An expeditious entry to rare tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-ones: A single-step gateway synthesis of glochidine congeners

Article abstract of DOI:10.1016/j.tet.2019.130760

A single-step gateway synthesis of glochidine and its congeners that possess the rare uncommon tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidine core was developed employing histamine and readily available γ-ketoesters. Key features of the developed reaction involve tandem three C–N bonds formation and concomitant annulation of two rings in one pot to access this unique and complex tricyclic structure. Exploration of the unknown bioactivity of these compounds revealed that they elicit antiproliferative activity comparable to the anticancer drug imatinib against 6 cancer cell lines.

Full text of DOI:10.1016/j.tet.2019.130760

Journal Pre-proof
An expeditious entry to rare tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-
ones: A single-step gateway synthesis of glochidine congeners
Jeong Moo Seo, Ahmed H.E. Hassan, Yong Sup Lee
PII:
S0040-4020(19)31153-6
https://doi.org/10.1016/j.tet.2019.130760
TET 130760
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 August 2019
Revised Date: 13 October 2019
Accepted Date: 1 November 2019
Please cite this article as: Seo JM, Hassan AHE, Lee YS, An expeditious entry to rare
tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-ones: A single-step gateway synthesis of
glochidine congeners, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130760.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

Graphical Abstract:

An expeditious entry to rare tetrahydroimidazo[1,5-c]pyrrolo[1,2-
a]pyrimidin-7(8H)-ones: A single-step gateway synthesis of glochidine
congeners
Jeong Moo Seoa,1, Ahmed H.E. Hassanb,c,1 and Yong Sup Leea,b
a Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Korea.
b Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.
c Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Abstract
A single-step gateway synthesis of glochidine and its congeners that possess the rare uncommon
tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidine core was developed employing histamine and
readily available γ-ketoesters. Key features of the developed reaction involve tandem three C-N
bonds formation and concomitant annulation of two rings in one pot to access this unique and
complex tricyclic structure. Exploration of the unknown bioactivity of these compounds revealed
that they elicit antiproliferative activity comparable to the anticancer drug imatinib against 6
cancer cell lines.
Keywords
Imidazo[1,5-c]pyrrolo[1,2-a]pyrimidines; tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-
7(8H)-ones; Tandem reaction; Cyclization reactions; Natural products analogs; Anticancers
Corresponding author: e-mail: kyslee@khu.ac.kr
1 Both of Ahmed H.E. Hassan and Jeong Moo Seo contributed equally to this work.
1

1. Introduction
Imidazo[1,5-c]pyrrolo[1,2-a]pyrimidines, dipyrrolo[1,2-a:1',2'-c]pyrimidines and pyrido[1,2-
c]pyrrolo[1,2-a]pyrimidines (Fig. 1) are unique fused azaheterotricyclic ring systems possessing
ring-junction nitrogen atoms. They are rarely encountered in natural products and scarcely found
in synthetic reports. As of September 2019, SciFinder sub-structure search presents glochidine as
the only known example of natural products having imidazo[1,5-c]pyrrolo[1,2-a]pyrimidine ring
system and reveals also that there is no known synthetic congener other than the unsubstituted
tricyclic skeleton [1]. Meanwhile, several natural tetraponerines T1–8 (dipyrrolo[1,2-a:1',2'-
c]pyrimidines or pyrido[1,2-c]pyrrolo[1,2-a]pyrimidines; Fig. 1) are known and they were found
to possess interesting cytotoxic, neurotoxic, and insecticidal bioactivities [2]. In literature,
several reports are found for the synthesis of natural as well as non-natural tetraponerines which
afforded multiple synthetic approaches to access tetraponerines [2b,2d,3]. Accordingly, it was
possible to explore biological activities of natural tetraponerines and their synthetic congeners.
On the opposite, the biological activity of glochidine, which is the sole known member of
substituted imidazo[1,5-c]pyrrolo[1,2-a]pyrimidines is completely unknown.
Figure 1. Ring systems and structures of glochidine and tetraponerines
Up-to-date, two synthetic approaches to access glochidine were reported which involves in situ
generation of N-acyliminium cation as a key intermediate [4]. The first approach involves: 1)
succinic anhydride-histamine condensation to succinimide followed by 2) Grignard reagent
2

addition to form the key intermediate hydroxylactam that was employed in 3) N-acyliminium
cation-mediated cyclization (Scheme 1A) [4a]. Such approach would necessitate the use of
custom Grignard reagents if varied angular substituents are desired. The second recently reported
method is a photochemical approach includes: 1) LED light-irradiation using a photosensitizer to
catalyze photo-oxygenation of furan derivatives followed by 2) condensation with a primary
amine to afford 2-pyrrolidinone derivative then 3) treatment with formic acid to generate N-
acyliminium cation (Scheme 1B) [4b,4c]. Despite its usefulness, such photochemical approach
requires special instrumentation [4c]. Despite the presence of these two approaches, we found no
attempt was reported up-to-date to synthesize congeners other than glochidine itself or the
unsubstituted tricyclic skeleton. In lieu of the complete absence of biological activity information
for this unique ring system while the structurally closely related tetraponerines possess
interesting bioactivities, addition of an alternative efficient route is needed to access derivatives
of unique ring system. Therefore, we conducted this work aiming to develop a novel, more
practical, efficient, economic and divergent route to access glochidine and its synthetic
congeners in order to fill this vacant chemical space.
2. Results and discussion
Pursuing ideality, economy, and targeting development of diversity enabling reactions are
important in planning a successful practical synthetic route [5]. Imines and iminium ions are
powerful intermediates for construction of C-N and C-C bonds that enable rapid entry into
complex structures employing using simple fragments [6]. Aiming to develop a practical
synthetic method to access the almost unknown tetrahydroimidazo[1,5-c]pyrrolo[1,2-
a]pyrimidin-7(8H)-ones in a single-step, we envisioned that reacting histamine with the readily
3

available diverse γ-ketoesters would afford transient imine intermediates that would undergo
tandem formation of three C-N bonds with concomitant bicyclization (Scheme 1C). Quite
different form the reported N-acyliminium cation-mediated cyclizations, we anticipated aminals
might be formed in situ upon addition of the imidazole’s nucleophilic nitrogen atom to the
transient imines obtained through condensation of the carbonyl group of γ-ketoesters with the
amino group of histamine. Intramolecular aminolysis of the formed aminals would afford the
desired tricyclic tetrahydroimidazo[1,5-c]pyrimidines derivatives 1 as a product of one pot
tandem reaction (Scheme 1C). The designed route would open a convenient gateway for
synthesis of tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-ones employing the
commercially available or readily accessible γ-ketoesters and would circumvent the limitations
of the litature reported routes. In addition, the readily available diverse γ-ketoesters array would
offers possibilities for divergent synthesis of compounds’ library bearing substituents at all
available position of the pyrrolidine ring including the angular position.
4

Previous Work
O
A
O
O
NH2
O
N
HN
HN
N
N
O
n-Hexyl bromide
Mg, THF
O
D
Only Glochidine
in Three Steps
N
HN
N
Toluene
Overall 38% yield
HO
n-C6H13
Hydroxylacatm
B
OH
O
O2, Rose Bengal
White LED Me2S
O
n-C6H13
MeOH
n-C6H13
OMe
NH2
MeOH
HN
N
O
N
HCOOH
rt, 18h
Only Glochidine
in Three Steps
Overall 62% yield
HN
N
n-C6H13
Current Work
C
OCH3
R3
O
O
R1
OCH3
NH2
N
O
HN
HN
R2
N
N
3-Keto-esters
R1
R3
R2
Histamine
Iminies
N
N
N
N
R1
R2
N
NH
R3
O
OCH3
O
R1
R2
R3
1
Aminals
Glochidine and Congeners
in a Single Step
Scheme 1. Literature reported Syntheses of glochidine (A and B) and the designed new route (C).
We started to explore our envisioned synthetic method by investigating the one pot reaction of
histamine with methyl levulinate (2a). As Table 1 shows, refluxing histamine dihydrochloride
with methyl levulinate in methanol did not afford a product (Table 1, entry 1). Replacement of
histamine dihydrochloride salt with the freebase afforded exclusively the desired glochidine
analog (1a) in 41% yield (Table 1, entry 2). This outcome confirmed the crucial role of
nucleophilicity of histamine for the reaction’s success. Towards more economic route, the use of
5

histamine dihydrochloride as a starting material is desirable since it is more stable and
commercially ca. 6 times cheaper. Therefore, sodium carbonate was added to histamine
dihydrochloride and methyl levulinate (2a) mixture in methanol to generate in situ histamine
freebase. Successfully, the desired glochidine analog (1a) was obtained but in 35% yield after
refluxing for 24 h (Table 1, entry 3). Biosynthetic reactions occur in aqueous phase and, in
addition, aqueous reactions are more economic, environmentally benign and, furthermore, water
might affect the reactivity [7]. Therefore, the carbon–nitrogen bond-forming reaction to be
developed was tested in an aqueous solution but, unfortunately, water was not a suitable
reaction’s solvent (Table 1, entry 4). The use of aprotic polar solvents such as acetonitrile and
N,N-dimethylformamide in the presence of triethylamine (3 equivalents) afforded glochidine
analog (1a), but in poor yields after heating at 70°C for 48 hours (Table 1, entries 5 and 6).
Switching back to methanol while maintaining the use of trimethylamine (3 equivalents)
afforded exclusively glochidine analog (1a) in satisfactory yields after refluxing for 24 hours
(Table 1, entry 7). Increasing the stoichiometric ratio of trimethylamine to 5 equivalents
improved the isolated yield to 77% (Table 1, entry 8). Incorporation of molecular sieves or
increasing refluxing time did not improve the yield while increasing the stoichiometric ratio of
trimethylamine to 10 equivalents lowered the yield (Table 1, entries 9, 10 and 11).
Table 1. Optimizing conditions using methyl levulinate (2a).
Entry[a] Solvent[b] Additive (equiv.) Time (h) Yield (%)[c]
[d]
1
MeOH
MeOH
—
—
24
24
—
2[e]
41
6

3
4
MeOH
H2O
Na2CO3 (10)
Na2CO3 (10)
NEt3 (3)
24
24
48
48
24
24
24
48
48
35
5
5
CH3CN
DMF
9
6
NEt3 (3)
15
66
77
75
78
65
7
MeOH
MeOH
MeOH
MeOH
MeOH
NEt3 (3)
8
NEt3 (5)
9[f]
10
11
NEt3 (5)
NEt3 (5)
NEt3 (10)
[a] 1.1 Equivalents of methyl levulinate. [b] Reflux for MeOH and heating at 70°C for other solvents. [c] Isolated
yields. [d] No reaction. [e] Histamine freebase. [e] In the presence of 10 wt.% 4 Å molecular sieve.
With optimum reaction conditions in hand, we proceeded to explore the scope of the developed
method using diverse γ-ketoesters substrates. As shown in Table 2, the reaction of histamine
dihydrochloride salt was first explored with γ-ketoesters 2b–e whose R1 groups were primary
aliphatic chains. The reaction of these substrates afforded under the established optimum
condition glochidine analogs 1b–e possessing angularly 9a-substituted tetrahydroimidazo[1,5-
c]pyrrolo[1,2-a]pyrimidine ring system in good yields (Table 2, entries 1–4). Glochidine (1c)
itself could be obtained in 59% isolated yield which is higher than the previously reported three-
steps approach A (Scheme 1A) and comparable to approach B that employed photo-oxygenation
as initial step to prepare the key substrate (Scheme 1B). Interestingly, β-substituted-γ-ketoester
2d and aslo α-substituted-γ-ketoester 2e afforded cyclized products 1d and 1e in higher yields
1
than α,β-unsubstituted
-
γ-ketoester substrates 2b and 2c. H NMR spectra of the product 1d
showed a weak preferance to form the 1,2-cis over the 1,2-trans diastereomer (ca 1 : 1.23 1,2-
trans to 1,2-cis ratio). The product 1e showed more predominace for the 1,3-trans over the 1,3-
cis diastereomer (ca 1 : 1.74 1,3-cis to 1,3-trans ratio). These low cis/trans ratios for products 1d
7

and 1e might indicate a limited influence of R2 and R3 substituents on the products’
diastereoselectivity.
Table 2. Scope of the one-pot cyclization reaction.
Entry[a]
Substrate
Product
Yield (%)[b]
1
52
2
3
4
59
77
72
N
N
N
O
5
18[e]
H3CO
1f
[a] 1.1 Equivalents of histamine dihydrochloride. [b] Isolated yields. [c] Ratio of 1,2-trans:1,2-cis diastereomers = 1 :
1.23 (1H NMR analyses). [d] Ratio of 1,3-cis:1,3-trans diastereomers = 1 : 1.74 (1H NMR analyses). [e] Reflux for 4
days.
8

Next, hindered substrates were used such as γ-ketoester 2f whose R1 was the aromatic 4-
methoxyphenyl moiety. The reaction of substrate 2f afforded the cyclized product 1f in low 18%
yield after an extended refluxing time for 4 days (Table 2, entry 5). This might indicate that the
steric effect of R1 was detrimental to the formation of the imine intermediates or to the
cyclization step in γ-ketoester substrates in which R1 set to an aromatic moiety. After several
variations of reaction conditions, compound 1f could be obtained in an improved 54% yield
(brsm) by increasing the stoichiometric ratios of histamine hydrochloride to 3 equivalents and
the triethylamine to 6 equivalents (Table 3, entry 1). Under the modified reaction conditions,
diverse hindered γ-ketoesters substrates 2g–j whose R1 groups were aromatic or aliphatic cycles
were successfully converted to the corresponding glochidine analogs 1g–j in acceptable 65–42%
yields (brsm). As shown in Table 3, the α,β-unsubstituted-γ-ketoester substrates 2g, 2f and 2i in
which the phenyl ring was unsubstituted or bearing the activating 4-methoxy or 4-methyl
substituents, respectively, afforded products 1g, 1f and 1i in almost similar yield (65–54%)
which might suggest low impact of 4-substituents on the reaction. Again, the hindered α-
substituted-γ-ketoester substrate 2h afforded the product 1h that possessed an almost equal ratio
of 1,3-trans and 1,3-cis diastereomers (ca 1 : 1.09 1,3-cis:1,3-trans) which confirms the limited
influence of R2 substituents on the products’ diastereoselectivity. Finally, the reaction of the
hindered substrate 2j possessing the aliphatic cyclopropyl ring as a replacement to the aromatic
ring afforded also the product 2j in similar yield. Thus, the scope of this reaction might be
extendable to hindered substrates to allow access of the tetrahydroimidazo[1,5-c]pyrrolo[1,2-
a]pyrimidine ring system possessing a cyclic substituent at 9a angular-position.
Table 3. One-pot reaction with hindered substrates.
9

Entry
Substrate
Product
Yield (%)[a]
N
N
N
O
1
32 (54)
H3CO
1f
2
3
4
5
40 (56)
35 (42)
40 (65)
46 (55)
10

[a] Isolated yields. Yields between parentheses are based on recovered γ- ketoesters. [b] Ratio of 1,3-cis:1,3-trans
diastereomers = 1 : 1.09 (1H NMR analyses).
With derivatives in our hands, we started to explore the unknown biological activities of
compounds belonging to this ring system. As the structurally related tetraponerines were
reported as antiproliferatives [2c], we investigated the cytotoxic activity of glochidine (1c) and
its analogs 1d–j on the growth of cancer cells relative to the marketed anticancer drug imatinib at
10 µM dose using SRB assay [8]. Glochidine was more effective than imatinib as a growth
inhibitor against HL-60 cancer cells (blood cancers; Table 4). In addition, compounds 1d–j were
more effective growth inhibitors of some cancer cell lines relative to imatinib. Notably,
glochidine analogs 1e and 1j were more effective against some blood cancers while glochidine
analogs 1d, 1h and 1i were more effective against some renal cancers. Furthermore, glochidine
and most of tested analogs elicited significant growth inhibition against NCI-H522 cell line (lung
cancer).
Table 4. Percentage inhibition of cancer cells growth by 10 µM dose of imatinib, glochidine (1c) and glochidine
congeners (1d–j).
Cancer
Disease
Cell
Line
Imatinib [a]
1c
1d
1e
1f
1g
1h
1i
1j
HL60
K562
NI[b]
NT[c]
18
15
NI
NI
NI
NI
NI
38
13
12
12
NI
NI
2
4
4
44
NI
35
Blood
Cancers
NI
NI
NI
NI
NI
NI
MOLT4
Lung
Cancer
H522
NTc
10
8
15
13
14
1
12
1
RXF393
UO31
6
8
8
6
NI
7
1
2
2
3
12
6
13
3
3
Renal
Cancers
NI
10
NI
[a] Imatinib; an FDA approved drug as a standard. [b] NI: No inhibition of cancer cells growth. [c] NT: Not tested.
3. Conclusion
11

In summary, a single-step one-pot synthesis was developed to access glochidine and its
congeners which possess the very uncommon tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidine
ring system starting from the readily available γ-ketoesters and histamine. The key feature of the
developed method is a tandem formation of three C-N bonds in a single-step. The developed
method allow simple and convenient preparation of this class of compounds that circumvent
limitations of other methods. The reaction scope was extened to hindered substrates to afford the
desired products in acceptable yields. This methods opens a gateway to access unprecedented
diverse library of glochidine analogs. Finally, the unkown biological activity of this class of
compounds were explored for the first time and they were found to possess antiproliferative
activity comprarable to imatinib against six cancer cell lines.
4. Experimental Section
General instrumentation and chemicals
NMR spectra were recorded on Bruker AC 400 spectrometer operating at 400 MHz for 1H-NMR
and 100 MHz or 125 MHz for 13C-NMR. Chemical shifts (δ) are reported in ppm, downfield
from internal TMS standard. High resolution mass spectra (HRMS) were recorded on Jeol
accuTOF (JMS-T100TD) equipped with a DART (direct analysis in real time) ion source from
ionsense, Tokyo, Japan in the positive modes. Flash column chromatography was performed
using Merck Kiesegel 60 Art 9385 (230-400 mesh).
Reaction of methyl levulinate (2a) with histamine dihydrochloride using Na2CO3
A solution of histamine dihydrochloride (276 mg, 1.5 mmol), methyl levulinate (2a, 215 mg, 1.7
mmol) and sodium carbonate (1.59 g, 15.0 mmol) in MeOH (10 mL) was heated at reflux for 24
12

h. The mixture was evaporated in vacuo and the residue was treated with water followed by
extraction with CH2Cl2. The combined organic phase was washed with brine, dried over
anhydrous MgSO4, filtered, and evaporated. The residue was purified by flash column
chromatography (CH2Cl2/CH3OH/NH4OH = 20:1:0.01) to afford 1a (100 mg, 35%).
9a-methyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1a): White
solid; mp 140.1 ºC; 1H NMR (400 MHz, CDCl3) δ 7.49 (1H, s, H-1), 6.78 (1H, s, H-3), 4.34 (1H,
ddd, J = 13.7, 4.9, 3.4 Hz, H-5a), 3.14 (1H, dt, J = 13.7, 8.3 Hz, H-5b), 2.88-2.85 (2H, m, H-4),
2.67-2.43 (4H, m, H-8, H-9), 1.72 (3H, s, -CH3); 13C NMR (125 MHz, CDCl3) δ 167.9, 127.4,
120.1(2C), 71.0, 29.6, 28.5, 24.9, 23.8, 15.6; HR-MS calcd for C10H14N3O [M+H]+ 192.1131,
found 192.1145.
General Procedure for reaction of γ-ketoesters (2a–e) with histamine dihydrochloride in
MeOH using trimethylamine
A solution of histamine dihydrochloride (184 mg, 1.0 mmol), γ-ketoesters (2a–e, 1.2 mmol) and
triethylamine (0.69 ml, 5.0 mmol) in MeOH (10 mL) was heated at reflux for 24 h. The mixture
was evaporated in vacuo and the residue was treated with water followed by extraction with
CH2Cl2. The combined organic phase was washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated. The residue was purified by flash column chromatography to afford the
desired products 1a–e.
13

9a-Pentyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1b): orange
1
semisolid; Yield 52%. H NMR (400 MHz, CDCl3) δ 7.48 (1H, s, H-1), 6.79 (1H, s, H-3), 4.34
(1H, ddd, J = 13.2, 6.4, 2.4 Hz, H-5a), 3.10 (1H, ddd, J = 13.2, 10.7, 6.4 Hz, H-5b), 2.95-2.82
(2H, m, H-4), 2.66-2.40 (4H, m, H-8, H-9), 1.98-1.94 (2H, m, H-1’), 1.39-1.22 (6H, m, H-2’, H-
3’, H-4’), 0.88 (3H, t, J = 6.5 Hz, -CH3); 13C NMR (125 MHz, CDCl3) δ 173.7, 132.5, 125.2,
125.0, 78.7, 41.7, 33.7, 31.6, 31.6, 30.1, 23.6, 22.6, 20.3, 14.1; HR-MS calcd for C14H22N3O
[M+H]+ 248.1757, found 248.1770.
9a-Hexyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1c, Glochidine):
White solid; mp 44.3 ºC; Yield 59%. 1H NMR (500 MHz, CDCl3) δ 7.48 (1H, s, H-1), 6.79 (1H,
s, H-3), 4.36-4.32 (1H, m, H-5a), 3.13-3.07 (1H, m, H-5b), 2.94-2.83 (2H, m, H-4), 2.65-2.40
(4H, m, H-8, H-9), 1.98-1.94 (2H, m, H-1’), 1.36-1.21 (8H, m, H-2’, H-3’, H-4’, H-5’), 0.87 (3H,
t, J = 6.9 Hz, -CH3); 13C NMR (125 MHz, CDCl3) δ 173.7, 132.5, 125.3, 125.0, 78.7, 41.8, 33.7,
31.8, 31.7, 30.1, 29.1, 23.9, 22.7, 20.4, 14.2; HR-MS calcd for C15H24N3O [M+H]+ 262.1914,
found 262.1867.
9,9a-Dimethyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one
(1d):
1
Yellowish white solid; mp 111.3 ºC; Yield 77%. H NMR (400 MHz, CDCl3) δ 7.54 (0.55H, s,
H-1), 7.45 (0.45H, s, H-1), 6.82 (0.45H, s, H-3), 6.80 (0.55H, s, H-3), 4.41-4.35 (1H, m, H-5a),
3.08-2.97 (1H, m, H-5b), 2.94-2.80 (2H, m, H-4), 2.79-2.56 (2H, m, H-8), 2.29-2.18 (1H, m, H-
9), 1.74 (1.35H, s, -CH3), 1.60 (1.65H, s, -CH3), 1.41 (1.65H, d, J = 6.9 Hz, -CH3), 0.76 (1.35H,
d, J = 6.9 Hz, -CH3); 13C NMR (125 MHz, CDCl3) δ 171.1, 171.0, 133.5, 132.0, 126.2, 125.2,
14

124.9, 124.7, 78.3, 77.9, 41.4, 39.7, 39.1, 38.4, 33.6, 33.5, 27.5, 22.8, 21.6, 21.3, 16.5, 14.8; HR-
MS calcd for C11H16N3O [M+H]+ 206.1288, found 206.1365.
8,9a-Dimethyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1e): White
solid; mp 113.5 ºC; Yield 72%. 1H NMR (400 MHz, CDCl3) δ 7.49 (0.37H, s, H-1), 7.48 (0.63H,
s, H-1), 6.78 (0.63H, s, H-3), 6.76 (0.37H, s, H-3), 4.36-4.28 (1H, m, H-5a), 3.25-3.08 (1H, m,
H-5b), 2.96-2.77 (3H, m, H-4, H-9a), 2.65 (1H, m, H-8), 2.05 (1H, m, H-9), 1.76 (1.11H, s, -
CH3), 1.72 (1.89H, s, -CH3), 1.31 (1.11H, d, J = 7.3 Hz, -CH3), 1.23 (1.89H, d, J = 7.3 Hz, -CH3);
13C NMR (125 MHz, CDCl3) δ 177.6, 174.5, 132.6, 132.3, 125.5, 125.3, 124.9, 75.0, 73.9, 44.1,
41.9, 36.1, 35.7, 34.0, 33.4, 30.5, 27.9, 21.0, 20.1, 16.8, 15.9; HR-MS calcd for C11H16N3O
[M+H]+ 206.1288, found 206.1381.
General Procedure for reaction of hindered γ-ketoesters (2f–j) with histamine
dihydrochloride in MeOH using trimethylamine:
A solution of histamine dihydrochloride (806 mg, 4.4 mmol), γ-ketoesters (2f–j, 1.5 mmol), and
triethylamine (1.25 ml, 9.0 mmol) in MeOH (10 mL) was heated at reflux for 48 h. The mixture
was evaporated in vacuo and the residue was treated with water followed by extraction with
CH2Cl2. The combined organic phase was washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated. The residue was purified by flash column chromatography
(CH2Cl2/CH3OH/NH4OH = 20/1/0.01) to afford the desired products 1f–j.
15

9a-(4-Methoxyphenyl)-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one
(1f): White solid; mp 115.1 ºC; Yield 54% (brsm). 1H NMR (400 MHz, CDCl3) δ 7.69 (1H, s, H-
1), 6.91 (1H, s, H-3), 6.85 (2H, d, J = 8.8 Hz, Ar-2’, Ar-6’), 6.76 (2H, d, J = 8.8 Hz, Ar-3’, Ar-
5’), 4.09 (1H, ddd, J = 13.2, 7.3, 2.4 Hz, H-5a), 3.79 (3H, s, -OCH3), 3.04-2.96 (1H, m, H-5b),
2.93-2.77 (4H, m, H-4, H-8), 2.73-2.59 (2H, m, H-9); 13C NMR (125 MHz, CDCl3) δ 173.7,
160.0, 133.7, 126.3(2C), 126.1, 125.7, 114.9, 114.3(2C), 80.3, 55.4, 35.0, 33.8, 29.8, 19.4; HR-
MS calcd for C16H18N3O2 [M+H]+ 284.1394, found 284.1459.
9a-Phenyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1g): White
1
solid; mp 179.6 ºC; Yield 56% (brsm). H NMR (400 MHz, CDCl3) δ 7.71 (1H, s, H-1), 7.37-
7.34 (3H, m, Ar-2’, Ar-4’, Ar-6’), 6.92 (1H, s, H-3), 6.88-6.85 (2H, m, H-3’, H-5’), 4.10 (1H,
ddd, 13.2, 7.3, 2.5 Hz, H-5a), 3.05-2.94 (1H, m, H-5b), 2.92-2.79 (4H, m, H-4, H-8), 2.72-2.64
(2H, m, H-9); 13C NMR (125 MHz, CDCl3) δ 169.0, 137.0, 128.9, 124.38(2C), 124.35, 121.5,
121.0(2C), 120.1, 75.7, 30.2, 29.2, 25.0, 14.6; HR-MS calcd for C15H16N3O [M+H]+ 254.1288,
found 254.1278.
8-Methyl-9a-phenyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1h):
White solid; mp 138.0 ºC; Yield 42% (brsm). 1H NMR (400 MHz, CDCl3) δ 7.74 (0.48H, s, H-1),
7.69 (0.52H, s, H-1), 7.36-7.33 (3H, m, H-2’, H-4’, H-6’), 6.91 (1H, s, H-3), 6.90-6.85 (2H, m,
H-3’, H-5’), 4.09 (1H, m, H-5a), 3.18 (0.48H, dd, J = 13.7, 8.8 Hz, H-5b), 3.12 (0.52H, dd, J =
13.7, 8.8 Hz, H-5b), 3.06-2.94 (2H, m, H-4), 2.88-2.59 (2H, m, H-8, H-9a), 2.51 (0.52H, dd, J =
13.7, 7.3 Hz, H-9b), 2.51 (0.48H, dd, J = 13.7, 9.8 Hz, H-9b), 1.41 (1.44H, d, J = 7.3 Hz, -CH3),
1.28 (1.52H, d, J = 7.3 Hz, -CH3); 13C NMR (125 MHz, CDCl3) δ 178.0, 175.8, 141.9, 141.7,
16

134.1, 133.6, 129.4(2C), 129.3(3C), 129.3, 126.5, 126.4, 126.3, 125.54, 125.49(2C), 124.9(2C),
79.8, 78.4, 44.3, 43.5, 36.3, 35.9, 34.5, 34.4, 19.7, 19.3, 16.9, 16.3; HR-MS calcd for C16H18N3O
[M+H]+ 268.1444, found 268.1467.
9a-p-Tolyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one (1i): White
1
solid; mp 145.0 ºC; Yield 65% (brsm). H NMR (400 MHz, CDCl3) δ 7.68 (1H, s, H-1), 7.14
(2H, d, J = 8.3 Hz, Ar-2’, Ar-6’), 6.91 (1H, s, H-3), 6.74 (2H, d, J = 8.3 Hz, Ar-3’, Ar-5’), 4.09
(1H, ddd, J = 13.2, 7.4, 1.5 Hz, H-5a), 3.00 (1H, m, H-5b), 2.92-2.77 (2H, m, H-4), 2.72-2.59
(4H, m, H-8, H-9), 2.34 (3H, s, -CH3); 13C NMR (125 MHz, CDCl3) δ 173.8, 139.1, 138.8, 133.6,
129.7(2C), 126.3, 125.7, 124.8(2C), 80.4, 35.0, 33.9, 29.8, 21.0, 19.3; HR-MS calcd for
C16H18N3O [M+H]+ 268.1444, found 268.1493.
9a-Cyclopropyl-4,5,9,9a-tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidin-7(8H)-one
(1j):
1
White solid; mp 138.3 ºC; Yield 55% (brsm). H NMR (400 MHz, CDCl3) δ 7.40 (1H, s, H-1),
6.78 (1H, s, H-3), 4.32 (1H, ddd, J = 13.7, 6.8, 2.0 Hz, H-5a), 3.43 (1H, m, H-5b), 2.98-2.84 (2H,
m, H-4), 2.64-2.35 (4H, m, H-8, H-9), 1.37 (1H, m, H-1’), 0.69-0.57`(2H, m, H-2a’, H-3a’), 0.36
(1H, m, H-2a’), 0.10 (1H, m, H-2b’); 13C NMR (125 MHz, CDCl3) δ 173.4, 132.7, 125.7, 125.4,
78.7, 33.7, 31.2, 29.9, 20.9, 20.1, 2.7, 1.2; HR-MS calcd for C12H16N3O [M+H]+ 218.1288, found
218.1317.
Acknowledgments
We acknowledge NCI for in vitro evaluation of the anticancer activity of tested compounds.
17

References
[1] a)
Johns,
S.;
Lamberton,
J.
Chem.
Commun.,
1966,
312,
https://doi.org/10.1039/c1966000312b; b) Johns, S., Lamberton, J. Aust. J. Chem., 1967, 20, 555,
https://doi.org/10.1071/CH9670555.
[2]
a) Braekman, J.C.; Daloze, D.; Pasteeis, J.; Van Hecke, P.; Declercq, J.P.; Sinnwell, V.;
Francke, W. Z. Naturforsch., C, J. Biosci. 1987, 42, 627, https://doi.org/10.1515/znc-1987-0520;
b) Merlin, P.; Braekman, J.C.; Daloze, D.; Pasteels, J.M. J. Chem. Ecol. 1988, 14, 517,
https://doi.org/10.1007/BF01013903; c) Bosque, I.; Gonzalez-Gomez, J.C.; Loza, M.I.; Brea, J. J.
Org. Chem. 2014, 79, 3982, https://doi.org/10.1021/jo500446f; d) Kem, W.R.; Wildeboer, K.;
LeFrancois, S.; Marszalec, W.; Braekman, J.C. Cell. Mol. Neurobiol. 2004, 24, 535,
https://doi.org/10.1023/B:CEMN.0000023628.65936.a7; e) Rouchaud, A.; Braekman, J.C. Eur. J.
Org. Chem. 2009, 2666, https://doi.org/10.1002/ejoc.200900064; f) Blum, M.S. J. Toxicol.
Pharmacol. 1992, 11, 115, https://doi.org/10.3109/15569549209033107.
[3]
a) Plehiers, M.; Heilporn, S.; Ekelmans, D.; Leclercq, S.; Sangermano, M.; Braekman,
J.C.; Daloze, D. Can. J. Chem. 2000, 78, 1030, https://doi.org/10.1139/v00-096; b) Devijver, C.;
Macours, P.; Braekman, J.C.; Daloze, D.; Pasteels, J.M. Tetrahedron 1995, 51, 10913,
https://doi.org/10.1016/0040-4020(95)00667-W; c) Strassnig, I.; Körber, K.; Hünger, U.; Kunz,
H. Synthesis 2015, 47, 2299, https://doi.org/10.1055/s-0034-1380215; d) Stragies, R.; Blechert, S.
J. Am. Chem. Soc. 2000, 122, 9584, https://doi.org/10.1021/ja001688i; e) Kim, J.T.; Butt, J.;
Gevorgyan, V. J. Org. Chem. 2004, 69, 5638, https://doi.org/10.1021/jo049259g; f) Bosque, I.;
González-Gómez, J.C.; Guijarro, A.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77, 10340,
https://doi.org/10.1021/jo302045y; g) Orejarena Pacheco, J.C.; Lipp, A.; Nauth, A.M.; Acke, F.;
18

Dietz, J.P.; Opatz, T. Chem. Eur. J. 2016, 22, 5409, https://doi.org/10.1002/chem.201504845; h)
Davies, S.G.; Fletcher, A.M.; Houlsby, I.T.; Roberts, P.M.; Thomson, J.E. J. Org. Chem. 2017,
82, 6689, https://doi.org/10.1021/acs.joc.7b00837; i) Kim, J.T.; Gevorgyan, V. Org. Lett. 2002, 4,
4697, https://doi.org/10.1021/ol027129t; j) Takahata, H.; Kubota, M.; Ikota, N. J. Org. Chem.
1999, 64, 8594, https://doi.org/10.1021/jo991034w; k) Charette, A.B.; Mathieu, S.; Martel, J.
Org. Lett. 2005, 7, 5401, https://doi.org/10.1021/ol052069n; l) Yue, C.; Gauthier, I.; Royer, J.;
Husson, H.P. J. Org. Chem. 1996, 61, 4949, https://doi.org/10.1021/jo960398a; m) Bisai, A.;
Singh, V.K. Tetrahedron Lett. 2007, 48, 1907, https://doi.org/10.1016/j.tetlet.2007.01.082; n)
Macours, P.; Braekman, J.C.; Daloze, D. Tetrahedron 1995, 51, 1415,
https://doi.org/10.1016/0040-4020(94)01030-4; o) Barluenga, J.; Tomas, M.; Kouznetsov, V.;
Rubio, E. J. Org. Chem. 1994, 59, 3699, https://doi.org/10.1021/jo00092a035; p) Jones, T.H.
Tetrahedron Lett. 1990, 31, 1535, https://doi.org/10.1016/0040-4039(90)80009-B; q) Jones, T.H.
Tetrahedron Lett. 1990, 31, 4543, https://doi.org/10.1016/S0040-4039(00)97670-6; r) Zhu, J.;
Quirion, J.C.; Husson, H.P. Tetrahedron lett. 1989, 30, 5137, https://doi.org/10.1016/S0040-
4039(01)93468-9; s) Merlin, P.; Braekman, J.C.; Daloze, D. Tetrahedron lett. 1988, 29, 1691,
https://doi.org/10.1016/S0040-4039(00)82019-5.
[4]
a) Lee, Y.S.; Kim, S.H.; Jung, S.H.; Lee, S.J.; Park, H. Heterocycles 1994, 37, 303,
https://doi.org/10.3987/COM-93-S2; b) Ioannou, G.I.; Kalaitzakis, D.; Vassilikogiannakis, G.
Eur. J. Org. Chem. 2016, 3304, https://doi.org/10.1002/ejoc.201600524; c) Ioannou, G.I.;
Montagnon, T.; Kalaitzakis, D.; Pergantis, S.A.; Vassilikogiannakis, G. ChemPhotoChem 2018,
2, 860, https://doi.org/10.1002/cptc.201800068.
[5]
a)
Gaich,
T.;
Baran,
P.S.
J.
Org.
Chem.
2010,
75,
4657,
https://doi.org/10.1021/jo1006812; b) Newhouse, T.; Baran, P.S.; Hoffmann, R.W. Chem. Soc.
19

Rev. 2009, 38, 3010, https://doi.org/10.1039/B821200G; c) Galloway, W.R.; Isidro-Llobet, A.;
Spring, D.R. Nat. Commun. 2010, 1, 80, https://doi.org/10.1038/ncomms1081.
[6]
a)
Wu,
P.;
Nielsen,
T.E.;
Chem.
Rev.
2017,
117,
7811,
https://doi.org/10.1021/acs.chemrev.6b00806; b) Lee, Y.S.; Alam M.M.; Keri, R.S.; Chem. Asian
J. 2013, 8, 2906, https://doi.org/10.1002/asia.201300814; c) Martin, S.F. Pure Appl. Chem. 2009,
81, 195, https://doi.org/10.1351/PAC-CON-08-07-03; d) Jo, H.; Hassan, A.H.E.; Jung, S.Y.; Lee,
J.K.; Cho, Y.S.; Min, S.J. Org. Lett. 2018, 20, 1175, https://doi.org/10.1021/acs.orglett.8b00098.
[7]
a) Li, C.J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68, https://doi.org/10.1039/B507207G; b)
Li, C.J. Chem. Rev. 2005, 105, 3095, https://doi.org/10.1021/cr030009u; c) Kobayashi, S. Pure
Appl. Chem. 2013, 85, 1089, https://doi.org/10.1351/PAC-CON-12-10-11; d) Dicks, A.P. Green
Chem. Lett. Rev. 2009, 2, 9, https://doi.org/10.1080/17518250902820182.
[8]
a) Hassan, A.H.E.; Choi, E.; Yoon, Y.M.; Lee, K.W.; Yoo, S.Y.; Cho, M.C.; Yang, J.S.;
Kim, H.I.; Hong, J.Y.; Shin, J.S.; Chung, K.S.; Lee, J.H.; Lee, K.T.; Lee, Y.S. Eur. J. Med.
Chem. 2019, 161, 559, https://doi.org/10.1016/j.ejmech.2018.10.062; b) Elkamhawy, A.; Paik, S.;
Hassan, A.H.E.; Lee, Y.S.; Roh, E.J. Bioorg. Chem. 2017, 75, 393,
https://doi.org/10.1016/j.bioorg.2017.10.009. c) Orellana, E.A.; Kasinski, A.L. Bio Protoc. 2016,
6, https://doi.org/10.21769/BioProtoc.1984.
20

Highlights:
•
•
•
•
Single-step one-pot gateway synthesis of glochidine and its congeners.
Tandem formation of three C-N bonds and annulation of two rings in a single-step
Employs the readily available γ-ketoesters and histamine as starting materials.
For the first time, the unknown biological activity was explored for this rare class of
compounds.

Declaration of Interest Statement
The authors declare no competing financial interest