Cu-Catalyzed iminative hydroolefination of unactivated alkynes en route to 4-imino-tetrahydropyridines and 4-aminopyridines

Article abstract of DOI:10.1039/C6CC08081B

A general method for synthesizing 4-imino tetrahydropyridine derivatives is achieved, from readily available β-enaminones and sulfonyl azides, which comprises a sequential copper catalyzed ketenimine formation and its hitherto inaccessible intramolecular hydrovinylation. The products are shown as ready precursors for highly valuable 4-sulfonamidopyridine derivatives via DDQ mediated oxidation.

Full text of DOI:10.1039/C6CC08081B

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DOI: 10.1039/C6CC08081B
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Cu-Catalyzed Iminative Hydroolefination of Unactivated Alkynes
En route to 4-Imino-Tetrahydropyridines and 4-Aminopyridines
Received 00th January 20xx,
Accepted 00th January 20xx
Ravi Kumar,a,b Shridhar H. Thoratc and Maddi Sridhar Reddy*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general method for 4-imino tetrahydropyridine derivatives is
achieved, from readily available β-enaminones and sulfonyl
azides, which comprises a sequential copper catalyzed ketenimine
formation and its hither to inaccessible intramolecular
hydrovinylation. The products are shown as ready precursors for
highly valuable 4-sulfonamidopyridine derivatives via DDQ
mediated oxidation.
Nitrogen embedded heterocycles occupy a huge space in the
realm of natural products as well as drug discovery.
Particularly, six membered cycles like pyridine and its
saturated (dihydro-, tetrahydro- and hexahydro-) derivatives
are ubiquitous in nature and show enormous pharmaceutical
properties.1 For instance, nifedipine (antihypertensive),
amlodipine (calcium ion channel blocker), clarinex
(antihistamine), multiflorine (hyperglycemic), arecoline
(stimulant), vulgaxanthin (antioxidant), eszopiclone (hypnotic),
imatinib (kinase inhibitor), ocinaplon (an anxiolytic), nicotine
Scheme 1 Aminopyridines from propargyl enaminones
same substrates via ketenimine formation followed by
cyclization and oxidation. Prior to the oxidation, the key
iminative
cyclization
affords
highly
functionalized
tetrahydropyridines. Although a series of transformations from
in situ formed ketenimines from acetylenes have been
reported5 since its inception in 2006 by Chang et al,6 only a few
examples in the literature revealed the use of carbon as
nucleophile to attack on electrophilic central carbon of
ketenimine which constitutes a C-C bond formation between
rare centers, i.e. terminal carbon of acetylene and a given
nucleophilic carbon.
(stimulant),
etoricoxib
(COX-2
inhibitor),
rosiglitazone (antidiabetic), omeprazole (proton pump
inhibitor), niacin (vitamin B3), etc. are some of the prominent
pyridine or hydropyridine containing pharmaceuticals.
Consequently, organic chemists paid significant attention
towards the synthesis of pyridine and its derivatives in an
efficient and step economical pathways.1-3 Alkyne based
substrates were also identified as versatile precursors for the
synthesis of these privileged scaffolds.3 In this line, Cheng et al
reported an elegant method for the synthesis of 2-
aminopyridines from N-propargyl-β-enaminones (Scheme 1).3a
As part of our ongoing program of unveiling the novel
reactivities of functionalized alkynes,4 we herein report a
strategy for 4-aminocounterparts of aforementioned from the
On this line, Glasnov et al and Cui et al reported an elegant
5g-h
cyclization of N-propargyl anilines (
1 to 2 and 3 to 4)
containing activated acetylinic group (conjugation was
essential) as shown in Scheme 2 (A & B). Surprisingly, no
unactivated system like
5 (a close congener of 1 & 3) was
explored, perhaps it was found to be unreactive due to weaker
electrophilicity of the resultant ketenimine. Endorsing this fact,
an attempt by us to convert
5 to 6 was totally failed (Scheme
2C). Infact, in any type of N-sulfonylketenimine chemistry from
acetylenes, propargyl amines were hardly explored. Talukdar
et al used N-propargyl 3o-amines for ketenimine formation
a.Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-
10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
b.Academy of Scientific and Innovative Research, New Delhi 110001, India.
c. Centre for Materials Characterization, CSIR-NCL, Dr Homi Bhabha Road, Pune-
411008, India.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
which underwent
a rare amine group migration (for
amidines),5n where notably secondary amines were not tested
again for unknown reason.
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Journal Name
(entry 1). No reaction occurred and the starting VmiewatAertricialelOwnlianse
recovered as such. When the solvent wDasOIs:w10i.t1c0h3e9/dC6toCCC0H802C81l2B,
the desired product was obtained in 15% yield (entry 2). Other
inorganic bases (entries 3-5) did not improve the reaction.
Pleasingly, the use of organic base DIPEA led to improving the
yield to 42% (entry 6). Further screening of organic bases
(entries 7-9) revealed that TEA was the best choice which
afforded the product in 89% yield (entry 9). The other solvents
like MeCN, Et2O, toluene and DCE were found to be
inappropriate for the reaction (entries 10-13). Other copper
catalysts like Cu(OTf), CuBr and CuCl were not as effective as
CuI. With these observations, we decided to move on with CuI
as catalyst and TEA as base in CH2Cl2.
With the optimized conditions in hand (Table 1, entry 9), we
next investigated the scope and limitations of the Cu-catalyzed
iminative ring closure of N-propargyl β-enaminones. The scope
with respect to the substitution at β-carbon (pro C1) was
initially investigated. Like 7a, substrates bearing β-phenyl ring
with pendant methyl, t-Bu and phenyl groups (7b-d) smoothly
delivered the products 8ba-da in excellent yields (84-87%).
Halo groups like F and Cl were unaffected during the
conversion of 7e-f to 8ea-fa but caused a slight erosion of
yields (68-72%). Electron rich methoxy phenyl substrate 7g
smoothly afforded the desired product 8ga in 81% yield. Next,
Scheme 2 Iminative cyclization of acetylenes
In light of this, our discovery of conversion of
7 to 8 has, apart
from the first use of this chemistry for the synthesis of
valuable tetrahydropyridines and pyridines with high new
functional decoration, the following highlights: (1) an
unprecedented intramolecular hydrovinylization (note:
hydroarylations5g-k are known) of ketenimines, (2) involvement
of unactivated ketenimines i.e. use of non-conjugated
propargyl amines and (3) use of unprotected secondary
amines.
Table 2 Scope of enaminones.a
We began our studies with the optimization of the
conversion of 7a7 to 8aa (Table 1). Initially, we treated 7a with
1.2 equivalents of TsN3 in presence of 10 mol% of CuI in MeCN
Table 1 Optimization of reaction conditions.a
β-alkyl substituted substrates were tested. Thus, 2-n-butyl and -n-
hexyl adducts 8ha-ia were successfully obtained but in somewhat
lower yields (65-70%). In a little contrast, 2-cycloalkyl (cyclopropyl,
cyclopentyl and cyclohexyl) adducts 8ja-la were obtained in better
yields (81-85%) compared to their non-cyclic counterparts. Finally
7m with allylic benzoxy group was also smoothly transformed to the
corresponding product 8ma in excellent yield of 90%.
2 | J. Name., 2012, 00, 1-3
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Next, the generality of the method against the variation of Impact of aliphatic substitution was then verified. ThVuise,wnA-rthicelexOyln,linne-
DOI: 10.1039/C6CC08081B
substitution at C1 (keto terminal) of enaminones was investigated. propyl, isopropyl and isobutyl groups on ketone terminal (7t-w)
p-Isopropylphenyl substrate 7n reacted as smoothly as 7a to afford were undisturbed and the products (8ta-wa) were obtained in 75-
8na in 79% yield. Methylenedioxy substituted electron rich
82% yields. Benzylic enaminone 7x was next subjected to the title
cyclization to obtain the desired adduct 8xa in 71% yield.
Table 3 Extended scope of enaminones.a
We next moved to verify the scope of sulfonyl azides in the
reaction. Thus, various sulfonyl azides were treated with 7a and the
results are summarized in Table 4. Similar to TsN3, benzene sulfonyl
azide also reacted smoothly under the standard conditions to afford
the desired product 8ab in 87% yield. Chloro and fluoro substitution
(8ac-ad) did not affect the yield (81-85%) whereas presence of
trifluoromethyl group slightly reduced the yield to 71%. Electron
poor nitrophenyl- and electron rich thiophenyl sulfonyl azides were
converted to the desired adducts (8af-ag) without any difficulty (72-
79%). Finally methylsulfonyl azide as an aliphatic variant was
identified as an equally good substrate for this iminative cyclization
to afford 8ah in 82% yield.
We next turned to aromatization of the above saturated adducts to
privileged aminopyridine derivatives (Table 5). Treatment of the
purified 8aa with 2.2 equivalents of DDQ in CH2Cl2 cleanly produced
the corresponding 3-acyl-4-aminopyridine derivative 9a in 94%. To
avoid a purification step, we conducted the dehydrogenation on the
unpurified crude material 8aa after the work up of the iminative
cyclization step. Pleasingly, the product was obtained in 81% overall
yield in 2 steps. Similarly, alkyl phenyl substituted adducts (9b-c)
were obtained in excellent overall yields. Aminopyridine derivative
with alkyl (n-propyl) chain on ketone terminal (9d) was obtained
with equal ease. Similar to tosyl derivatives, trifluoromethylphenyl-
(9e) and methyl sulfonyl amino pyridines (9f) were synthesized in as
high as 76% overall yields.
substrate 7o and nitro bearing electron poor starting material 7p
both gave the products (8oa-pa) in satisfactory yields (72-77%).
Similarly, naphthyl substituted adduct 8qa was obtained in 69%.
Further, heteroaryl ketones (7r-s) were also transformed to the
corresponding products smoothly under standard conditions.
Table 5 Aromatization of 1 to 4-aminopyridines 9.a
Table 4 Scope of sulfonyl azides.a
Subsequently, we investigated the reactivity of phosphoryl azide as
amino surrogate (Scheme 3). It indeed gave the desired phosphoryl
amide adduct 10 but in just 28% yield.
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