Divergent Access to Imidazopyrazinones and Imidazodiazepinones by Regioswitchable Post-Ugi Heteroannulation

Article abstract of DOI:10.1002/ejoc.201901511

A metal-free expeditious strategy for the divergent synthesis of structurally diverse bicyclic imidazo[1,5-a]pyrazine and imidazo[1,5-a][1,4]diazepine scaffolds is disclosed by combining an Ugi four-component reaction of easily available building blocks a

Full text of DOI:10.1002/ejoc.201901511

A Journal of
Accepted Article
Title: Divergent Access to Imidazopyrazinones and
Imidazodiazepinones by Regioswitchable Post-Ugi
Heteroannulation
Authors: Danjun Wu, Xueling Zhang, Yi Li, Sanjun Ying, Lixi Zhu,
Zhenghua Li, Gensheng Yang, and Erik Van der Eycken
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901511
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901511
Supported by

10.1002/ejoc.201901511
European Journal of Organic Chemistry
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Divergent Access to Imidazopyrazinones and Imidazodiazepinones
by Regioswitchable Post-Ugi Heteroannulation
Danjun Wu,[a] Xueling Zhang,[a] Yi Li,[a] Sanjun Ying, [a] Lixi Zhu,[a] Zhenghua Li*[b] Gensheng Yang*[a]
and Erik V. Van der Eycken*[b,c]
Abstract:
A
metal-free expeditious strategy for the divergent
post-Ugi heteroannulation or hydroarylation with various
nucleophiles of π-systems activated by metal catalysts such as
gold,[7] silver[8] and indium.[9] On the other hand,
organophosphine-mediated organic reactions have also
emerged as a versatile method for the preparation of cyclic and
heterocyclic compounds in recent decades.[10] In general, tertiary
phosphine-triggered cyclizations begin via nucleophilic addition
of phosphines to activated olefins, allenes and alkynes. The
resultant zwitterionic intermediates may react with various
electrophiles or nucleophiles for C−C and C-hetero bond
formation (Scheme 1).[11] It will be quite promising to develop a
cost-effective and sustainable process for the diverse
compounds through the collaboration of MCR and phosphine
reagents.
synthesis of structurally diverse bicyclic imidazo[1,5-a]pyrazine and
imidazo[1,5-a][1,4]diazepine scaffolds is disclosed by combining an
Ugi four-component reaction of easily available building blocks and
an exo/endo selectivity-switchable post-Ugi intramolecular
heterocyclization. Using PPh3, the intramolecular umpolung aza-
Michael
addition
is
mediated
to
selectively
generate
imidazopyrazinones through a 6-exo-dig cyclization, while without
PPh3 fused imidazodiazepinones are obtained through a thermal 7-
endo-dig cyclization in moderate yields.
Introduction
The synthesis of diverse heterocyclic scaffolds resembling
biologically active pharmaceuticals and natural products has
attracted continuous attention from the synthetic chemists.[1]
Imidazole-based heterocycles[2] possessing the bicyclic
imidazo[1,5-a]pyrazine or imidazo[1,5-a][1,4]diazepine core
have emerged as a class of interesting target chemical entities.
They
appear
in
commercially
available
synthetic
pharmaceuticals such as furimazine, bretazenil and flumazenil
(Figure 1).[3] Though lots of achievements have been obtained,
most synthetic accesses to the imidazo[1,5-a]pyrazine and
imidazo[1,5-a][1,4]diazepine scaffold rarely escape multiple-step
sequences and harsh conditions and are lacking the substituent
diversity.[4] Consequently, the development of new efficient and
diversity-oriented routes for these imidazole-based heterocycles
is still highly desirable, especially considering their potential as
drug candidates for high-throughput screening in drug discovery.
Over recent decades, the combination of multicomponent
reactions (MCR)[5] and transition metal-catalysis has emerged as
Figure 1. Representative imidazole-based bioactive heterocycles
a
powerful access toward complex heterocycles in two
operational steps as compared to traditional multistep
processes.[6] In this context, Van der Eycken’s group has
developed several diversity-oriented approaches for the
construction of carbo- and heterocyclic frameworks through
[a]
Dr. D. Wu, X. Zhang, Y. Li, L. Zhu, Prof. Dr. G. Yang
College of Pharmaceutical Science, Zhejiang University of
Technology
Scheme 1. Phosphine-mediated umpolung Michael reaction of α,β-
unsaturated esters through zwitterionic intermediates
18 Chaowang Road, 310014 Hangzhou, China
E-mail: yanggs@zjut.edu.cn
[b]
Dr. Z. Li, Prof. Dr. E. V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC)
Department of Chemistry, KU Leuven
Celestijnenlaan 200F, Heverlee 3001, Leuven, Belgium.
E-mail: ahlzhchem@gmail.com; erik.vandereycken@kuleuven.be
https://chem.kuleuven.be/en/research/mds/lomac
Prof. Dr. E. V. Van der Eycken
Peoples Friendship University of Russia (RUDN University)
6 Miklukho-Maklaya street, Moscow, 117198, Russia
In 2013, we described an intramolecular cationic gold
catalyzed post-Ugi heteroannulation of imidazoles with the
activated alkynes for the diversity-oriented synthesis of
imidazo[1,4]diazepin-7-ones had been elaborated.[12] Inspired by
the interesting bioactivity of imidazole-based heterocycles and
as a result of our interest in the development of more efficient
strategies for these heterocycles, we herein report a metal-free
expeditious strategy for the divergent synthesis of structurally
diverse bicyclic imidazo[1,5-a]pyrazine and imidazo[1,5-
[c]
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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a][1,4]diazepine scaffolds through the combination of an Ugi
four-component reaction of easily available building blocks and
an exo/endo selectivity-switchable post-Ugi heteroannulation
(Scheme 2).
cyclization performed smoothly generating the imidazo[1,5-
a]pyrazine 6f and 6g in 82% and 63% yield, respectively.
Different R3- and R4-substituents on the imidazole ring give the
desired products 6h and 6i in good yields. The effect of the R5-
substituent of the tertiary propiolamide was investigated. With a
methyl group, the exo product 6j was obtained as an
unseparated mixture of Z/E isomers with a ratio of 2:3 in a
moderate yield of 59%. Using a phenyl group, this 6-exo-dig
cyclization performed well affording the imidazo[1,5-a]pyrazine
6k in a yield of 68%.
Table 1. Optimization of the intramolecular post-Ugi heteroannulation[a]
Scheme 2. Divergent synthesis of diverse imidazopyrazinone and
imidazodiazepinone scaffolds
Results and Discussion
The acyclic precursor 5a was easily synthesized via the Ugi
four
component
reaction
(Ugi-4CR)[13]
of
4-
imidazolecarboxaldehyde (1a), p-methoxybenzylamine (2a),
propiolic acid (3a), and tert-butyl isocyanide (4a) in methanol at
r.t., and chosen as a model substrate to optimize the reaction
conditions of the intramolecular heteroannulation. Initially, while
employing 20 mol% of PPh3 in ethanol at 80 oC for 6 h, this
cyclization proceeds via a 6-exo-dig or a 7-endo-dig fashion
delivering the imidazo[1,5-a]pyrazine 6a and imidazo[1,5-
a][1,4]diazepine 7a in yields of 53% and 29%, respectively
(Table 1, entry 1). Further screening of different solvents such
as ethyl acetate, toluene and chloroform indicated that the
selectivity of exo product 6a versus endo product 7a is
enhanced to 79%:21% (Table 1, entries 2-4). Increasing the
loading amount of PPh3 to 1.0 equiv. led to the almost selective
formation of 6a in an 88% isolated yield (Table 1, entries 5 and
6). The application of electron-rich PBu3 and PMe2Ph led to
lower yields (Table 1, entries 7 and 8). Delightfully, performing
this cyclization at room temperature for a long time (14 h) also
selectively gave the desired exo product 6a in yield of 87%
(Table 1, entry 9). Interesting, the selective formation of endo
product 7a in a yield of 63% was observed without phosphine
Phosphine
(equiv)
time
[h]
Temp.
[oC]
Yield of
6a [%][b]
Yield of
7a [%][b]
Entry
Solvent
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.4)
EtOH
EtOAc
Toluene
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
THF-D8
C2D2Cl4
6
6
80
80
80
80
80
80
80
80
rt
53
30
11
79
88
29
70
23
21
12
4
1
2
6
3
1
4
1
5
PPh3 (1.0)
PBu3 (1.0)
1
96(88[c]
)
6
1
17
61
87[c]
0
5
7
PMe2Ph (1.0)
1
4
8
PPh3 (1.0)
14
22
16
2
4
9
—
—
—
80
80
110
63[c]
41
50[c]
10
11
12
0
0
[a] All the reactions were run with 5a (0.05 mmol), phosphines and 1.0 mL of
solvent in a sealed vial. [b] Yields are determined by 1H NMR spectroscopy
using 2,4,6-trimethoxybenzaldehyde as internal standard. [c] Isolated yields.
o
reagents in chloroform at 80 C for 22 h (Table 1, entry 10). No
amelioration was obtained when using tetrahydrofuran or
1,1,2,2-tetrachloroethane as solvent (Table 1, entries 11 and 12).
With the optimized conditions in hand, various substituted Ugi
adducts 5b–k were subjected to this exo/endo selectivity-
switchable post-Ugi intramolecular heterocyclization. Mostly the
6-exo-dig cyclization proceeds smoothly generating imidazo[1,5-
a]pyrazines 6b–k in good yields (Table 2). R1-substituents like the
benzyl fragment bearing an electron-donating (tBu, 6b) or
electron-withdrawing groups (F, Cl, 6c-d), as well as an aliphatic
butyl fragment (6e) are well tolerated. The variation of the R2-
substituent of the secondary amide was then explored. With an
benzyl or para-methoxyphenyl group, this umpolung aza-Michael
The same Ugi-products 5b–k were subjected to 7-endo-dig
cyclization by reactions heating at 80 oC. Pleasingly, various
substituents on the amine, the secondary amide, the imidazole
ring and the tertiary propiolamide are also well tolerated
smoothly
producing
the
corresponding
imidazo[1,5-
a][1,4]diazepine scaffolds 7 in moderate to good isolated yields
(Table 2). Fortunately, performing the reaction at a higher
temperature of 110 oC for 24 h in case of the methyl- and pheny-
substituted
propiolamide,
delivered
the
imidazo[1,5-
a][1,4]diazepine 7j and 7k in yields of 58% and 60%,
respectively.
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Table 2. Scope of the divergent synthesis of the imidazo[1,5-a]pyrazine and imidazo[1,5-a][1,4]diazepine scaffolds[a,b]
[a] Conditions A: Unless otherwise stated, all reactions were run with 5b-k (0.25 mmol), PPh3 (1.0 equiv) and CHCl3 (2.0 mL) in a sealed vial at rt for 14-24 h;
Conditions B: Unless otherwise stated, all reactions were run with 5b-k (0.25 mmol) and CHCl3 (2.0 mL) in a sealed vial at 80 oC for 22-30 h. [b] All yields are
isolated yields. [c] 80 oC for 24 h in CHCl3. [d] The product 6j appears as an unseparated mixture of Z/E isomers with a ratio of 2:3. [e] 110 oC for 24 h in 1,1,2,2-
tetrachloroethane. PMP = para-methoxyphenyl.
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To get insight into the reaction mechanism, we conducted
deuterium-labeling experiments on 6-exo-dig and 7-endo-dig
cyclizations of Ugi adduct 5a under the optimization conditions
with 10 equiv of deuterated methanol in deuterochloroform
(Scheme 3). According to the NMR spectra, the incorporation of
2 deuterium atoms occurred on the methylene group in product
6a-D, while the deuterium was located on the endocyclic double
bond of the 1,4-diazepine ring in product 7a-D (For more details,
please see supporting information). This result indicates that
anionic species were formed at the β-position of 6a-D and α-
position of 7a-D during the reaction sequences, and the
incorporation of another deuterium atom at the β-position of 6a-
D or 7a-D is ascribed to the H/D exchange of terminal
propiolamide moiety in 5a with the deuterated solvent.[14]
Scheme 4. Proposed mechanism
Scheme 3. Deuterium labelling experiments
Conclusions
Based on these experimental results and previous
In summary, we have elaborated an exo/endo selectivity-
switchable post-Ugi intramolecular heterocyclization for the
divergent synthesis of structurally diverse bicyclic imidazo[1,5-
a]pyrazine and imidazo[1,5-a][1,4]diazepine scaffolds from
easily available starting materials. The scaffold diversity of the
desired compounds is guaranteed by the Ugi-4CR.
Triphenylphosphine plays a crucial role in the regioselectivity
switch of this umpolung aza-Michael addition. Employing PPh3
or only heating, the ring closure can be directed towards a 6-
exo-dig fashion or a 7-endo-dig fashion, respectively, leading to
the selective formation of 6-membered pyrazines 6 and 7-
membered 1,4-diazepines 7.
investigations,
a plausible mechanism for this phosphine-
tiggered exo/endo selectivity-switchable post-Ugi intramolecular
cyclization is depicted in Scheme 4.[10,11] In case of using PPh3,
the nucleophilic addition of PPh3 to the propargylamide moiety of
Ugi adduct 5a generates a phosphonium intermediate A, which
acts as a as a Brønsted base to abstract an acidic proton from
imidazole moiety. Thereafter, the resultant intermediate B
undergoes umpolung aza-Michael addition at the α‐position
facilitated by the electron-withdrawing power of the
phosphonium cation delivering the zwitterionic intermediate C.
The intermediate C finally transfers to the exo product 6a
through proton transfer and elimination of phosphine from the
intermediate D which is supported by the result of the H/D
exchange experiment.[15] In details, the incorporation of
deuterium atom in the exo product 6a indicates that the
intermediate C has relatively long lifetime to allow the H/D
exchange with the deuterated solvent. Moreover, the sequential
monitoring of the reaction mixture by 31P NMR revealed the
Experimental Section
General Methods: Commercially available reagents were used without
additional purification, unless otherwise stated. Flash column
chromatography was performed using 70-230 mesh silica gels. Melting
points were determined with a Yanaco micro melting point apparatus
without correction. NMR spectra spectroscopic data were recorded with a
Bruker AV-500 spectrometers or JEOL ECS-400 instrument using CDCl3
as solvent and tetramethylsilane (TMS) as the internal standard.
Resonance patterns are reported in ppm relative to TMS at δ = 0 ppm for
1H NMR and relative to CDCl3 at δ = 77.16 ppm for 13C NMR, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad
formation of the phosphine intermediate with
a closely
associated downfield peak compared to triphenylphosphine (For
more details, please see supporting information). On the
contrary only heating resulted in the nucleophilic attack of the
imidazole on the propargylamide moiety in a 7-endo-dig fashion,
delivering the imidazo[1,5-a][1,4]diazepine 7a. The imidazole
moiety may act as a base catalyst for this Michael addition.[16]
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10.1002/ejoc.201901511
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signal), coupling constant (Hz), and integration. For high resolution EI
mass spectrometry, spectra were acquired on a Bruker micrOTOF-Q III
(ESI-) instrument with a resolution of 10,000.
5.76 (d, J = 1.5 Hz, 1H), 5.20 (d, J = 15.2 Hz, 1H), 5.01 (s,1), 4.14 (d, J =
15.2 Hz, 1H), 1.24 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 165.9, 160.0,
135.7, 132.8, 132.6, 132.4, 131.4, 131.0, 130.6, 128.2, 124.4, 121.5,
107.0, 57.1, 52.3, 48.9, 28.5. HRMS (ESI) calculated for
C19H20Cl2N4NaO2 [M+Na]+: 429.0856; found: 429.0849.
General Procedure for the Synthesis of Ugi Adducts 5: To a solution
of 4-imidazolecarboxaldehydes 1 (1.0 mmol) in methanol (4 mL) were
added successively Na2SO4 (1.0 g), amines 2 (1.2 equiv), propiolic acids
3 (1.2 equiv) and isonitriles 4 (1.2 equiv) in a round-bottom flask
equipped with a magnetic stir bar. The reaction mixture was stirred at r.t.
for 12-24 h in a closed vial. After completion of the reaction, the mixture
was diluted with water (15 mL) and extracted with dichloromethane (3 ×
15 mL). Organic layer was then dried over magnesium sulfate and
evaporated under reduced pressure to obtain residue which was
subjected to silica gel column chromatography (2–4ꢀ% MeOH in CH2Cl2)
affording the desired Ugi adducts 5a–k. Ugi products appear as a mixture
of two rotamers, so the 1H NMR and 13C NMR spectra are not very
characteristic.
N-(tert-butyl)-7-butyl-5-methylene-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6e): White solid,
o
1
79% yield, melting point: 193–195 C. H NMR (500 MHz, CDCl3) δ 7.91
(s, 1H), 7.08 (s, 1H), 6.99 (s, 1H), 6.17 (s, 1H), 5.71 (s, 1H), 5.26 (s, 1H),
3.94 – 3.83 (m, 1H), 3.12 – 3.07 (m, 1H), 1.68 – 1.51 (m, 2H), 1.41 –
1.31 (m, 2H), 1.30 (s, 9H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 166.9, 159.6, 132.5, 131.9, 124.5, 121.9, 105.9, 58.2, 52.2,
47.3, 29.7, 29.4, 28.5, 20.2, 13.8. HRMS (ESI) calculated for C16H24N4
NaO2 [M+H]+: 327.1791; found: 327.1796.
N-benzyl-7-(4-methoxybenzyl)-5-methylene-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6f): White solid,
o
General Procedure for the Synthesis of Imidazopyrazinone Scaffold
6: In an oven-dried 10 mL screw-cap vial were charged with
triphenylphosphine (65.5 mg, 0.25 mmol, 1.0 equiv.) and Ugi adduct 5
(0.25 mmol) along with dry chloroform (2 mL). The reaction mixture was
stirred at r.t. until it is complete. The reaction mixture was then purified by
column chromatography (2–4% MeOH in DCM) to afford
imidazopyrazinone scaffold 6.
82% yield, melting point: 84–85 C. 1H NMR (500 MHz, CDCl3) δ 7.60 (t,
J = 5.5 Hz, 1H), 7.46 (s, 1H), 7.30 – 7.21 (m, 2H), 7.20 – 7.13 (m, 1H),
7.13 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H),
6.66 (s, 1H), 6.19 (d, J = 1.8 Hz, 1H), 5.62 (d, J = 1.8 Hz, 1H), 5.35 (d, J
= 14.8 Hz, 1H), 5.05 (s, 1H), 4.36 (dd, J = 14.6, 5.7 Hz, 1H), 4.25 (dd, J =
14.6, 5.5 Hz, 1H), 3.91 (d, J = 14.9 Hz, 1H), 3.72 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 167.1, 159.8, 159.5, 137.9, 137.4, 132.3, 131.5, 130.3,
129.0, 128.8, 128.2, 127.9, 127.8, 126.8, 125.3, 124.6, 121.3, 114.3,
106.7, 55.5, 55.3, 48.96, 44.1. HRMS (ESI) calculated for C23H22N4NaO3
[M+Na]+: 425.1584; found: 425.1580.
N-(tert-butyl)-7-(4-methoxybenzyl)-5-methylene-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6a): White solid,
88% yield, melting point: 98–100 oC. 1H NMR (500 MHz, CDCl3) δ 7.81 (s,
1H), 7.19 (d, J = 8.4 Hz, 2H), 6.90 (s, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.26
(d, J = 1.7 Hz, 1H), 5.76 (s, 1H), 5.72 (d, J = 1.8 Hz, 1H), 5.37 (d, J =
14.9 Hz, 1H), 4.84 (s, 1H), 4.00 (d, J = 14.9 Hz, 1H), 3.79 (s, 3H), 1.26 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 166.3, 159.9, 159.5, 132.3, 131.6,
130.2, 127.1, 124.3, 121.8, 114.3, 106.4, 56.3, 55.4, 52.1, 48.9, 28.5.
HRMS (ESI) calculated for C20H24N4NaO3 [M+Na]+: 391.1741; found:
391.1737.
7-(4-methoxybenzyl)-N-(4-methoxyphenyl)-5-methylene-6-oxo-
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6g): White
solid, 63% yield, melting point: 101–102 oC. 1H NMR (500 MHz, CDCl3) δ
9.33 (s, 1H), 7.68 (s, 1H), 7.31 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.4 Hz,
2H), 6.90 (s, 1H), 6.81 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 6.30
(d, J = 1.8 Hz, 1H), 5.73 (d, J = 1.8 Hz, 1H), 5.38 (d, J = 14.9 Hz, 1H),
5.23 (s, 1H), 4.09 (d, J = 14.9 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 165.0, 159.9, 159.6, 156.8, 132.4, 131.5,
130.4, 126.9, 124.5, 121.6, 121.5, 114.4, 114.2, 107.0, 56.0, 55.5, 55.4,
49.1. HRMS (ESI) calculated for C23H22N4NaO4 [M+Na]+: 441.1533;
found: 441.1532.
N-(tert-butyl)-7-(4-(tert-butyl)benzyl)-5-methylene-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6b): White solid,
1
90% yield, melting point: 120–122 oC. H NMR (500 MHz, CDCl3) δ 7.82
(s, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H),
6.23 (d, J = 1.8 Hz, 1H), 6.15 (s, 1H), 5.71 (d, J = 1.8 Hz, 1H), 5.30 (d, J
= 14.8 Hz, 1H), 4.99 (s, 1H), 4.08 (d, J = 14.9 Hz, 1H), 1.29 (s, 9H), 1.23
(s, 9H). 13C NMR (126 MHz, CDCl3) δ 166.2, 159.9, 151.3, 132.5, 132.1,
131.6, 128.4, 125.9, 124.7, 121.5, 106.4, 57.0, 52.2, 49.5, 34.6, 31.3,
28.5. HRMS (ESI) calculated for C23H30N4NaO2 [M+Na]+: 417.2261;
found: 417.2262.
N-(tert-butyl)-7-(4-methoxybenzyl)-1-methyl-5-methylene-6-oxo-
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6h): White
solid, 80% yield, melting point: 201–203 oC. 1H NMR (500 MHz, CDCl3) δ
7.78 (s, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.18 (d, J
= 1.7 Hz, 1H), 5.67 (d, J = 1.7 Hz, 1H), 5.42 (s, 1H), 5.26 (d, J = 14.9 Hz,
1H), 4.76 (s, 1H), 4.13 (d, J = 14.9 Hz, 1H), 3.79 (s, 3H), 2.18 (s, 3H),
1.24 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 165.9, 159.8, 159.6, 133.5,
131.6, 131.2, 130.0, 127.1, 116.2, 114.4, 105.7, 57.3, 55.3, 52.3, 49.3,
28.6, 12.8. HRMS (ESI) calculated for C21H26N4NaO3 [M+Na]+: 405.1897;
found: 405.1905.
N-(tert-butyl)-7-(4-fluorobenzyl)-5-methylene-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6c): White solid,
o
1
73% yield, melting point: 102–103 C. H NMR (500 MHz, CDCl3) δ 7.79
(s, 1H), 7.25 (dd, J = 8.2, 5.5 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 6.90 (s,
1H), 6.43 (s, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.73 (d, J = 1.9 Hz, 1H), 5.30
(d, J = 15.0 Hz, 1H), 4.97 (s, 1H), 4.07 (d, J = 15.0 Hz, 1H), 1.24 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 166.1, 162.6 (d, J = 247.1 Hz), 160.0,
132.6, 131.5, 131.1 (d, J = 3.2 Hz), 130.5 (d, J = 8.2 Hz), 124.5, 121.4,
115.8 (d, J = 21.4 Hz), 106.7, 52.3, 49.1, 28.5. 19F NMR (376MHz,
CDCl3) δ -113.4. HRMS (ESI) calculated for C19H22FN4O2 [M+H]+:
357.1721; found: 357.1733.
N-(tert-butyl)-3-butyl-7-(4-methoxybenzyl)-5-methylene-6-oxo-
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6i): White
solid, 69% yield, melting point: 180–181 oC. 1H NMR (500 MHz, CDCl3) δ
7.18 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.79 (s, 1H), 6.36 (d, J
= 1.6 Hz, 1H), 5.70 (s, 1H), 5.61 (d, J = 1.5 Hz, 1H), 5.20 (d, J = 14.8 Hz,
1H), 4.79 (s, 1H), 4.14 (d, J = 14.8 Hz, 1H), 3.77 (s, 3H), 2.82 (t, J = 7.7
Hz, 2H), 1.88 – 1.72 (m, 2H), 1.48 – 1.40 (m, 2H), 1.23 (s, 9H), 0.96 (t, J
= 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.4, 161.7, 159.5, 148.2,
133.6, 130.1, 127.1, 122.6, 121.8, 114.4, 109.6, 56.3, 55.3, 52.2, 49.4,
29.1, 28.9, 28.5, 22.5, 13.8. HRMS (ESI) calculated for C24H32N4NaO3
[M+Na]+: 447.2367; found: 447.2374.
N-(tert-butyl)-7-(3,4-dichlorobenzyl)-5-methylene-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6d): White solid,
o
1
76% yield, melting point: 125–126 C. H NMR (500 MHz, CDCl3) δ 7.81
(s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 1.45 Hz, 1H), 7.16 (dd, J =
8.2, 1.6 Hz, 1H), 6.91 (s, 1H), 6.59 (s, 1H), 6.27 (d, J = 1.35 Hz, 1H),
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10.1002/ejoc.201901511
European Journal of Organic Chemistry
FULL PAPER
N-(tert-butyl)-5-ethylidene-7-(4-methoxybenzyl)-6-oxo-5,6,7,8-
N-(tert-butyl)-8-(3,4-dichlorobenzyl)-7-oxo-8,9-dihydro-7H-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6j): White solid,
59% yield, melting point: 92–93 oC. The product 6j appears as an
unseparated mixture of Z/E isomers with a ratio of 2:3. 1H NMR (500
MHz, CDCl3) δ 7.86 (s, 0.4H), 7.67 (s, 0.6H), 7.23 – 7.11 (m, 2H), 6.92 –
6.82 (m, 3.4H), 6.41 (q, J = 7.5 Hz, 0.6H), 5.92 (s, 0.6H), 5.82 (s, 0.4H),
5.28 – 5.22 (m, 1H), 4.84 (s, 1H), 4.12 (d, J = 14.9 Hz, 0.4H), 4.08 (d, J =
14.9 Hz, 0.6H), 3.78 (s, 3H), 2.38 (d, J = 7.5 Hz, 1.7H), 2.13 (d, J = 7.7
Hz, 1.3H), 1.26 – 1.20 (m, 9H). 13C NMR (126 MHz, CDCl3) δ 166.3,
166.2, 161.8, 161.1, 159.5(2C), 135.0, 131.9, 130.4, 130.1, 130.0, 127.4,
127.3, 127.2, 125.4, 125.0, 124.3, 123.9, 122.5, 122.2, 121.9, 114.4,
56.3, 56.1, 55.4, 52.1(2C), 49.4, 48.6, 28.5(2C), 13.9(2C). HRMS (ESI)
calculated for C21H26N4NaO3 [M+Na]+: 405.1897; found: 405.1890.
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7d): White solid, 53%
yield, melting point: 202–203 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (s,
1H), 7.44 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2,
2.1 Hz, 1H), 7.08 (d, J = 9.9 Hz, 1H), 6.98 (s, 1H), 5.88 (d, J = 9.9 Hz,
1H), 5.00 (s, 1H), 4.91 (s, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.65 (d, J = 15.2
Hz, 1H), 1.16 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 165.2, 164.3, 137.5,
136.3, 133.1, 132.4, 131.0, 130.4, 129.1, 127.9, 127.7, 125.7, 115.0,
56.4, 52.2, 51.7, 28.4. HRMS (ESI) calculated for C19H20Cl2N4NaO2
[M+Na]+: 429.0856; found: 429.0847.
N-(tert-butyl)-8-butyl-7-oxo-8,9-dihydro-7H-imidazo[1,5-
a][1,4]diazepine-9-carboxamide (7e): White solid, 52% yield, melting
point: 150–151 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.15 (s,
1H), 7.03 (d, J = 9.9 Hz, 1H), 5.82 (d, J = 9.8 Hz, 1H), 5.30 (s, 1H), 4.98
(s, 1H), 3.86 – 3.77 (m, 1H), 3.43 – 3.38 (m, 1H), 1.69 – 1.49 (m, 2H),
1.36 – 1.29 (m, 2H), 1.26 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 164.9, 164.6, 137.2, 128.8, 128.5, 125.1, 115.7, 57.3,
52.2, 49.6, 30.0, 28.5, 20.1, 13.8. HRMS (ESI) calculated for C16H24N4
NaO2 [M+H]+: 327.1791; found: 327.1799.
(Z)-5-benzylidene-N-(tert-butyl)-7-(4-methoxybenzyl)-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6k): White solid,
o
1
68% yield, melting point: 233–235 C. H NMR (500 MHz, CDCl3) δ 7.81
(s, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.35 (t, J = 7.3
Hz, 1H), 7.17 (s, 1H), 7.15 (d, J = 3.7 Hz, 2H), 6.88 (s, 1H), 6.84 (d, J =
8.6 Hz, 2H), 6.32 – 6.17 (m, 1H), 5.22 (d, J = 14.9 Hz, 1H), 4.95 (s, 1H),
4.14 (d, J = 14.9 Hz, 1H), 3.74 (s, 3H), 1.23 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 166.0, 160.3, 159.5, 132.9, 132.1, 130.2, 130.1, 128.9, 128.0,
127.4, 126.7, 124.7, 124.5, 123.1, 114.4, 56.2, 55.3, 52.0, 49.0, 28.5.
HRMS (ESI) calculated for C26H29N4O3 [M+H]+: 445.2234; found:
445.2239.
N-benzyl-8-(4-methoxybenzyl)-7-oxo-8,9-dihydro-7H-imidazo[1,5-
a][1,4]diazepine-9-carboxamide (7f): White solid, 60% yield, melting
point: 184–185 oC. 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.25 (p, J =
3.7 Hz, 3H), 7.20 (d, J = 8.6 Hz, 2H), 7.01 (dd, J = 7.2, 2.3 Hz, 2H), 6.98
(d, J = 9.9 Hz, 1H), 6.82 (s, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.07 (s, 1H),
5.79 (d, J = 9.9 Hz, 1H), 5.05 (s, 1H), 4.73 (q, J = 14.7 Hz, 2H), 4.26 (dd,
J = 14.7, 6.1 Hz, 1H), 4.19 (dd, J = 14.7, 5.7 Hz, 1H), 3.76 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 166.1, 165.0, 159.6, 137.4, 137.2, 130.2,
128.9, 128.6, 127.6, 127.5, 125.9, 114.9, 114.4, 55.2, 55.1, 51.6, 44.1.
HRMS (ESI) calculated for C23H22N4NaO3 [M+Na]+: 425.1584; found:
425.1581.
General Procedure for the Synthesis of Imidazodiazepinone
Scaffold 7: In an oven-dried 10 mL screw-cap vial were charged with Ugi
adduct 5 (0.25 mmol) and dry chloroform (2 mL). The reaction mixture
was stirred at 80 oC until it is complete. The reaction mixture was then
purified by column chromatography (2–4% MeOH in DCM) to afford
imidazopyrazinone scaffold 7.
N-(tert-butyl)-8-(4-methoxybenzyl)-7-oxo-8,9-dihydro-7H-
8-(4-methoxybenzyl)-N-(4-methoxyphenyl)-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7g): White solid, 55%
yield, melting point: 215–216 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (s,
1H), 7.35 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 10.0 Hz, 3H), 7.01 (s, 1H), 6.93
(d, J = 8.5 Hz, 2H), 6.85 (s, 1H), 6.76 (d, J = 8.9 Hz, 2H), 5.89 (d, J = 9.8
Hz, 1H), 5.17 (s, 1H), 4.91 (d, J = 14.6 Hz, 1H), 4.68 (d, J = 14.6 Hz, 1H),
3.81 (s, 3H), 3.75 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.0, 163.9,
159.9, 156.9, 137.4, 130.5, 129.7, 129.3, 127.8, 127.4, 126.3, 121.4,
114.9, 114.8, 114.1, 55.8, 55.5, 55.4, 51.8. HRMS (ESI) calculated for
C23H22N4NaO4 [M+Na]+: 441.1533; found: 441.1530.
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7a): White solid, 63%
yield, melting point: 176–178 oC. 1H NMR (500 MHz, CDCl3) δ 7.67 (s,
1H), 7.33 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 9.9 Hz, 1H), 6.96 (s, 1H), 6.91
(d, J = 8.6 Hz, 2H), 5.84 (d, J = 9.8 Hz, 1H), 5.07 (s, 1H), 4.98 (s, 1H),
4.95 (d, J = 14.5 Hz, 1H), 4.46 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 1.09 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 165.0, 164.9, 159.8, 137.1, 130.4,
129.0, 128.0, 126.3, 114.7, 114.5, 56.0, 55.4, 52.0, 51.7, 28.3. HRMS
(ESI) calculated for C20H24N4NaO3 [M+Na]+: 391.1741; found: 391.1744.
N-(tert-butyl)-8-(4-(tert-butyl)benzyl)-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7b): White solid, 67%
yield, melting point: 225–226 oC. 1H NMR (500 MHz, CDCl3) δ 7.67 (s,
1H), 7.42 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 9.9 Hz,
1H), 6.99 (s, 1H), 5.83 (d, J = 9.8 Hz, 1H), 5.11 (d, J = 14.5 Hz, 1H), 5.09
(s, 1H), 5.00 (s, 1H), 4.35 (d, J = 14.5 Hz, 1H), 1.32 (s, 9H), 1.05 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 165.0, 164.8, 151.7, 137.0, 133.1, 129.1,
128.9, 127.9, 126.6, 126.4, 114.3, 56.2, 51.9, 34.6, 31.3, 28.2. HRMS
(ESI) calculated for C23H30N4NaO2 [M+Na]+: 417.2261; found: 417.2264.
N-(tert-butyl)-8-(4-methoxybenzyl)-1-methyl-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7h): White solid, 83%
yield, melting point: 165–166 oC. 1H NMR (500 MHz, CDCl3) δ 7.57 (s,
1H), 7.26 (d, J = 7.5 Hz, 2H), 7.04 – 6.96 (m, 1H), 6.90 (d, J = 8.6 Hz,
2H), 5.78 (d, J = 9.9 Hz, 1H), 5.01 (s, 1H), 4.88 (s, 1H), 4.85 (d, J = 14.6
Hz, 1H), 4.65 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 1.95 (s, 3H), 1.14 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 165.4, 165.1, 159.7, 137.3, 135.3, 130.3,
127.9, 126.3, 126.2, 123.5, 114.7, 113.8, 55.4, 54.7, 52.0, 51.6(2C), 28.4,
12.1. HRMS (ESI) calculated for C21H26N4NaO3 [M+Na]+: 405.1897;
found: 405.1911.
N-(tert-butyl)-8-(4-fluorobenzyl)-7-oxo-8,9-dihydro-7H-imidazo[1,5-
a][1,4]diazepine-9-carboxamide (7c): White solid, 58% yield, melting
o
point: 194–196 C. 1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.35 (dd, J
N-(tert-butyl)-3-butyl-8-(4-methoxybenzyl)-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7i): White solid, 68%
= 8.4, 5.4 Hz, 2H), 7.10 (d, J = 9.9 Hz, 1H), 7.05 (t, J = 8.6 Hz, 2H), 6.94
(s, 1H), 5.86 (d, J = 9.9 Hz, 1H), 5.06 (s, 1H), 4.96 (s, 1H), 4.80 (d, J =
14.8 Hz, 1H), 4.74 (d, J = 14.8 Hz, 1H), 1.12 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 165.1, 164.7, 162.6 (d, J = 247.5 Hz), 137.3, 131.9 (d, J = 3.2
Hz), 130.64 (d, J = 8.2 Hz), 129.0, 127.9, 126.0, 116.0 (d, J = 21.4 Hz),
114.8, 56.9, 56.2, 52.1, 51.7, 28.3. 19F NMR (376MHz, CDCl3) δ -113.2.
HRMS (ESI) calculated for C19H22FN4O2 [M+H]+: 357.1721; found:
357.1726.
o
yield, melting point: 122–123 C. 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J
= 8.5 Hz, 2H), 6.96 (d, J = 9.9 Hz,1), 6.90 (d, J = 8.6 Hz, 2H), 6.82 (s,
1H), 5.80 (d, J = 9.9 Hz, 1H), 5.08 (s, 1H), 4.96 (d, J = 14.5 Hz, 1H), 4.89
(s, 1H), 4.45 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 2.82 – 2.47 (m, 2H), 1.74
(p, J = 7.7 Hz, 2H), 1.41 (h, J = 7.4 Hz, 2H), 1.09 (s, 9H), 0.95 (t, J = 7.4
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.2, 165.0, 159.7, 149.2, 130.4,
128.1, 127.7, 127.1, 125.7, 114.6, 113.8, 56.3, 55.4, 51.9, 51.5, 29.6,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901511
European Journal of Organic Chemistry
FULL PAPER
28.3, 26.9, 22.4, 13.7. HRMS (ESI) calculated for C24H32N4NaO3
[M+Na]+: 447.2367; found: 447.2375.
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imidazo[1,5-a][1,4]diazepine-9-carboxamide (7j): White solid, 58%
yield, melting point: 207–209 oC. 1H NMR (500 MHz, CDCl3) δ 7.74 (s,
1H), 7.32 (d, J = 8.5 Hz, 2H), 6.93 (s, 1H), 6.90 (d, J = 8.6 Hz, 2H), 5.73
(s, 1H), 5.09 (s, 1H), 4.98 (d, J = 14.5 Hz, 1H), 4.92 (s, 1H), 4.37 (d, J =
14.5 Hz, 1H), 3.81 (s, 3H), 2.32 (s, 3H), 1.09 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 165.4, 164.9, 159.8, 136.4, 135.1, 130.4, 128.7, 128.3, 128.1,
114.7, 113.3, 55.9, 55.4, 51.8, 51.2, 28.2, 21.3. HRMS (ESI) calculated
for C21H26N4NaO3 [M+Na]+: 405.1897; found: 405.1887.
[4]
N-(tert-butyl)-8-(4-methoxybenzyl)-7-oxo-5-phenyl-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7k): White solid, 60%
yield, melting point: 247–249 oC. 1H NMR (500 MHz, CDCl3) δ 7.51 –
7.42 (m, 5H), 7.41 – 7.32 (m, 3H), 6.98 (s, 1H), 6.92 (d, J = 8.6 Hz, 2H),
5.95 (s, 1H), 5.23 (s, 1H), 5.07 (d, J = 14.4 Hz, 1H), 5.02 (s, 1H), 4.39 (d,
J = 14.4 Hz, 1H), 3.82 (s, 3H), 1.02 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
165.4, 165.3, 159.8, 139.9, 137.5, 134.5, 130.9, 130.5, 129.6, 129.0,
128.5, 128.1, 128.1, 114.7, 113.5, 56.1, 55.4, 51.9, 51.2, 28.2. HRMS
(ESI) calculated for C26H28N4NaO3 [M+Na]+: 467.2054; found: 467.2041.
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Acknowledgments
The authors are thankful to the financial support of the National Natural
Science Foundation of China (grant No. 51803181) and the Natural
Science Foundation of Zhejiang Province (grant No. LY20H300006).
E.V.D.E. appreciates the FWO [Fund for Scientific Research-Flanders
(Belgium)], the Research Fund of the University of Leuven (KU Leuven)
and RUDN University Program 5-100 for the financial support.
Keywords: Nitrogen heterocycle • Imidazole • Divergent
synthesis• Phosphines • Ugi reaction
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Author(s), Corresponding Author(s)*
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Title
((Insert TOC Graphic here: max.
width: 5.5 cm; max. height: 5.0 cm;
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Nitrogen Heterocycles
D. Wu, X. Zhang, Y. Li, S. Ying, L. Zhu,
Z. Li,* G. Yang,* and E. V. Van der
Eycken*
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Exo/endo-Selectivity Switch: A divergent access to structurally diversified bicyclic
imidazo[1,5-a]pyrazine and imidazo[1,5-a][1,4]diazepine scaffolds has been
elaborated through a phosphine-triggered selective intramolecular 6-exo-dig and a
thermal 7-endo-dig post-Ugi heterocyclization.
Divergent Access to
Imidazopyrazinones and
Imidazodiazepinones by
Regioswitchable Post-Ugi
Heteroannulation*
*one or two words that highlight the emphasis of the paper or the field of the study
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