An Aliphatic Bischler-Napieralski Reaction: Dihydropyridones by Cyclocarbonylation of 3-Allylimidazolidin-4-ones

Article abstract of DOI:10.1021/acs.orglett.9b04250

The N-chloroformylimidazolidinone derivative of enantiopure l-alanine was deprotonated to form an enolate and functionalized with a series of allylic halides. Treatment of the resulting carbamoyl chlorides with potassium iodide led to cyclization of the allylic substituent onto the carbonyl group in an intramolecular aliphatic Friedel-Crafts-type acylation that corresponds to an aliphatic Bischler-Napieralski reaction. The product 3,4-dihydropyridinones were amenable to further functionalization, and finally hydrolysis, to deliver a series of enantio-enriched pipecolic acid derivatives.

Full text of DOI:10.1021/acs.orglett.9b04250

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
An Aliphatic Bischler−Napieralski Reaction: Dihydropyridones by
Cyclocarbonylation of 3‑Allylimidazolidin-4-ones
Mostafa M. Amer, Olatz Olaizola, Jennifer Carter, Hossay Abas, and Jonathan Clayden*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
ABSTRACT: The N-chloroformylimidazolidinone derivative of enantiopure L-alanine was deprotonated to form an enolate
and functionalized with a series of allylic halides. Treatment of the resulting carbamoyl chlorides with potassium iodide led to
cyclization of the allylic substituent onto the carbonyl group in an intramolecular aliphatic Friedel−Crafts-type acylation that
corresponds to an aliphatic Bischler−Napieralski reaction. The product 3,4-dihydropyridinones were amenable to further
functionalization, and finally hydrolysis, to deliver a series of enantio-enriched pipecolic acid derivatives.
Scheme 1. Dihydroisoquinolones by Cyclization of Amino
Acid-Derived N-Chloroformylimidazolidones
he dihydropyridin-2-one scaffold and its derivatives are
Tfound embedded in many naturally occurring alkaloids and
constitutes the core of many other biologically relevant
compounds. Examples include the small molecule direct
thrombin inhibitor argatroban, which acts as an anticoagulant.1,2
Dutasteride is a 5α-reductase inhibitor, approved for the
treatment of enlarged prostate.3,4 Setrobuvir is an experimental
drug candidate (Phase II) that is used alongside interferon for
the treatment of hepatitis C patients.5 Piperlongumine belongs
to the Piperaceae family of natural products, which are widely
known for their anticancer properties (see Figure 1).6,7
Recently reported connective syntheses of the dihydropyr-
idinone ring system have involved intramolecular attack of
enamines on Michael acceptors8 or epoxides,9 cycloadditions of
imines,10 and carbamoylation of alkenes.11 We recently reported
a synthesis of the benzo-fused analogues of 3,4-dihydropyridin-
2-onesnamely, 3,4-dihydroisoquinolinonesby an unusual
version of the Bischler−Napieralski cyclization entailing the
intramolecular KI-promoted Friedel−Crafts acylation of N-
chloroformylimidazolidinones (see Scheme 1).12 The starting
materials for these reactions, imidazolidinone-derived carba-
moyl chlorides carrying a 3-benzyl substituent, were formed
diastereoselectively either directly from aromatic amino acids
(for example, L-Phe)12 or by stereoselective benzylation13 of the
stable enolates14 of their N-chloroformyl substituted precur-
sors.15
We now show that 3,4-dihydropyridin-2-ones may likewise be
formed by an intramolecular Friedel−Crafts reaction, from
imidazolidinones bearing 3-allyl substituents. This aliphatic
version11 of the Bischler−Napieralski reaction16,17 forms
Received: November 26, 2019
Figure 1. Bioactive 4,5-dihydropyridin-2-one derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04250
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Scheme 2. Diastereoselective Allylation
Figure 2. X-ray crystal structures of (a) 3a, (b) 4a, and (c) E-7i.
Scheme 3. Scope of the Cyclocarbonylation*
Table 1. Optimization of the Cyclocarbonylation
Isolated Yield (%)
crude ratio,
c
e
entry
base (equiv)
2,6-Lutidine (1.1)
[AlCl3]
DBU (1.1)
DBU (3.0)
2,6-Lutidine (1.1) then
DBU (5)
2,6-Lutidine (1.1) then
DBU (5)
2,6-Lutidine (1.1) then
DBU (3)
3a:4a
3a
4a
1
2
3
4
41:59
−
63:37
77:23
85:15
39
46
34
19
43
50
22
21
19
d
a
5
−
b
6
85:15
39
−
*
The following footnotes were applied for this scheme: aYield isolated
b
after step a, and combined isolated yield from step a and step b.
c
f
g
f
7
−
45 + 43
50
a
b
Treated with DBU (2 h, 150 °C) before workup. Treated with
c
DBU (2 h, 150 °C) after workup. Products separated and isolated;
The work started with the enantiopure N-chloroformylimi-
dazolidinone derivative 1a, formed as a single trans diaster-
eoisomer12 from L-Ala. The potassium enolate of this hetero-
cycle, formed by treatment with KHMDS, is stable enough to be
trapped with allylic electrophiles at −78 °C.14 Better yields were
obtained by shortening the interval between the addition of the
base and the electrophile (see the SI for optimization table), and
the optimal conditions involved treating N-chloroformylimida-
zolidinone 1a with KHMDS (1.2 equiv) and stirring for 2 min
d
4a then treated with DBU (2 h, 150 °C). No base used; AlCl3 in
e
f
CH2Cl2 used instead of KI. Yield of 5. Yield formed in initial
g
cyclization. Further material isolated after isomerization from 4a.
versatile products that may be used as precursors to function-
alized saturated or unsaturated pipecolic acid derivatives bearing
a quaternary center α to nitrogen (see Scheme 1).
B
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Scheme 4. Cyclization of Terminally Substituted Allyl
Substituents
Scheme 6. Hydrolysis to Give Pipecolic Acid Derivatives
R1 or R2 ≠ H). Using these optimized reaction conditions, we
synthesized a range of enantiopure N-chloroformylimidazolidi-
nones 2a−2k carrying a variety of differently substituted allyl
substituents (Scheme 2) in good to excellent yields. As observed
previously, the addition of the electrophile was fully
diastereoselective (none of the cis-allylated diastereomer was
observed by 1H NMR), with NOE confirming that the
electrophile approaches anti to the bulky tert-butyl group.
Intramolecular electrophilic attack of the N-chloroformyl
group onto the alkene was induced by treatment with KI, which
we assume generates a transient acyl iodide intermediate.18
Using 3-allyl N-chloroformylimidazolidinone 2a as a model
substrate (Table 1), we found that cyclization was complete after
2 h in the presence of 1.1 equiv 2,6-lutidine (Table 1, entry 1)
but gave a mixture of alkene regioisomers: the conjugated
product 3a and unconjugated product 4a formed in a 41:59
ratio. The products were separated by flash chromatography,
and their structures confirmed by X-ray crystallography (Figure
2). Alternative activation of the chloroformyl group by
complexation to AlCl3 gave a single diastereoisomer of the
chlorinated product 5 in significant amounts (Table 1, entry 2).
Looking to improve the isolated yield of the more useful
conjugated product 3a, we explored the reaction in the presence
of alternative bases. Donohoe et al. reported the use of DBU to
isomerize an unconjugated double bond into conjugation in a
related heterocycle.19 Using DBU in place of 2,6-lutidine (Table
1, entries 3 and 4) improved the proportion of 3a in the crude
material to 63%−77%, but isolated yields were moderate. More
satisfactory was a stepwise protocol (Table 1, entry 5) in which
the starting material was treated with KI and 2,6-lutidine to
induce cyclization, followed by DBU to effect isomerization to
3a, either with or without workup between the steps (Table 1,
entries 6, 7). This procedure gave solely 3a, but still in relatively
poor yield. The optimal procedure turned out to be the
separation of 4a from 3a, followed by isomerization of the
isolated 4a to 3a in a separate step, which gave an overall
combined yield of 88% 3a (Table 1, entry 7).
Scheme 5. Functionalization of the Dihydropyridinone
Scaffold*
*
a
The following footnotes were applied for this scheme: Condition
(a), and bCondition (b). In addition, 18% dithioester formed (see the
Supporting Information).
The scope of the intramolecular aliphatic Friedel−Crafts
acylation, which amounts to an aliphatic equivalent of the
Bischler−Napieralski cyclization, was explored by cyclization of
imidazolidinones 2b−2h. These substrates, bearing 2-substi-
tuted allyl groups, cyclized to give chromatographically
separable mixtures of regioisomers 3 and 4 in ratios comparable
to those seen with 2a. As noted previously, treatment with DBU
before adding the electrophile, which was left to react for 2 h at
−78 °C.
The enolate reacted successfully with allyl bromides bearing a
variety of functional groups and substitution patterns (i.e., where
C
DOI: 10.1021/acs.orglett.9b04250
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returned good yields of the conjugated products 3b−3g (see
Scheme 3). Imidazolidinone 2h, with a 2-methallyl substituent,
gave (in addition to 3h and 4h) a third regioisomer 6h
containing an exocyclic double bond.
Substrates in which the allyl group was substituted at the
terminal position also gave a more diverse range of outcomes
(Scheme 4). Cinnamyl-substituted 2i (Scheme 4a), underwent
cyclization to form a five-membered ring, presumably as a result
of the more stable benzylic cation that forms. Two alkene
stereoisomers E- and Z-7i were formed, their geometry being
assigned from the X-ray crystal structure of the E isomer (see
Figure 2c).
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.clayden@bristol.ac.uk.
ORCID
Jonathan Clayden: 0000-0001-5080-9535
Notes
The authors declare no competing financial interest.
The crotyl substituent of 2j gave, under the same conditions,
both 6-membered (3j) and 5-membered cyclized products
(Scheme 4b), with the 5-membered products being generated as
a mixture of double bond isomers 7j and 8j.
Attempts were made to bias this cyclization toward the six-
membered ring 3 by incorporation of a silyl directing group in
precursor 2k. Six-ring selectivity improved as a result, with 3a
becoming the major product, but surprisingly 5-ring 7k was still
formed in significant amounts (see Scheme 4c).
ACKNOWLEDGMENTS
■
This work was supported by the Presidential Leadership
Programme of Egypt, the European Research Council (AdG
ROCOCO), and the EPSRC.
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ASSOCIATED CONTENT
■
S
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04250.
Full experimental details and spectroscopic character-
ization of all new compounds in this research (PDF)
Accession Codes
CCDC 1967823−1967826 contain the supplementary crystallo-
graphic 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 Cam-
D
DOI: 10.1021/acs.orglett.9b04250
Org. Lett. XXXX, XXX, XXX−XXX