Two-Step Synthesis of 3,4-Dihydropyrrolopyrazinones from Ketones and Piperazin-2-ones

Article abstract of DOI:10.1021/acs.orglett.8b00197

An expedient two-step synthesis of 3,4-dihydropyrrolopyrazinones has been achieved via a Vilsmeier-Haack reaction of ketones, followed by an annulation of the corresponding chloroaldehydes with commercially available piperazin-2-ones. A variety of cyclic and acyclic ketones and piperazin-2-ones participated in this two-step chemistry, affording the desired 3,4-dihydropyrrolopyrazinones in up to 78% yield.

Full text of DOI:10.1021/acs.orglett.8b00197

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Two-Step Synthesis of 3,4-Dihydropyrrolopyrazinones from Ketones
and Piperazin-2-ones
Cosme Sandoval, Ngiap-Kie Lim, and Haiming Zhang*
Department of Small Molecule Process Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United
States
S
* Supporting Information
ABSTRACT: An expedient two-step synthesis of 3,4-
dihydropyrrolopyrazinones has been achieved via a Vilsme-
ier−Haack reaction of ketones, followed by an annulation of
the corresponding chloroaldehydes with commercially avail-
able piperazin-2-ones. A variety of cyclic and acyclic ketones
and piperazin-2-ones participated in this two-step chemistry,
affording the desired 3,4-dihydropyrrolopyrazinones in up to
78% yield.
Scheme 1. Synthetic Approaches to 3,4-
Dihydropyrrolopyrazinones
3,4-Dihydropyrrolopyrazinones are unique structural motifs
found in numerous biologically active natural products and
medicinally relevant compounds and thus have received much
attention in the organic and medicinal communities.1−7 For
example, highly complex natural alkaloids such as immunosup-
pressive palau’amine,2 antimetastatic agelastatin A−F,3 cyclo-
oroidin,4 phakellin,5 and anti-HIV investigational compound
MK-20486 and aldose reductase inhibitor ranirestat7 all possess a
3,4-dihydropyrrolopyrazinone heterocyclic core (Figure 1).
Figure 1. Selected biologically active compounds containing a 3,4-
dihydropyrrolopyrazinone core.
(Scheme 1, C). A Beckmann rearrangement12 approach also
affords substituted 3,4-dihydropyrrolopyrazinones, but the
synthesis of the starting material 2,3-dihydropyrrolizin-1-one is
tedious and the scope of this approach is very limited (Scheme 1,
D).11 Moreover, all of these strategies are initiated with pyrrole
derivatives, and the substitution on the pyrrole ring has not been
adequately explored. Therefore, the development of a more
direct and efficient synthesis of substituted 3,4-dihydropyrrolo-
pyrazinones with functionalization at both the pyrrole and
piperazinone moieties is highly desirable.
Despite the biological and medicinal interests in 3,4-
dihydropyrrolopyrazinones, there are surprisingly few synthetic
approaches reported in the literature.4e,8−11 The conventional
syntheses involve the functionalization of pyrrole-2-carboxylates,
followed by further functional group manipulation to construct
the piperazinone ring (Scheme 1, A and B).8,9 Unfortunately,
these methods often suffer from multiple-step operations in low
yields and/or the use of the toxic reagent haloacetonitrile. Trost
has reported an elegant palladium-catalyzed transformation of
vinyl aziridines with pyrrole-2-carboxylates to access enantioen-
riched vinyl-functionalized 3,4-dihydropyrrolopyrazinones4e,10
Received: January 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
To support an internal drug research and development
program in our laboratories, we were tasked to develop an
efficient synthesis of a variety of 3,4-dihydropyrrolopyrazinones
for structure−activity relationship studies and further process
development. We decided to focus on a synthetic strategy
involving an annulation reaction of Vilsmeier−Haack13 products
2 (from ketones 1) and piperazin-2-ones 3. Herein, we report a
facile two-step synthesis of 3,4-dihydropyrrolopyrazinones via a
Vilsmeier−Haack reaction of ketones, followed by an annulation
of the chloroaldehyde products with commercially available
piperazin-2-ones (Scheme 1, E).
Table 2. Scope of Piperazin-2-ones (3)
We initiated our studies by examining the Vilsmeier−Haack
reaction of 3,3-dimethylcyclopentan-1-one (1a) to produce 2-
chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde (2a) and
the annulation reaction of chloroaldehyde 2a with commercially
available piperazin-2-one (3a) to form tricyclic dihydropyrrolo-
pyrazinone 4a (Table 1). The Vilsmeier−Haack reaction could
a
Table 1. Optimization of 4a Formation
b
entry
variation from the “standard conditions”
assay yield (%)
c
1
2
3
4
5
6
7
8
9
none
69 (61)
80 °C instead of 115 °C
i-Pr2NEt as base
DBU as base
56
67
14
52
7
2,6-lutidine as base
K2CO3 as base
DMA as solvent
NMP as solvent
PhMe as solvent
a
Reaction conditions: 1a (1.50 mmol, 168 mg), POCl3 (3.15 mmol,
483 mg), DMF (3.75 mmol, 275 mg), DCM (3.0 mL), 40 °C, 18 h; 3
(1.00 mmol), NMM (1.50 mmol, 152 mg), DMF (2.0 mL), 115 °C, 5
47
19
59
b
h. Isolated yield.
a
Reaction conditions: 1a (0.75 mmol, 84.0 mg), POCl3 (1.58 mmol,
ones 3b−f substituted with alkyl, benzyl, and aryl groups at the 1-
position readily participated in the annulation reactions,
generating the desired tricyclic dihydropyrrolopyrazinone
products 4b−f in moderate to good yields (Table 2, entries 1−
5). Furthermore, 6-methylpiperazin-2-one 3g and bicyclic 4,7-
diazaspiro[2.5]octan-5-one 3h afforded the target products 4g
and 4h smoothly in 62 and 52% yield, respectively (Table 2,
entries 6 and 7). Finally, 1,5-dimethylpiperazin-2-one produced
the desired tricyclic product 4i in 40% yield (Table 2, entries 8).
The relatively low yield of this reaction was presumably caused
by the increased steric hindrance introduced by the 5-methyl
substituent.
We also investigated the scope of the ketones in the
Vilsmeier−Haack/annulation chemistry by employing piper-
azin-2-one (3a) as the reaction partner (Table 3). Cyclo-
pentanone (1b) underwent the two-step protocol and generated
the desired product 5b in 60% yield (Table 3, entry 1). 2-
Methylcyclopentanone (1c) only gave 39% yield of product 5c
(Table 3, entry 2). The lower yield was presumably caused by the
steric effect introduced by the 2-methyl group. Interestingly,
cyclohexanone (1d), cyclopentanone (1e), and cyclooctanone
(1f) produced the desired tricyclic products 5d−f, albeit in only
30−44% yields, and 29−40% yields of the isomeric dihydro-
pyrrolopyrazinone products 5d′−f′ (Table 3, entries 3−5, and
Figure 2). Acyclic ketone 3-pentanone (1g) similarly formed a
mixture of two isomers 5g and 5g′ in 20 and 34% yields,
242 mg), DMF (1.88 mmol, 138 mg), DCM (1.5 mL), 40 °C, 18 h; 3a
(0.50 mmol, 50.0 mg), base (0.75 mmol), DMF (1.0 mL), 115 °C, 5 h.
b
c
Assay yields were obtained by quantitative HPLC analysis. Isolated
yield.
be readily achieved in full conversion employing 2.1 equiv of
POCl3 and 2.5 equiv of DMF in DCM at 40 °C. It is worth noting
that product 2a is not stable on silica gel column or upon storage
and, therefore, was directly used in the subsequent annulation
after aqueous workup. Under the best annulation conditions
described in Table 1, the reaction afforded 69% HPLC assay yield
and 61% isolated yield by employing 0.5 mmol of 3a, 1.5 equiv of
2a, and 1.5 equiv of N-methylmorpholine (NMM) as the base in
DMF at 115 °C for 5 h (Table 1, entry 1). Performing the
reaction at a lower temperature of 80 °C generated slightly lower
56% assay yield (Table 1, entry 2). The reaction using i-Pr2NEt as
the base afforded a similar assay yield of 67% (Table 1, entry 3),
whereas other bases such as DBU, 2,6-lutidine, and K2CO3 all
resulted in inferior assay yields (Table 1, entries 4−6). A test of
solvents such as DMA, NMP, and toluene did not afford any
advantage over the solvent of choice, DMF (Table 1, entries 7−
9).
With a set of optimized conditions in hand, we next examined
the scope and limitations of this two-step approach by employing
3,3-dimethylcyclopentan-1-one (1a) and various substituted
piperazin-2-ones 3 (Table 2). As shown in Table 2, piperazin-2-
B
DOI: 10.1021/acs.orglett.8b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
chemistry, they were nevertheless very difficult to prepare by any
other means.
Table 3. Scope of Ketones
We propose a mechanism for this annulation process
exemplified by the reaction of 2-chlorocyclohex-1-ene-1-
carbaldehyde (2d) and piperazin-2-one (3a) (Scheme 2). We
Scheme 2. Proposed Mechanism
believe that chloroaldehyde 2d can undergo either a 1,4-addition
or 1,2-addition pathway when reacting with piperazin-2-one
(3a). A 1,4-aza-Michael addition14 would lead to an amination
intermediate 7d that readily transforms to an intramolecular
aldol product 8d in the presence of base NMM. Intermediate 8d
then loses water and aromatizes to afford the desired tricyclic
lactam 5d. On the other hand, a 1,2-addition of piperazin-2-one
(3a) to chloroaldehyde 2d leads to the formation of an iminium
species 7d′. Intermediate 7d′ then undergoes an intramolecular
cyclization followed by loss of HCl in the presence of base NMM
to generate the isomeric tricyclic lactam 5d′.
a
Reaction conditions: 1 (1.50 mmol), POCl3 (3.15 mmol, 483 mg),
DMF (3.75 mmol, 275 mg), DCM (3.0 mL), 40 °C, 18 h; 3a (1.0
mmol, 100 mg), NMM (1.50 mmol, 152 mg), DMF (2.0 mL), 115 °C,
b
It is not entirely clear why certain substrates, for example,
cyclopentanones 1a−c, only produced a single isomer arising
from the 1,4-addition pathway while other ketones such as 1d−f
afforded a mixture of isomers. One plausible explanation, taking
cyclopentanone (1b), for example, is that 1,4-addition of
piperazin-2-one (3a) to the Vilsmeier−Haack product 2b
releases the ring strain of the cyclopentene core of 2b more
than that of the cyclohexene, cycloheptene, or cyclooctene core
of 2d−f, thus rendering a more facile and predominant 1,4-
addition. The primary formation of isomer 5h′ from
propiophenone (1h) is presumably attributed to the steric effect
introduced by the phenyl group that disfavors the 1,4-addition. In
the case of 1-tetralone (1i), the steric element on the phenyl ring
possibly slows down the 1,4-addition reaction, resulting in the
formation of the 1,2-addition product 5i′ as the minor product,
whereas 2-tetralone (1j), without any steric interference of the
phenyl ring, only afforded 1,4-addition product 5j in 50% yield.
In conclusion, we have developed an expedient two-step
synthesis of 3,4-dihydropyrrolopyrazinones via a Vilsmeier−
Haack reaction of ketones, followed by an annulation of the
resulting products with commercially available piperazin-2-ones.
A variety of cyclic and acyclic ketones and piperazin-2-ones
participated in this two-step chemistry, affording the desired 3,4-
dihydropyrrolopyrazinones in moderate to good yields. We
anticipate that this practical method will provide rapid access to
5 h. Isolated yield. The number in parentheses is the yield of the
undesired isomer.
Figure 2. Undesired isomeric 3,4-dihydropyrrolopyrazinones.
respectively (Table 3, entry 6, and Figure 2), whereas
propiophenone (1h) only afforded predominantly a single
isomer 5h′ in 71% yield (Table 3, entry 7, and Figure 2). 1-
Tetralone (1i) produced a mixture of isomers 5i and 5i′ in 61 and
16% yields, favoring the desired product 5i (Table 3, entry 8, and
Figure 2). Interestingly, only the desired isomer 5j was isolated in
50% yield when 2-tetralone (1j) was employed in this two-step
reaction (Table 3, entry 9). The structures of the isomers were
confirmed by NOESY spectra (see Supporting Information). It is
worth noting that, although the isomeric products 5d′−i′, which
still possess medicinally relevant dihydropyrrolopyrazinone
functional core, were isolated as undesired products in this
C
DOI: 10.1021/acs.orglett.8b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00197.
General experimental procedures, characterization of new
1
compounds, and copies of H NMR, 13C NMR, and
NOESY spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhang.haiming@gene.com.
ORCID
Haiming Zhang: 0000-0002-2139-2598
Notes
(9) (a) Shiokawa, Z.; Kashiwabara, E.; Yoshidome, D.; Fukase, K.;
Inuki, S.; Fujimoto, Y. ChemMedChem 2016, 11, 2682. (b) Shiokawa, Z.;
Inuki, S.; Fukase, K.; Fujimoto, Y. Synlett 2016, 27, 616.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank Drs. Chong Han, Qingping Tian, Sushant
Malhotra (Genentech, Inc.), and Prof. Scott Denmark
(University of Illinois, UrbanaChampaign) for helpful
discussions, Dr. Kenji Kurita (Genentech, Inc.) for collecting
HRMS data, and Dr. Francis Gosselin (Genentech, Inc.) for
proof-reading the manuscript. C.S. was an undergraduate
(University of California, Santa Cruz) summer intern at
Genentech, Inc.
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D
DOI: 10.1021/acs.orglett.8b00197
Org. Lett. XXXX, XXX, XXX−XXX