-component synthesis of thiohydantoin-fused tetrahydropyrazine derivatives 5ba–bh
Thiohydantoin-fused
tetrahydropyrazine 5
DD 2
Isothiocyanate 3
Entry
R
R1
R2
R3
Yielda (%)
1
2
3
4
5
6
7
8
2g
2c
2h
2b
2c
2e
2d
2g
Et
Et
Me
Me
Et
Me
Et
CONHPh
CO2Me
CO2Et
Me
Me
Me
Me
Me
Et
3a
3f
3b
3f
3a
3a
3d
3g
Ph
5ba
5bb
5bc
5bd
5be
5bf
77 (87b)
59
61
65
78
61
55
30
4-NO2–Ph
4-MeO–Ph
4-NO2–Ph
Ph
Ph
4-Cl–Ph
CH2CO2Et
CO2Bn
CO2Me
CO2t-Bu
CO2t-Bu
CONHPh
Me
Me
5bg
5bh
Et
a Yield of isolated pure product based on DD 1. b Yield of isolated pure product based on intermediate 4ba.
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Scheme 3 Mechanism pathways for the sequential 3CRs/cyclizations strategy.
From a mechanistic point of view, the 2-thiohydantoin 4
ring annulation commences from the preliminary aza-Michael
addition of amine 1 to DD 2 to generate intermediate A, which
Experimental
Materials and methods
subsequently reacts with isothiocyanate 3. Then, an intramole- All chemicals and solvents were purchased from commercial
cular ring closure of the hydrazone intermediate B produces suppliers and used as received. 1,2-Diaza-1,3-dienes (DDs)
2-thiohydantoin 4 (4a or 4b) upon loss of an alcohol molecule. were prepared as reported16a,29 and used as EE/EZ isomer mix-
The formation of an additional tetrahydropyrazine ring would tures. Melting points were determined in open capillary tubes
occur via an intramolecular nucleophilic attack of the hydrazo- and are uncorrected. FT-IR spectra were obtained as Nujol
nic nitrogen onto the pendant CuC or CvO system mulls or neat. Mass spectra (MS) were carried out by electron
(Scheme 3, path a and path b, respectively). When 1-propargyl- impact (EI) at an ionizing voltage of 70 eV. 1H NMR (400 MHz)
amine 1a is used a NaH-promoted hydroamination leads to and 13C NMR (100 MHz) spectra were recorded in DMSO-d6, or
product 5a via a 6-exo-dig ring closing process (Scheme 3, path in CDCl3 as specified below. For all new compounds the
a). Alternatively,
a pathway that involves NaH-mediated reported chemical shift values are referred to the prevalent
alkyne–allene isomerization followed by 6-endo-trig cyclization stereoisomer. Chemical shifts (δH) and (δC) are reported in
could also occur. With respect to glycine ethyl ester 1b as an parts per million (ppm), and were referred to solvent signals
amine component, an intramolecular 6-exo-trig cyclization of as follows: δ = 2.50 ppm for proton (middle peak) and δ =
4b via a nucleophilic acyl substitution results in the formation 39.50 ppm for carbon in DMSO; δ = 7.26 ppm for proton and
of bicyclic product 5b (Scheme 3, path b).
δ = 77.00 ppm for carbon (middle peak) in CDCl3. All coupling
Presumably, the driving force of all these intramolecular constants (J values) are given in hertz (Hz). The following
cyclizations derives from the appreciable acidity of the proton abbreviations are used to describe peak patterns where appro-
in the α-position to the CvN hydrazone function which being priate: s, singlet; d, doublet; dd, double-doublet; t, triplet;
susceptible to tautomerization under basic conditions allows q, quartet; m, multiplet; br, broad. All the NH exchanged with
activation of sp2 nitrogen towards the ring closure.
D2O. Precoated silica gel plates of 0.25 mm were employed for
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analytical thin layer chromatography and silica gel of 35–70 anal. calcd for C16H16N4O3S (344.39) C, 55.80; H, 4.68; N,
µm for column chromatography. All new compounds showed 16.27; found C, 55.68; H, 4.77; N, 16.20.
satisfactory elemental analysis.
tert-Butyl 2-{1-[1-(4-methoxyphenyl)-5-oxo-3-(2-propynyl)-2-
thioxo-4-imidazolidinyl]ethylidene}-1-hydrazinecarboxylate
(4ad). Yield 249.9 mg (60%); white powder 145–147 °C
(dec.) (from hot EtOH); IR (Nujol, ν, cm−1) 3325, 3271, 2122,
General procedure for the one-pot synthesis of 1-propargyl-
2-thiohydantoin derivatives 4aa–ag
1
1752, 1717, 1608; H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 9H),
To a stirred solution of propargylamine 1a (1 mmol) in CHCl3 1.82 (s, 3H), 3.40 (s, 1H), 3.80 (s, 3H), 4.57 (d, J = 17.6 Hz, 1H),
(5 mL), DD derivatives 2a–f (1 mmol) were added at room 4.70 (d, J = 17.6 Hz, 1H), 5.10 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H),
temperature. After the disappearance of the reagents (0.1–8 h) 7.24 (d, J = 8.4 Hz, 2H), 10.14 (s, 1H); 13C NMR (100 MHz,
(TLC check), isothiocyanate derivatives 3a–e were added and DMSO-d6) δ 13.0, 28.1, 35.3, 55.4, 68.6, 76.1, 77.0, 79.9, 114.2,
the reaction mixture was allowed to stand overnight at room 126.0, 129.8, 142.8, 152.8, 159.4, 169.8, 182.5; MS (EI) m/z (%)
temperature for the completion (TLC check). After the removal 416 (M+, 10), 360 (23), 316 (9), 300 (9), 219 (17), 165 (21),
of the reaction solvent thiohydantoins 4aa–ad and 4af,ag 125 (59), 111 (100); anal. calcd for C20H24N4O4S (416.49)
were obtained by crystallization from appropriate solvents, C, 57.68; H, 5.81; N, 13.45; found C, 57.81; H, 5.67;
whereas 4ae was achieved after chromatographic purification N, 13.37.
(cyclohexane–ethyl acetate mixtures) and subsequent
crystallization.
tert-Butyl 2-{1-[1-benzyl-5-oxo-3-(2-propynyl)-2-thioxo-4-imi-
dazolidinyl]propylidene}-1-hydrazinecarboxylate (4ae). Yield
Ethyl 2-{1-[5-oxo-1-phenyl-3-(2-propynyl)-2-thioxo-4-imidazo- 261.1 mg (63%); white powder 142 °C (dec.) (from EtOAc–
lidinyl]ethylidene}-1-hydrazinecarboxylate
(4aa). Yield cyclohexane); IR (Nujol, ν, cm−1) 3246, 2127, 1753, 1724, 1704;
229.4 mg (64%); white powder; mp 160–162 °C (dec.) (from 1H NMR (400 MHz, DMSO-d6) δ 0.84 (t, J = 7.6 Hz, 3H), 1.45 (s,
hot EtOH–EtOAc); IR (Nujol, ν, cm−1) 3277, 3229, 2127, 1760, 9H), 2.04–2.13 (m, 1H), 2.41–2.50 (m, 1H), 3.38 (s, 1H), 4.40 (d,
1
1722, 1712; H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J = 6.8 Hz, J = 18.0 Hz, 1H), 4.76 (d, J = 18.0 Hz, 1H), 4.91–5.12 (m, 3H),
4
3H), 1.85 (s, 3H), 3.40 (t, J = 2.4 Hz, 1H), 4.15 (q, J = 6.8 Hz, 7.26–7.32 (m, 5H), 10.18 (s, 1H); 13C NMR (100 MHz, DMSO-
2
4
2
2H), 4.61 (dd, J = 17.6 Hz, J = 2.4 Hz, 1H), 4.67 (dd, J = 17.6 d6) δ 9.1, 20.5, 28.0, 35.2, 44.7, 66.3, 76.3, 78.2, 79.8, 127.3,
Hz, 4J = 2.4 Hz, 1H), 5.16 (s, 1H), 7.34 (d, J = 6.8 Hz, 2H), 127.4, 127.7, 128.2, 128.3, 135.7, 146.4, 152.7, 170.3, 182.0; MS
7.44–7.53 (m, 3H), 10.41 (br s, 1H); 13C NMR (100 MHz, (EI) m/z (%) 414 (M+, 13), 358 (22), 314 (53), 298 (23), 244 (40),
DMSO-d6) δ 12.9, 14.5, 35.3, 60.8, 68.7, 76.0, 76.9, 128.6, 128.7, 203 (100), 149 (23), 111 (41); anal. calcd for C21H26N4O3S
128.9, 133.5, 143.4, 153.8, 169.5, 182.1; MS (EI) m/z (%) 358 (414.52) C, 60.85; H, 6.32; N, 13.52; found C, 60.71; H, 6.46;
(M+, 84), 285 (5), 270 (33), 229 (2), 189 (20), 135 (74), 107 (100); N, 13.61.
anal. calcd for C17H18N4O3S (358.41) C, 56.97; H, 5.06; N,
15.63; found C, 57.08; H, 4.93; N, 15.68.
Benzyl 2-{1-[1-(4-chlorophenyl)-5-oxo-3-(2-propynyl)-2-thioxo-
4-imidazolidinyl]propylidene}-1-hydrazinecarboxylate (4af).
Benzyl 2-{1-[5-oxo-1-phenyl-3-(2-propynyl)-2-thioxo-4-imida- Yield 384.5 mg (82%); white powder 155–157 °C (dec.) (from
1
zolidinyl]ethylidene}-1-hydrazinecarboxylate
(4ab). Yield CH2Cl2); IR (Nujol, ν, cm−1) 3294, 3222, 2130, 1751, 1725; H
231.2 mg (55%); white powder 158 °C (dec.) (from EtOAc– NMR (400 MHz, DMSO-d6) δ 0.97 (t, J = 7.2 Hz, 3H), 2.21–2.26
4
Et2O–light petroleum ether); IR (Nujol, ν, cm−1) 3263, 3247, (m, 1H), 2.56–2.61 (m, 1H), 3.43 (t, J = 2.4 Hz 1H), 4.48 (dd,
2120, 1752, 1735, 1706, 1673; 1H NMR (400 MHz, DMSO-d6) 2J = 18.0 Hz, 4J = 2.4 Hz, 1H), 4.82 (dd, 2J = 18.0 Hz, 4J = 2.4 Hz,
δ 1.86 (s, 3H), 3.42 (t, 4J = 2.4 Hz, 1H), 4.61 (dd, 2J = 17.6 Hz, 4J = 1H), 5.17–5.20 (m, 3H), 7.34–7.43 (m, 7H), 7.58 (d, J = 8.8 Hz,
2.4 Hz, 1H), 4.69 (dd, 2J = 17.6 Hz, 4J = 2.4 Hz, 1H), 2H), 10.64 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 9.5, 20.6,
5.16–5.22 (m, 3H), 7.31–7.55 (m, 10H), 10.57 (s, 1H); 13C NMR 35.4, 66.3, 76.5, 76.7, 128.2, 128.5, 128.8, 128.9, 129.1, 130.5,
(100 MHz, DMSO-d6) δ 13.0, 35.3, 66.2, 68.6, 76.1, 76.9, 128.1, 132.3, 133.7, 136.3, 147.8, 153.8, 169.6, 181.7; MS (EI) m/z (%)
128.4, 128.6, 128.9, 129.0, 133.5, 136.3, 144.0, 153.8, 169.5, 470 [M+ + 2, (8)], 468 (23), 333 (18), 169 (12), 149 (46), 121
182.1; MS (EI) m/z (%) 420 (M+, 69), 285 (38), 271 (16), 189 (13), (100); anal. calcd for C23H21ClN4O3S (468.96) C, 58.91; H, 4.51;
151 (11), 135 (64), 107 (100); anal. calcd for C22H20N4O3S N, 11.95; found C, 58.83; H, 4.64; N, 12.08.
(420.48) C, 62.84; H, 4.79; N, 13.32; found C, 62.97; H, 4.68;
N, 13.40.
Methyl 2-{1-[1-ethyl-5-oxo-3-(2-propynyl)-2-thioxo-4-imidazo-
lidinyl]ethylidene}-1-hydrazinecarboxylate (4ag). Yield
Methyl 2-{1-[5-oxo-1-phenyl-3-(2-propynyl)-2-thioxo-4-imida- 154.1 mg (52%); white powder 141–142 °C (from EtOH);
zolidinyl]ethylidene}-1-hydrazinecarboxylate
(4ac). Yield IR (Nujol, ν, cm−1 3289, 3217, 2121, 1740, 1709; 1H
)
196.3 mg (57%); white powder 163–164 °C (dec.) (from hot NMR (400 MHz, DMSO-d6) δ 1.12 (t, J = 7.2 Hz, 3H), 1.69 (s,
EtOH); IR (Nujol, ν, cm−1) 3323, 3239, 2120, 1757, 1711, 1598; 3H), 3.34 (s, 1H), 3.69 (s, 3H), 3.75 (q, J = 7.2 Hz, 2H), 4.54 (s,
1H NMR (400 MHz, DMSO-d6) δ 1.84 (s, 3H), 3.41 (s, 1H), 3.70 2H), 4.97 (s, 1H), 10.39 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
(s, 3H), 4.63 (s, 2H), 5.15 (s, 1H), 7.33 (d, J = 6.8 Hz, 2H), δ 12.7, 12.8, 35.0, 36.8, 52.0, 68.1, 75.8, 76.9, 143.5, 154.3,
7.46–7.51 (m, 3H), 10.46 (br s, 1H); 13C NMR (100 MHz, 169.8, 181.9; MS (EI) m/z (%) 296 (M+, 25), 264 (9), 222 (49),
DMSO-d6) δ 13.0, 35.3, 52.2, 68.8, 76.1, 76.9, 128.7, 129.0, 181 (11), 141 (100), 115 (5); anal. calcd for C12H16N4O3S
129.1, 133.5, 143.6, 154.4, 169.6, 182.2; MS (EI) m/z (%) 344 (296.35) C, 48.64; H, 5.44; N, 18.91; found C, 48.76; H, 5.31;
(M+, 40), 312 (9), 270 (15), 230 (11), 189 (100), 135 (25), 115(19); N, 18.78.
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General procedure for the synthesis of thiohydantoin-fused
tetrahydropyrazine derivatives 5aa–ag
1H); 13C NMR (100 MHz, DMSO-d6) δ 11.2, 27.9, 44.3, 55.3,
81.1, 94.5, 106.1, 113.9, 126.4, 129.8, 135.8, 136.0, 154.1, 159.0,
160.6, 169.6; MS (EI) m/z (%) 416 (M+, 2), 316 (3), 219 (12), 165
To a stirred solution of 2-thiohydantoins 4aa–ag (1 mmol) in (23), 149 (29), 125 (63), 111 (100); anal. calcd for C20H24N4O4S
anhydrous EtOH (5 mL), NaH (60% dispersion in mineral oil) (416.49) C, 57.68; H, 5.81; N, 13.45; found C, 57.55; H, 5.93; N,
(1 eq.) was added portionwise at room temperature. The reac- 13.40.
tion mixture was allowed to stand overnight at room tempera-
tert-Butyl
N-(2-benzyl-8-ethyl-6-methylene-1-oxo-3-thioxo-
ture and then the reaction solvent was removed under reduced 1,2,3,5,7-hexahydroimidazo[1,5-a]pyrazin-7-yl)carbamate (5ae).
pressure. The residue was suspended in H2O and acidified at Yield 385.5 mg (93%); light yellow powder 95–97 °C (from
pH 5 with HCl (2 N). The aqueous phase was extracted with EtOH–H2O); IR (Nujol, ν, cm−1) 3244, 1738, 1723, 1711, 1693,
1
EtOAc (3×); the organic phase was dried over Na2SO4 and evap- 1642, 1632; H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J = 7.2 Hz,
orated under reduced pressure. The organic residue was crys- 3H), 1.43 (s, 9H), 2.46–2.50 (m, 1H), 2.95–3.01 (m, 1H),
tallized from the appropriate solvent or solvent mixture to give 4.63–4.75 (m, 4H), 4.94 (s, 2H), 7.25–7.31 (m, 5H), 10.11 (br s,
pure derivatives 5aa–ag.
Ethyl
1H); 13C NMR (100 MHz, DMSO-d6) δ 12.5, 18.4, 27.9, 43.8,
N-(8-methyl-6-methylene-1-oxo-2-phenyl-3-thioxo- 44.3, 80.9, 94.8, 105.3, 127.3, 127.5, 128.3, 136.0, 136.6, 141.7,
1,2,3,5,7-hexahydroimidazo[1,5-a]pyrazin-7-yl)carbamate (5aa). 154.2, 160.2, 169.3; MS (EI) m/z (%) 414 (M+, 26), 358 (80), 314
Yield 240.1 mg (67%); light yellow powder 183–185 °C (char- (5), 298 (40), 208 (19), 149 (47), 121 (100); anal. calcd for
coals) (from hot EtOH–EtOAc); IR (Nujol, ν, cm−1) 3261, 1725, C21H26N4O3S (414.52) C, 60.85; H, 6.32; N, 13.52; found C,
1
1703, 1695, 1659; H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J = 60.76; H, 6.48; N, 13.41.
6.8 Hz, 3H), 2.31 (s, 3H), 4.17 (q, J = 6.8 Hz, 2H), 4.67–4.80 (m,
Benzyl N-[2-(4-chlorophenyl)-8-methyl-6-methylene-1-oxo-3-
4H), 7.33 (d, J = 7.2 Hz, 2H), 7.41–7.51 (m, 3H), 10.29 (br s, thioxo-1,2,3,5,7-hexahydroimidazo[1,5-a]pyrazin-7-yl]carba-
1H); 13C NMR (100 MHz, DMSO-d6) δ 11.2, 14.4, 44.3, 61.7, mate (5af). Yield 426.7 mg (91%); orange powder 178–180 °C
94.8, 106.1, 128.4, 128.7, 133.8, 135.7, 136.0, 155.1, 160.4, (dec.) (from hot EtOH–EtOAc); IR (Nujol, ν, cm−1) 3170, 1754,
1
169.3; MS (EI) m/z (%) 358 (M+, 100), 285 (5), 270 (40), 195 (4), 1745, 1692, 1628; H NMR (400 MHz, DMSO-d6) δ 1.09 (t, J =
135 (78), 107 (99); anal. calcd for C17H18N4O3S (358.41) C, 7.2 Hz, 3H), 2.40–2.50 (m, 1H), 2.97–3.07 (m, 1H), 4.65–4.82
56.97; H, 5.06; N, 15.63; found C, 56.82; H, 5.14; N, 15.56.
Benzyl
(m, 4H), 5.21 (s, 2H), 7.30–7.42 (m, 7H), 7.56 (d, J = 8.4 Hz,
N-(8-methyl-6-methylene-1-oxo-2-phenyl-3-thioxo- 2H), 10.59 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 12.4, 18.3,
1,2,3,5,7-hexahydroimidazo[1,5-a]pyrazin-7-yl)carbamate (5ab). 44.3, 67.0, 95.1, 105.6, 127.9, 128.2, 128.5, 128.7, 130.5, 132.6,
Yield 319.5 mg (76%); yellow powder 165 °C (from EtOAc– 133.0, 135.7, 136.0, 141.2, 155.1, 159.7, 169.2; MS (EI) m/z (%)
Et2O); IR (Nujol, ν, cm−1) 3287, 1721, 1706, 1669, 1640; 1H 470 [M+ + 2 (7)], 468 (M+, 20), 333 (9), 319 (14), 298 (13), 169
NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.67–4.80 (m 4H), (12), 149 (56), 121 (100); anal. calcd for C23H21ClN4O3S
5.20 (s, 2H), 7.32–7.49 (m, 10H), 10.51 (s, 1H); 13C NMR (468.96) C, 58.91; H, 4.51; N, 11.95; found C, 58.78; H, 4.63; N,
(100 MHz, DMSO-d6) δ 11.1, 44.2, 67.0, 94.8, 106.2, 127.9, 11.84.
128.2, 128.4, 128.5, 128.7, 133.8, 135.6, 135.8, 136.0, 155.0,
Methyl
N-(2-ethyl-8-methyl-6-methylene-1-oxo-3-thioxo-
160.4, 169.4; MS (EI) m/z (%) 420 (M+, 75), 285 (37), 271 (15), 1,2,3,5,6,7-hexahydroimidazo[1,5-a]pyrazin-7-yl)carbamate
135 (62), 122 (38), 107 (100); anal. calcd for C22H20N4O3S (5ag). Yield 160.0 mg (54%); light orange needles 152–154 °C
(420.48) C, 62.84; H, 4.79; N, 13.32; found C, 62.71; H, 4.87; N, (from hot EtOH); IR (Nujol, ν, cm−1) 3285, 1712, 1682, 1660,
1
13.43.
Methyl
1643; H NMR (400 MHz, DMSO-d6) δ 1.11 (t, J = 6.8 Hz, 3H),
N-(8-methyl-6-methylene-1-oxo-2-phenyl-3-thioxo- 2.26 (s, 3H), 3.63–3.76 (m, 5H), 4.57–4.80 (m, 4H), 10.34 (s,
1,2,3,5,7-hexahydroimidazo[1,5-a]pyrazin-7-yl)carbamate (5ac). 1H); 13C NMR (100 MHz, DMSO-d6) δ 11.2, 13.1, 35.8, 44.2,
Yield 199.7 mg (58%); light orange powder 168 °C (from hot 53.1, 94.9, 106.3, 135.8, 136.0, 155.7, 160.7, 169.1; MS (EI) m/z
EtOH–EtOAc); IR (Nujol, ν, cm−1) 3269, 1719, 1660, 1646, 1628; (%) 296 (M+, 12), 222 (9), 135 (21), 57 (100); anal. calcd for
1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 3.72 (s, 3H), C12H16N4O3S (296.35) C, 48.64; H, 5.44; N, 18.91; found C,
4.69–4.81 (m, 4H), 7.33 (d, J = 7.2 Hz, 2H), 7.43–7.51 (m, 3H), 48.77; H, 5.36; N, 19.01.
10.39 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 11.1, 44.3, 52.9,
General one-pot three-component procedure for the synthesis
94.9, 106.1, 128.4, 128.7, 133.8, 135.7, 135.9, 155.6, 160.4,
of thiohydantoin-fused tetrahydropyrazine derivatives 5ba–bh
169.4; MS (EI) m/z (%) 344 (M+, 67), 270 (32), 181 (6), 135 (75),
107 (100); anal. calcd for C16H16N4O3S (344.39) C, 55.80; H, To a suspension of glycine ethyl ester hydrochloride 1b
4.68; N, 16.27; found C, 55.66; H, 4.79; N, 16.18.
(1 mmol) in CHCl3 (4 mL), DIPEA (1 eq.) was added and the
tert-Butyl N-[2-(4-methoxyphenyl)-8-methyl-6-methylene-1- suspension was stirred at room temperature for 0.5 h. After
oxo-3-thioxo-1,2,3,5,7-hexahydroimidazo[1,5-a]pyrazin-7-yl]car- this time, DD 2b–e,g,h (1 mmol) was added portionwise as a
bamate (5ad). Yield 324.8 mg (78%); light yellow powder solid or dissolved in CHCl3 (2 mL) and the reaction mixture
180 °C (charcoals) (from hot EtOH); IR (Nujol, ν, cm−1) 3278, was left at room temperature until complete disappearance of
1747, 1717, 1694, 1653, 1647, 1630; 1H NMR (400 MHz, DMSO- 2 (0.5–2 h, TLC check). Then, isothiocyanate derivative 3a,b,d,
d6) δ 1.46 (s, 9H), 2.28 (s, 3H), 3.80 (s, 3H), 4.64–4.77 (m, 4H), f,g (0.95 mmol) was added and the reaction mixture was
7.02 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 10.05 (br s, allowed to stand at room temperature (24–48 h). After this
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time, the reaction mixture was refluxed without (5bb,bd,bf)
Ethyl
[2-(4-methoxyphenyl)-8-methyl-1,6-dioxo-3-thioxo-
(4–8 h) or with the addition of DIPEA (5ba,bc,be,bg,bh) 2,3,5,6-[1,5-a]pyrazin-7(1H)-yl]carbamate (5bc). Yield 238.1 mg
(4–18 h) for the completion. The crude was purified by crystal- (61%); light yellow powder 126–130 °C (from Et2O–n-pentane);
lization obtaining pure 5ba,bb,bd,be,bg or by column chrom- IR (Nujol, ν, cm−1) 3206, 1760, 1720, 1713, 1672, 1667; 1H
atography
subsequent crystallization as in the case of 5bc,bf,bh.
Ethyl
(cyclohexane–ethyl
acetate
mixtures)
and NMR (400 MHz, DMSO-d6) δ 1.24 (t, J = 6.8 Hz, 3H), 2.32 (s,
3H), 3.80 (s, 3H), 4.16 (q, J = 6.8 Hz, 2H), 4.77 (d, J = 18.8 Hz,
{5-[N-(anilinocarbonyl)(ethanehydrazonoyl]-4-oxo-3- 1H), 4.84 (d, J = 18.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.24 (d,
phenyl-2-thioxoimidazolidin-1-yl)}acetate (4ba). Following the J = 8.8 Hz, 2H), 10.24 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
same one-pot procedure described above, the reaction was δ 11.0, 14.3, 47.7, 55.4, 61.8, 109.6, 114.1, 125.7, 129.7, 131.1,
stopped after stirring at room temperature for 24 h once the 155.6, 159.3, 160.7, 160.8, 172.0; MS (EI) m/z (%) 390 (M+, 100),
isothiocyanate 3a (1 mmol) was added. After the removal of 344 (6), 196 (8), 165 (39), 137 (43); anal. calcd for C17H18N4O5S
the solvent under reduced pressure, the crude reaction mixture (390.41) C, 52.30; H, 4.65; N, 14.35; found C, 52.21; H, 4.79; N,
was crystallized from EtOAc–Et2O to yield 4ba.
14.42.
Benzyl [8-methyl-2-(4-nitrophenyl)-1,6-dioxo-3-thioxo-2,3,5,6-
(5bd).
Yield 353.7 mg (78%); beige powder 153–156 °C (from
EtOAc–Et2O); IR (Nujol, ν, cm−1) 3359, 3208, 1756, 1742, 1713, tetrahydroimidazo[1,5-a]pyrazin-7(1H)-yl]carbamate
1595; 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J = 7.2 Hz, 3H), 2.04 Yield 303.8 mg (65%); light orange powder 229–232 °C (from
(s, 3H), 4.14 (d, J = 17.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 5.00 CHCl3–n-pentane); IR (Nujol, ν, cm−1) 3262, 3081, 1772, 1736,
(d, J = 17.2 Hz, 1H), 5.13 (s, 1H), 7.11 (t, J = 7.2 Hz, 1H), 1709, 1688, 1676, 1612, 1595; 1H NMR (400 MHz, DMSO-d6)
7.32–7.36 (m, 4H), 7.47–7.52 (m, 5H), 8.09 (s, 1H), 9.00 (s, 1H); δ 2.34 (s, 3H), 4.82 (d, J = 18.8 Hz, 1H), 4.88 (d, J = 18.8 Hz,
13C NMR (100 MHz, CDCl3) δ 13.1, 14.6, 47.1, 62.6, 69.3, 120.1, 1H), 5.18 (d, J = 12.4 Hz, 1H), 5.23 (d, J = 12.4 Hz, 1H),
124.4, 128.7, 129.6, 129.8, 130.0, 133.5, 137.9, 140.2, 153.3, 7.36–7.42 (m, 5H), 7.72 (d, J = 8.8 Hz, 2H), 8.38 (d, J = 8.8 Hz,
167.9, 169.6, 184.4; MS (EI) m/z (%) 453 (M+, 2), 407 (3), 360 2H), 10.47 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 11.0, 47.7,
(6), 176 (100), 135 (20); anal. calcd for C22H23N5O4S (453.51) C, 67.1, 109.6, 124.1, 127.9, 128.2, 128.5, 129.9, 131.9, 135.9,
58.26; H, 5.11; N, 15.44; found C, 58.39; H, 4.99; N, 15.33.
138.7, 147.1, 155.6, 160.0, 160.7, 170.5; MS (EI) m/z (%) 467
N-(8-Methyl-1,6-dioxo-2-phenyl-3-thioxo-2,3,5,6-tetrahydroimi- (M+, 13), 333 (4), 180 (4), 149 (13), 108 (100); anal. calcd for
dazo[1,5-a]pyrazin-7(1H)-yl)-N′-phenylurea (5ba). To a stirred C21H17N5O6S (467.45) C, 53.96; H, 3.65; N, 14.98; found
solution of 4ba (0.5 mmol) dissolved in CHCl3 (4 mL), a cata- C, 54.10; H, 3.77; N, 14.89.
lytic amount of DIPEA (0.05 mmol) was added and the reaction
mixture was refluxed for 4 h. Then, the solvent was removed hydroimidazo[1,5-a]pyrazin-7(1H)-yl)carbamate
Methyl
(8-methyl-1,6-dioxo-2-phenyl-3-thioxo-2,3,5,6-tetra-
(5be). Yield
in vacuo and the crude reaction mixture was crystallized to 270.1 mg (78%); light yellow powder 108–110 °C (from Et2O–
afford the desired compound 5ba.
light petroleum ether); IR (Nujol, ν, cm−1) 3282, 1754, 1727,
1
Yield 177.3 mg (87% from 4ba); 156.8 mg (77% from 1a); 1685, 1601; H NMR (400 MHz, DMSO-d6) δ 2.33 (s, 3H), 3.72
beige powder 238–239 °C (from Et2O–MeOH–light petroleum (s, 3H), 4.79 (d, J = 18.8 Hz, 1H), 4.85 (d, J = 18.8 Hz, 1H), 7.34
ether); IR (Nujol, ν, cm−1) 3267, 3138, 3077, 1745, 1713, 1687, (d, J = 7.6 Hz, 2H), 7.48–7.54 (m, 3H), 10.29 (s, 1H); 13C NMR
1
1664, 1599; H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 4.82 (100 MHz, DMSO-d6) δ 10.9, 47.7, 52.9, 109.6, 128.5, 128.8,
(s, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.36 (d, 128.9, 131.3, 133.2, 156.1, 160.5, 160.8, 171.5; MS (EI) m/z (%)
J = 7.6 Hz, 2H), 7.46–7.55 (m, 5H), 8.94 (br s, 1H), 9.38 (br s, 346 (M+, 100), 273 (5), 244 (13), 183 (19), 155 (46), 137 (29);
1H); 13C NMR (100 MHz, DMSO-d6) δ 11.3, 47.8, 109.3, 118.7, anal. calcd for C15H14N4O4S (346.36) C, 52.02; H, 4.07; N,
122.7, 128.6, 128.7, 128.8, 128.9, 132.8, 133.2, 138.8, 154.3, 16.18; found C, 52.19; H, 4.15; N, 16.10.
160.5, 161.4, 171.1; MS (EI) m/z (%) 407 (M+, 59), 314 (12), 288
(70), 273 (52), 137 (43), 119 (100); anal. calcd for C20H17N5O3S hydroimidazo[1,5-a]pyrazin-7(1H)-yl)carbamate
tert-Butyl (8-ethyl-1,6-dioxo-2-phenyl-3-thioxo-2,3,5,6-tetra-
(5bf). Yield
(407.45) C, 58.96; H, 4.21; N, 17.19; found C, 59.09; H, 4.29; N, 245.5 mg (61%); light yellow powder 150–155 °C (from EtOAc–
17.02.
Methyl
light petroleum ether); IR (Nujol, ν, cm−1) 3252, 3052, 1725,
[8-methyl-2-(4-nitrophenyl)-1,6-dioxo-3-thioxo- 1709, 1672, 1601; H NMR (400 MHz, DMSO-d6) δ 1.12 (t, J =
1
2,3,5,6-tetrahydroimidazo[1,5-a]pyrazin-7(1H)-yl]carbamate 7.6 Hz, 3H), 1.46 (s, 9H), 2.56–2.67 (m, 1H), 2.92–3.00 (m, 1H),
(5bb). Yield 231.0 mg (59%); light pink powder 214–218 °C 4.81 (s, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.48–7.54 (m, 3H), 10.02
(from hot EtOAc); IR (Nujol, ν, cm−1) 3186, 1765, 1736, 1717, (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 12.2, 18.1, 27.8, 47.6,
1
1678, 1599; H NMR (400 MHz, DMSO-d6) δ 2.34 (s, 3H), 3.72 81.2, 109.1, 128.6, 128.7, 128.8, 133.2, 136.5, 154.7, 160.1,
(s, 3H), 4.81 (d, J = 18.8 Hz, 1H), 4.87 (d, J = 18.8 Hz, 1H), 7.71 161.0, 171.7; MS (EI) m/z (%) 402 (M+, 36), 346 (66), 302 (100),
(d, J = 7.2 Hz, 2H), 8.38 (d, J = 7.2 Hz, 2H), 10.31 (br s, 1H); 13
C
287 (29), 258 (21), 139 (38), 135 (26), 123 (38); anal. calcd for
NMR (100 MHz, DMSO-d6) δ 11.1, 47.7, 53.0, 109.5, 124.1, C19H22N4O4S (402.47) C, 56.70; H, 5.51; N, 13.92; Found C,
129.9, 132.0, 138.7, 147.2, 156.1, 160.0, 160.7, 170.5; MS (EI) 56.58; H, 5.65; N, 14.01.
m/z (%) 391 (M+, 100), 363 (11), 317 (2), 289 (7), 183 (47), 155
tert-Butyl
[2-(4-chlorophenyl)-8-methyl-1,6-dioxo-3-thioxo-
(75), 137 (59), 115 (46), 109 (62); anal. calcd for C15H13N5O6S 2,3,5,6-tetrahydroimidazo[1,5-a]pyrazin-7(1H)-yl]carbamate
(391.36) C, 46.03; H, 3.35; N, 17.89; found C, 47.15; H, 3.48; N, (5bg). Yield 232.6 mg (55%); light yellow powder 179–181 °C
17.76.
(from EtOAc); IR (Nujol, ν, cm−1) 3272, 1735, 1725, 1708, 1668;
4616 | Org. Biomol. Chem., 2014, 12, 4610–4619
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1H NMR (400 MHz, DMSO-d6) δ 1.46 (s, 9H), 2.31 (s, 3H), 4.78 amines. This transformation involves a two-step reaction in
(d, J = 18.8 Hz, 1H), 4.84 (d, J = 18.8 Hz, 1H), 7.40 (d, J = 8.8 which the first step is intermolecular and the second is intra-
Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 9.98 (s, 1H); 13C NMR molecular and overall creates four C–N bonds and two new
(100 MHz, DMSO-d6) δ 11.0, 27.8, 47.7, 81.2, 109.5, 129.0, fused heterocyclic rings. In addition, the method benefits
130.5, 131.8, 132.0, 133.4, 154.5, 160.3, 160.8, 171.2; MS (EI) from operational simplicity, chemical efficiency, high selecti-
m/z (%) 424 [M+ + 2 (3)], 422 (M+, 6), 366 (11), 322 (15), 307 vity, and high molecular complexity and diversity. At present,
(13), 169 (16), 137 (39), 125 (65), 111 (100); anal. calcd for further exploration is currently underway.
C18H19ClN4O4S (422.89) C, 51.12; H, 4.53; N, 13.25; found C,
51.23; H, 4.41; N, 13.31.
Ethyl 2-(8-methyl-1,6-dioxo-7-(3-phenylureido)-3-thioxo-6,7-
Acknowledgements
dihydroimidazo[1,5-a]pyrazin-2(1H,3H,5H)-yl)acetate
(5bh).
Yield 125.2 mg (30%); light yellow solid 208–215 °C (from Financial support from the Ministero dell’Istruzione, dell’Uni-
EtOAc–Et2O); IR (Nujol, ν, cm−1) 3289, 3196, 1746, 1731, 1717, versità e della Ricerca (MIUR)-Roma and from the University of
1
1671, 1600; H NMR (400 MHz, DMSO-d6) δ 1.21 (t, J = 6.8 Hz, Urbino “Carlo Bo” is gratefully acknowledged.
3H), 2.37 (s, 3H), 4.16 (q, J = 6.8 Hz, 2H), 4.59 (s, 2H), 4.79 (s,
2H), 7.01 (t, J = 6.8 Hz, 1H), 7.28 (t, J = 6.8 Hz, 2H), 7.43 (d, J =
6.8 Hz, 2H), 8.86 (br s, 1H), 9.37 (br s, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 11.3, 14.0, 41.9, 47.7, 61.3, 109.2, 118.8,
Notes and references
122.7, 128.7, 133.6, 138.7, 154.3, 160.2, 161.4, 166.8, 172.0; MS
(EI) m/z (%) 417 (M+, 62), 298 (62), 283 (26), 152 (37), 137 (100),
119 (94); anal. calcd for C18H19N5O5S (417.44) C, 51.79; H,
4.59; N, 16.78; found C, 51.64; H, 4.67; N, 16.69.
1 For the synthesis of imidazo[1,5-a]pyrazines, see:
(a) D. D. Vachhani, S. G. Modha, A. Sharma and E. V. Van
der Eycken, Tetrahedron, 2013, 69, 358; (b) A. Shaabani,
A. Maleki and H. Mofakham, Mol. Divers., 2009, 13, 65;
(c) T. Trček and B. Verček, Synthesis, 2006, 3437;
(d) A. Gopalsamy and M. Shi, Org. Lett., 2003, 21, 3907;
(e) A. Gopalsamy and M. Shi, Org. Lett., 2003, 21, 3907;
(f) T. Trček, A. Meden and B. Verček, Synlett, 2000, 1458;
(g) M. T. Migawa and E. E. Swayze, Org. Lett., 2000, 21,
3309.
2 D. J. P. Pinto and R. Li, US 20030118023, 2003.
3 M. J. Mulvihill, Q.-S. Ji, H. R. Coate, A. Cooke, H. Dong,
L. Feng, K. Foreman, M. Rosenfeld-Franklin, A. Honda,
G. Mak, K. M. Mulvihill, A. I. Nigro, M. O’Connor, C. Pirrit,
A. G. Steinig, K. Siu, K. M. Stolz, Y. Sun, P. A. R. Tavares,
Y. Yao and N. W. Gibson, Bioorg. Med. Chem., 2008, 16,
1359.
Procedure for the conversion of 5aa to 6aa
To a stirred solution of bicyclic compound 5aa (0.5 mmol) in
anhydrous EtOH (5 mL), NaH (60% dispersion in mineral oil)
(1 eq.) was added portionwise. The reaction mixture was
refluxed for 9 h, and then the reaction solvent was removed
under reduced pressure. The residue was suspended in H2O
and acidified at pH 5 with HCl (2 N). The aqueous phase was
extracted with CH2Cl2 (3×); the organic phase was dried over
Na2SO4 and evaporated under reduced pressure. The organic
residue was purified after flash chromatography (cyclohexane–
ethyl acetate mixtures) to give pure 6aa.
Methyl
(6,8-dimethyl-1-oxo-2-phenyl-3-thioxo-2,3-dihydro-
4 M. S. Malamas, Y. Ni, J. J. Erdei, H. Stange, R. Schindler,
N. Hoefgen, U. Egerland and B. Langen, WO 2009070584
A1 20090604, 2009.
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X. Chen, H. Coate, A. Cooke, P. C. Gokhale, A. Honda,
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A. Cooke, M. A. Bittner, Y. Yao, A. Thelemann, Q. Ji,
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Chem. Lett., 2013, 23, 979.
imidazo[1,5-a]pyrazin-7(1H)-yl)carbamate (6aa). Yield 117.7 mg
(68%); red orange powder 155–156 °C (from hot-ethyl acetate);
IR (Nujol, ν, cm−1) 3267, 1697, 1643; 1H NMR (400 MHz,
DMSO-d6) δ 1.24 (t, J = 7.2 Hz, 3H), 1.85 (s, 3H), 2.26 (s, 3H),
4.18 (q, J = 7.2 Hz, 2H), 6.92 (s, 1H), 7.31–7.53 (m, 5H), 10.34
(s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 11.0, 14.3, 62.1, 107.1,
108.6, 128.4, 128.6, 129.7, 134.0, 144.3, 155.2, 155.8, 158.0; MS
(EI) m/z (%) 358 (M+, 36), 285 (8), 270 (18), 150 (30), 135 (100),
123 (24), 107 (88); anal. calcd for C16H16N4O3S (344.39) C,
55.80; H, 4.68; N, 16.27; found C, 55.66; H, 4.77; N, 16.34.
Conclusions
In summary, we have developed a novel and practical approach
for the construction of lead-like imidazo[1,5-a]pyrazine
scaffolds. Thus, 2-thiohydantoin derivatives 4 prepared in one-
pot sequential three-component reaction of primary amines 1,
1,2-diaza-1,3-dienes 2, and isothiocyanates 3, were converted
to thiohydantoin-fused tetrahydropyrazines with an exocyclic
CvCH2 or CvO bond depending on the specific primary
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Organic & Biomolecular Chemistry
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2
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2
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