Stereoselective One-Pot Synthesis of Dihydropyrimido[2,1-a]isoindole-6(2H)-ones

Article abstract of DOI:10.1021/acs.orglett.7b03545

A diastereoselective one-pot synthesis of highly substituted dihydropyrimido[2,1-a]isoindole-6(2H)-ones containing three continuous stereocenters is reported. The reaction sequence is based on a hetero-Diels-Alder reaction between an enimide and a N-acylimine followed by an unprecedented Br?nsted acid mediated rearrangement of an intermediate 5,6-dihydro-4H-1,3-oxazine to a pyrimido[2,1-a]isoindole.

Full text of DOI:10.1021/acs.orglett.7b03545

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective One-Pot Synthesis of
Dihydropyrimido[2,1‑a]isoindole-6(2H)‑ones
Philipp Kramer, Julia Schonfeld, Michael Bolte, and Georg Manolikakes*
̈
Department of Biochemistry, Chemistry and Pharmacy, Goethe-University, Max-von-Laue-Strasse 7, 60438 Frankfurt, Germany
S
* Supporting Information
ABSTRACT: A diastereoselective one-pot synthesis of highly
substituted dihydropyrimido[2,1-a]isoindole-6(2H)-ones con-
taining three continuous stereocenters is reported. The
reaction sequence is based on a hetero-Diels−Alder reaction
between an enimide and a N-acylimine followed by an
unprecedented Brønsted acid mediated rearrangement of an
intermediate 5,6-dihydro-4H-1,3-oxazine to a pyrimido[2,1-
a]isoindole.
Table 1. Development and Optimization of the Formation of
the Dihydropyrimido[2,1-a]isoindole-6(2H)-one 4
itrogen-containing heterocycles are abundant structural
Nmotifs in a myriad of natural products and biologically
active compounds.1 Despite all the great achievements in
heterocyclic chemistry, there remains a great need for further
progress in this area.2 In this context, the development of new
methods for the synthesis of uncommon or to date inaccessible
heterocyclic cores is of particular interest.3
Herein we report a novel one-pot approach for the
preparation of dihydropyrimido[2,1-a]isoindole-6(2H)-ones.
The isoindole motif4 and especially the pyrimidine core5 can
be found in various natural products and pharmaceutical
compounds. On the other hand, dihydropyrimido[2,1-a]-
isoindoles, formally derived by fusion of the aforementioned
heterocycles, are rarely mentioned in the chemical literature.6
In addition, the biological activity of these tricyclic hetero-
aromatics is scarcely studied.7 Therefore, novel methods for the
synthesis of this tricyclic core can provide new opportunities in
heterocyclic as well as medicinal chemistry.
The development of the herein described approach toward
dihydropyrimido[2,1-a]isoindoles started with a serendipitous
discovery during our work on the stereodivergent synthesis of
1,3-diamines.8 Whereas the reaction of enamides9,10 with
acylimine precursors11,12 in the presence of BF3·OEt2 afforded
new N,O-acetals, an analogous addition product of type 5 could
not be observed with phthaloyl enimide 2 (Table 1).8
selectivity
a
entry
L.A.
additive
(3a:3b:4a)
yield (%)
50
1
2
3
4
5
6
7
8
9
BF3·OEt2
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
−
−
−
H2O
24:28:48
85:15:0
40:16:44
7:16:77
0:<5:>95
87:13:0
−
88
80
TFA(aq)
71
TFA(aq) + nBu4NI
89%
b
c
TFA + nBu4NI
92
TFA(aq) + nBu4NI
decomposition
no reaction
84
d
SnCl4
−
−
d
SnCl4
SnCl4
TFA(aq)
+
33:0:67
nBu4NI
10
TFA(aq)
+
0:6:94
76
d
nBu4NI
Instead, three products were obtained in a 1:1:2 ratio and
50% overall yield: the two diasteromeric 5,6-dihydro-4H-1,3-
oxazines 3a and 3b and the dihydropyrimido[2,1-a]isoindole-
6(2H)-one 4a (entry 1). Formation of the two oxazines
products 3a and 3b could be rationalized by a [4 + 2]-
cycloaddition between the enimide and an in situ formed N-
acyl imine.13 Completely unexpected was the tricyclic product
4a. The structures of 4a and 3a could be unambiguously
assigned by single X-ray diffraction. The relative configuration
of 3b was determined by NOE experiments in combination
a
b
Overall isolated yield after column chromatography. In the absence
c
d
of water. Determined by NMR of the crude reaction mixture. With
only 0.25 equiv of the respective reagent. L.A. = Lewis acid; Phth =
Phthaloyl; TFA = Trifluoroacetic acid, Bz = benzoyl.
Since product 4a constitutes a very good example for an
uncommon or inaccessible heterocyclic core, we investigated
this reaction in more detail.
Received: November 15, 2017
14
3
with J-coupling constants.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03545
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Interestingly, the 5,6-dihydro-4H-1,3-oxazines 3a and 3b
could be obtained exclusively in 88% yield and 81:15 dr in the
presence of 2 equiv of SnCl4 as a Lewis acid, followed by a
controlled basic aqueous workup at low temperatures (entry 2).
Addition of water at room temperature or aqueous workup
under acidic conditions led to the formation of varying amounts
of tricycle 4a (entry 3). These results indicate a potential role of
aqueous acid in the formation of 4a. Indeed, the addition of 1
equiv of aqueous trifluoroacetic acid (TFA) after consumption
of the enimide led to an increased yield of the desired product
4a (entry 4). A clean conversion together with an improved
yield of 4a could be achieved through the addition of 1 equiv of
tetrabutylammonium iodide (TBAI) (entry 5).15 The presence
of water is crucial for the formation of the dihydropyrimido-
[2,1-a]isoindole-6(2H)-one 4a. The addition of anhydrous
TFA did not furnish the tricyclic product (entry 6). In the
absence of a Lewis acid, only decomposition of the starting
materials was observed (entry 7). Stoichiometric amounts of
SnCl4, aq. TFA, and TBAI are necessary for an efficient
transformation (entries 8−10).
Scheme 2. Variation of the Acylimine Precursors
As these results indicate a formation of the final dihydro-
pyrimido[2,1-a]isoindole-6(2H)-one through a rearrangement
of the oxazine 3, we elucidated this potential pathway. Indeed,
treatment of 5,6-dihydro-4H-1,3-oxazine 3a with aqueous TFA
furnished the expected product 4a in 95% yield (Scheme 1).
Under the same conditions, the reaction of diastereomer 3b
only led to slow decomposition of the starting material. No
rearrangement of 3b to 4a could be observed.
a
Yields of the isolated products. TFA = Trifluoroacetic acid, Bz =
Scheme 1. Formation of Dihydropyrimido[2,1-a]isoindole-
6(2H)-one 4a via Rearrangement of 3a
benzoyl.
a
Scheme 3. Variation of the Enimide
With the optimized reaction conditions, the scope of this
novel method was explored. First, reactions with different N-
acylimine precursors were investigated (Scheme 2). Aryl- or
heteroaryl aldehyde derived N,O-acetals are suitable substrates,
furnishing the desired dihydropyrimido[2,1-a]isoindole-6(2H)-
one 4b−j in 48−88% and excellent stereoselectivities. The
reaction of an isobutyraldehyde-based precursor gave product
4k in a low yield, albeit with a high degree of
diastereoselectivity. In a similar manner, benzamide-derived
N,O-acetals reacted efficiently and the products 4l−q were
obtained in 48−95% yield and >95:5 dr. Reactions of imine
precursors bearing an alkylamide moiety furnished the expected
products 4r−s in only 31−43% yield, again with a very high dr.
Next, we investigated reactions of various enimides (Scheme
3). N-Propenylphthalimides bearing different substituents on
the phthaloyl part are compatible with the reaction conditions,
and products 4t−w were isolated in 44−91% yield and
excellent diastereoselectivities. Only in the case of the
tetrafluoro derivative 4v a lower yield of 26% was obtained.
a
Yields of the isolated products. TFA = Trifluoroacetic acid, Bz =
benzoyl.
Reaction of aryl-subtituted N-vinylphthalimides furnished
dihydropyrimido[2,1-a]isoindole-6(2H)-one 4y−aa in 64−
70% yield and >95:5 dr. In the case of the unsubstituted N-
vinylphthalimide, product 4x was formed in only 26% yield.
B
DOI: 10.1021/acs.orglett.7b03545
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Unfortunately, only N-vinylphthalimides are suitable substrates
for this transformation. Reaction of the corresponding
succinimide-derived enimide 6 or bisenamide 7 did not lead
to the formation of the desired pyrimidines.
Based on the observed products and reactivities, we assume
the following mechanism (Scheme 4). Reaction of the N,O-
then can undergo various unproductive side reactions, leading
to a slow decomposition of 3b. Although, one could also
envision a mechanism through acyclic intermediates, any
pathway involving an initial ring opening of the oxazine should
proceed through a planar acylimin species (similar to V),
thereby failing to describe both the retention of stereochemistry
at C5 and the preferential rearrangement of 3a.
In summary, we have developed a novel one-pot approach
for the synthesis of dihydropyrimido[2,1-a]isoindole-6(2H)-
ones. This two-step reaction sequence consists of a polar [4 +
2] cycloaddition between an enimide and a N-acylimine and a
subsequent, to date unprecedented, acid-mediated rearrange-
ment of the oxazine intermediate. This method enables an
efficient and highly stereoselective construction of an
uncommon heterocyclic motif and can open new opportunities
in heterocyclic or medicinal chemistry.
a
Scheme 4. Proposed Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03545.
Syntheses, NMR spectra, and X-ray crystal structures
(PDF)
Accession Codes
CCDC 1579081−1579084 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
AUTHOR INFORMATION
Phth = Phthaloyl.
■
Corresponding Author
*E-mail: g.manolikakes@chemie.uni-frankfurt.de.
ORCID
acetal with the Lewis acids leads to the formation of an N-
acylimine. Reaction of the acylimine with the enimide delivers
the two diastereomeric 5,6-dihydro-4H-1,3-oxazines 3a and 3b.
The highly stereoselective formation of diastereomer 3a can be
rationalized by a concerted [4 + 2] cycloaddition between the
acylimine as a heterodiene and the enimide as a dienophile
proceeding through an endo transition state. The partial loss of
stereospecificity implies a bond rotation in an at least partially
stepwise process, as it has been observed for polar cyclo-
additions with acyliminium species.16 On the other hand, an
epimerization after the cycloaddition could also lead to the
formation of 3b. However, we could not detect any
epimerization of 3a under the reaction conditions. Upon
addition of a Brønsted acid, protonation of the basic oxazine
nitrogen should occur.17 Subsequent addition of water to the
activated CN bond leads to the formation of intermediate I.
Intramolecular attack of the oxazine nitrogen to a carbonyl
functionality of the imide generates the bicycle II. Upon
protonation of the newly formed OH group, a fragmentation of
III affords the final product (4a). In the case of oxazine 3a the
addition of water leads to a favorable all-equatorial
conformation in combination with the OH group in an axial
position (anomeric effect). On the other hand, the addition of
water to oxazine 3b would generate an unfavorable
conformation IV with the bulky phthaloyl group in an axial
position. We assume that, in this case, a ring opening of the
oxazine to an acyliminium ion V occurs. This reactive species
Georg Manolikakes: 0000-0002-4013-5757
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank the Polytechnische Gesellschaft
(Fellowship to P.K.) and the Fonds der Chemischen Industrie
(Liebig-Fellowship to G.M.) for financial support, Albemarle
(Frankfurt) for the generous donation of chemicals, and Prof.
Michael Gobel (Goethe-University Frankfurt) for his support.
̈
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