BF3·Et2O mediated one-step synthesis of N-substituted-1,2-dihydropyridines, indenopyridines and 5,6-dihydroisoquinolines

Article abstract of DOI:10.1039/c6ob02133f

A simple and efficient one-pot synthesis of N-substituted-1,2-dihydropyridines, indenopyridines and 5,6-dihydroisoquinolines by a BF₃·Et₂O mediated novel methodology, from easily available α,β-unsaturated ketones/arylidene ketones, phenyl acetylenes and substituted nitriles, has been described. This novel annulation provides quick access to complex polycyclic frameworks with an excellent substrate scope.

Full text of DOI:10.1039/c6ob02133f

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BF3.Et2O Mediated One-step Synthesis of N-substituted– 1,2-
Dihydropyridines, Indenopyridines and 5,6-Dihydroisoquinolines
C. T. Fathimath Salfeena,ab K. T. Ashitha,ab B. S. Sasidhar*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple and efficient one-pot synthesis of N-substituted, 1,2- - belong to fused-pyridine alkaloids which were investigated
dihydropyridines, indenopyridines and 5,6-dihydroisoquinolines for central nervous system stimulation and antitumor,
by BF3·Et2O mediated novel methodology, from easily available antibiotic effects, respectively.5 Azafluorenone derivatives
α,β-unsaturated ketones / arylidene ketones, phenyl acetylenes such as dielsine (Figure 1), dielsinol, onychnine, dielsiquinone,
and substituted
nitriles, has been described. This novel etc. were employed as important building blocks in the
annulation provides quick access to complex polycyclic synthesis of many bioactive natural products.6 Therefore,
frameworks with excellent substrate scope.
novel synthetic pathways leading to the highly functionalized
isoquinoline and pyridine derivatives continue to be the
targets of extensive synthetic interest.
As an important class of nitrogen-containing heterocycles,
pyridines and isoquinolines represent ubiquitous structural
motifs that occur in natural products and pharmaceutically
active molecules.1 In particular, fused pyridines and
isoquinolines are of high pharmaceutical relevance.2 For
instance, dopamine receptor agonists like glaucine and
apomorphine are clinically active drug candidates which are
explored against bronchitis, inflammation and Alzheimer's,
Parkinson’s disease respectively.3 ARC 111 (Topovale) is
presently under clinical trials as topoisomerase I targeting
antitumor drug (Figure 1).4 Harmaline and lavendamycin -
Numerous synthetic methods have been reported for the
preparation of functionalized pyridines and isoquinolines.7
Most of these methods were reported with Lewis acid
catalyzed tandem nucleophilic additions or cyclisation of
ortho-alkynylaldimines. Carbophilic Lewis acids like In(OTf)3,
AgNTf2, Au(PPh)3, AgOTf were used as catalysts in such
methods.8 Among these reactions, a selected few reports exist
utilizing ortho-alkynylaldehydes, amines and nucleophiles
using Lewis acid catalysts.9 Castillo et. al. reported an aza-
Diels-Alder reaction of benzyne with imine to afford the
corresponding dihydroisoquinoline.10 In 2014, Enders et. al.
reported asymmetric synthesis of tetrahydropyridines via an
organocatalytic one-pot multicomponent domino reaction.7a
Despite considerable advancement made in this field, the
existing methods often require the use of expensive metal
catalysts, ligands or starting materials that are not readily
available and in some cases require multi-step procedures.
Therefore, novel synthetic approaches to the functionalized
pyridines and dihydroisoquinolines, with simple substrates,
inexpensive catalysts, utilizing mild conditions are highly
desirable.
N
OMe
O
OMe
OMe
OMe
OH
N
N
OH
OMe
OMe
N
N
H
Glaucine
Apomorphine
ARC 111 (Topovale)
O
O
S
CH3
Cl
N
O
MeO
N
H
N
H
N
N
O
CH3
Harmaline
Dielsine
Etoricoxib
In a continuation of our efforts to develop new synthetic
protocols for heterocyclic frameworks and valuable polycyclic
building blocks,11 herein, we report BF3.Et2O mediated domino
Figure 1 Selected bio actives with isoquinoline and pyridine motifs
synthesis
of
N-substituted
1,2-dihydropyridines,
a.Academy of Scientific and Innovative Research (AcSIR), New Delhi-110001, India
b.Organic Chemistry Section, Chemical Sciences and Technology Division, Council of
Scientific and Industrial Research (CSIR)-National Institute for Interdisciplinary
Science and Technology (NIIST), Thiruvananthapuram-695019, India. E mail:
drsasidharbs@niist.res.in
indenopyridines and 5,6-dihydroisoquinolines from α,β-
unsaturated ketones / arylidene ketones, phenyl acetylenes
and substituted nitriles in one-pot (Scheme 1).
Electronic Supplementary Information (ESI) available: Experimental procedures,
optimization table, 1H and 13C NMR spectra of all new compounds (PDF)
X-ray crystal structure data for 3b (CIF)
X-ray crystal structure data for 7a (CIF)
See DOI: 10.1039/x0xx00000x
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Prevoius reports
optimized condition for demonstrating the generality of the
reaction.
1. Nucleophilic addition of orthoalkynylaldimines.8
R2
R2
R1
NuH or NuM
LA, Additives
NR1
N
Table 1 Optimization of substrates and catalysta
Nu
H
2. Multicomponent reactions; orthoalkynylaldehyde and amine in presence of a nucleophile.9
Nu
O
R2
NuH Or R3-Br
LA, Zn
N
H
R2NH2
+
R1
R1
3. Aza-Diels- Alder reaction of benzyne with imine.10
R5
R5
R1
R1
R2
4+2 aromatization
+
N
N
R2
R3
R4
R3 R4
Our Work
R
R2
O
R
O
BF3·Et2O (0.33 mmol)
H2O, 50 oC, 10-90 min
R3CN
2 mL
+
R2
+
N
R3
R1
R1
0.11 mmol 0.33 mmol
All the new compounds were characterized by various
spectroscopic techniques like 1H NMR, 13C NMR, HRMS
analysis (See Supporting Information) and finally the structures
were unambiguously confirmed by single-crystal X-ray analysis
(Figure 2).12 With the confirmation of new structure, we
investigated the scope of the reaction using various
Scheme 1 One-pot approach for N-substituted 1,2-dihydropyridines, indenopyridines
and 5,6-dihydroisoquinolines
At the outset, the model reaction of 2-(4-
chlorobenzylidene)-2,3-dihydroindenone
(1c) and 4-methyl
phenylacetylene (2b) was conducted in the presence of
BF3.Et2O (1.0 equiv) in CH3CN at room temperature (Table 1) in
an effort to synthesize indenopyrans. The desired product was
not observed, however, to our delight an unexpected product
having the same Rf as 1c was observed, and isolated to give
the unexpected N-acetylated indenopyridine (3f) in trace
amount. Encouraged by this serendipitous result, we screened
various reaction parameters to optimize the reaction
conditions (See Supporting Information). The effect of solvents
was tested by using CH3CN (2.0 equiv) with toluene, THF, DMF,
DCE, DCM, etc. However, none of them gave a desired
product. We have also investigated the reaction using different
Lewis acids like Sc(OTf)3, Zn(OTf)3, Cu(OTf)3, La(OTf)3, and
Bronsted acids like TFA, benzoic acid, and phenylboronic acid
but the reaction did not afford the expected product. Additives
such as gold catalysts, I2, CuI, etc. could not offer any
significant improvement in the yields. Encouraging results
were observed, when the reaction was conducted at elevated
temperature 50 °C., hence, 50 °C is found to be the optimized
temperature for the reaction. Further, we have observed that
the product formation has been suppressed when the reaction
conducted in presence of molecular sieves, or in dry condition,
indicating the role of water in the reaction. Hence, in an effort
to quantify the amount of water, the requirement of 2.0 equiv
of water for the desired product was also confirmed (See
Supporting Information). Attempts by varying the loading of
BF3.Et2O and phenyl acetylene were performed, and the
results indicated that in the presence of 3.0 equiv of BF3.Et2O
and phenyl acetylene the reaction could furnish 3f in 78% yield
(Table 1, entry 7). Therefore, entry 7 is finalized as the
substituted
2-
arylidene-2,3-dihydroindenones
and
phenylacetylenes and the representative results are
summarized in scheme 2. Interestingly, furan, thiophene and
naphthyl substituted arylidene ketones also afforded the
annulated products in moderate yields (3l-3q).
Scheme 2 Scope of the reaction for N-acetylated indenopyridinesa
2 | J. Name., 2012, 00, 1-3
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- was further examined by engaging αα,β-unsaturated ketones
) and phenylacetylenes ( ) to afford 2,4,6-trisubstituted 1,2-
(
6
2
dihydropyridines (Scheme 4). Gratifyinggly, it was observed that
the reaction proceeded efficiently with α,β-unsaturated
ketones bearing electron donating
substituents.
In order to confirm the role of acetonitrile in N-acetylation,
oor electron withdrawing
3b
7a
Figure 2 Single-crystal X-ray structures for 3b and 7a
the experiment was performed in CDD3CN. As expected, we
To further demonstrate the versatility oof this process, were pleased to observe the deeuterated N-acetylated
reactions between various substituted 2-arylidene-3,4- indenopyridine in 70% yield (Scheme 5
dihydronaphthalenone ( ) and substituted p enyl acetylenes
) in CH3CN in presence of BF3.Et2O has fur
acetylated 5,6-dihydroisoquinolines ( ) (Sche
moderate yields. N-acetylated 5,6-dihydrois
was obtained when the reaction was
benzylidene cyclohexanone with phenylacetylene
(Scheme 3). Subsequently, the uniqueness of t e annulations-
)).
4
hh
Scheme 5 Control experiment with CD3CN
(
2
nn
ished fused N-
5
mm
e 3) in good to
CH3
oo
quinoline (5k
tended to 2-
2a
)
exx
O
CD3
N
(
)
BF3.Et2O
H2O, 50 o
+
+
CD3CN
O
C
hh
CH3
8 (70%)
Cl
Cl
Scheme 3 One-pot access for N-acetylated dihydro-isoquinolines
In the light of successful N- acetyylation of pyridines and
R2
isoquinolines, we envisioned the synthesis of their amido
derivatives with various nitriles (Schemme 6). Interestingly, the
reaction worked well with benzonitrrile and acrylonitrile to
yield the corresponding amido derivatiives in good yield. Even
though the expected products were forrmed, by-products have
O
O
N
5
CH3
BF3.Et2O (3 equiv)
R1
CH3CN
+
+
R1
H2O, 50 o
C
R2
4
2
R2
R2
R2
dominated in the reaction with
cyanoacetate.
bbutyronitrile and ethyl
O
O
O
N
CH3
N
CH3
N
CH3
Scheme 6 Scope of nitriles
CH3
Cl
O
O
BF3.Et2
(3 equiv)
O
BF3.Et2O
(3 equiv)
5a, R2 = H, 66%
5b, R2 = Me, 72%
5c, R2 = H, 71%
5d, R2 = Me, 80%
5e,, R2 = H, 45%
9
10
+
5f, R2 = Me, 72%
+
R3CN, H2O
50 o
R3CN, H2OO
50 o
Cl
R2
R2
C
C
6b
O
2b
CH3
4a
2b
CH3
O
O
O
O
O
O
O
N
CH3
S
N
CH3
N
CH3
N
Ph
N
N
N
OEt
O
9c = 51%
9d = trace
9b = 53%
9a = trace
CH3
5i, R2 = H, 58 %
5g, R2 = H, 47%
5h, R2 = Me, 53%
5k, R2
= Me, 27 %
5j, R2 = Me, 75 %
O
O
O
O
O
OEt
NN
N
N
N
Ph
10a = trace
Scheme 4 One-pot approach for trisubstituted N-acetylated
11,2 dihydropyridines
10c = 35%
10b = 34%
Cl 10d = trace
Cl
Cl
Cl
R2
O
R
BF3.Et2O (3 equiv)
H2O, 50 o
+
Based on the aforementioned eexperimental results, a
plausible mechanistic pathway is outli ed in scheme 7. Since
+
CH3CN
R
R1
N
CH3
7
C
n
RR1
O
6
2
R2
R2
R2
R2
BF3.OEt2 is oxophilic it coordinates too the carbonyl oxygen
making 1,2 addition of phenylacetyylene to the arylidene
ketones favourable making a successsive addition of aceto
N
CH3
N
CH3
N
CH3
7a, R2=H,
R3=H, 50%
O
O
O
nitrile to phenyl acetylene. Intermediaate
hydrolysis of nitrile group on the interrmediate
of acidic condition. Followed by Intramolecular Michael
addition or cyclization of amide nitrogeen affords the product
B
is formed by the
7c,R2 = H, 35%
7e, R2 = H, 36%
7f, R2 = Me, 41%%
7b, R2= Me,
R3=Me, 52%
CF3
R3
7d, R2 = Me, 56% Cl
A
, in presence
R2
Br
R2
I
Cl
R2
3.
N
CH3
N
CH3
N
CH3
O
O
O
7k, R2 = H, 36%
7l, R2 = Me, 511%
7i, R2 = H, 37 %
7j, R2 = Me, 43 %
7g, R2 = H, 36%
7h, R2 = Me, 54%
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Scheme 7 Plausible mechanistic pathway
of Scientific and Industrial Research (12th FYP project, ORIGIN-
CSC-0108), New Delhi, is greatly acknowledged.
Notes and references
1
(a) J. Clardy And C. Walsh, Nature, 2004, 432, 829; K. W.
Bentley, Nat. Prod. Rep., 2005, 22, 249. (c) A. Cave, M.
Leboeuf and P. G. Waterman, In Alkaloids: Chemical and
Biological Perspective; S. W. Pelletier, Eds.; Wiley: London,
1987; Vol. 5, p 245. (d) S. G. Bradley and F. Marciano-Cabral,
In Principles of Pharmacology: Antiparasitic Drugs; P. L.
Munson, R. A. Mueller and G. R. Breese, Eds.; Chapman &
Hall: New York, 1994; Chapter 100. (e) R. B. Taylor, M.
MacCoss, and A. D. G. Lawson, J. Med. Chem., 2014, 57
5845.
,
The synthetic utility of the products
3 and 5 were also
demonstrated by further diversification of some selected
compounds (Schemes 8). Attempt towards deacetylation of 3f
to the corresponding dihydroindenopyridine using NaOH in
methanol resulted in aromatization and oxidation of the
2
For, Fused pyridines: (a) G. R. Heintzelman, K. M. Averill and
J. H. Dodd, World Patent WO 2002085894 A1 20021031,
2002. (b) G. R Heintzelman, K. M. Averill, J. H. Dodd, K. T.
Demarest, Y. Tang and P. F. Jackson, U.S. Patent US
2004082578 A1 20040429, 2004. (c) R. Miri, K. Javidnia, B.
Hemmateenejad, A. Azarpira and Z. Amirghofran, Bioorg.
Med. Chem., 2004, 12, 2529. Fused isoquinolines: (d) R. P.
Bakshi, D. Sang, A. Morrell, M. Cushman and T. A. Shapiro,
Antimicrob. Agents. Chemother., 2009, 53, 123. (e) M.
Nagarajan, X. Xiao, S. Antony, G. Kohlhagen, Y. Pommier and
M. Cushman, J. Med. Chem., 2003, 46, 5712. (f) R. Balaña-
Fouce, C. F. Prada, J. M. Requena, M. Cushman, Y. Pommier,
R. Álvarez-Velilla, J. M. Escudero-Martínez, E. Calvo-Álvarez,
Y. Pérez-Pertejo and R. M. Reguera, Antimicrob. Agents.
Chemother., 2012, 56, 5264.
methylene carbon to afford indenopyridinone 11 in
a
moderate yield (Schemes 7a).13 However, oxidation of 3f using
DDQ afforded the corresponding indenopyridine 12 (Scheme
8a). In contrast, when 5f was subjected under DDQ mediated
oxidative conditions the corresponding N-acetylated
benzo[f]isoquinolin (13) was formed (Schemes 8b).
Scheme 8 Synthetic utility of products 3f & 5f
3
(a) J. Cortijo, V. Villagrasa, R. Pons, L. Berto, M. MartõÂ-
Cabrera, M. Martinez-Losa, T. Domenech, J. Beleta and E. J.
Morcillo, Br. J. Pharmacol., 1999, 127, 1641. (b) H. A.
Lasheul, D. M. Hartley, D. Balakhaney, A. Aggarwal, S.
Teichberg and D. J. Callaway, J. Biol. Chem., 2002, 8, 42881.
(c) G. C. Cotzias, P. S. Papavasiliou, C. Fehling, B. Kaufman
and I. Mena, N. Engl. J. Med., 1970, 282, 31. (d) C. M. H.
Stibe, P. A. Kempster, A. J. Lees and G. M. Stern, Lancet,
1970, 331, 403.
4
5
4. T. Li, P.J. Houghton, S. D. Desai, P. Daroui, A. A. Liu, E. S.
Hars, A. A. Ruchelman, E. J. LaVoie and L. F. Liu, Cancer. Res.,
2003, 63, 8400.
5. (a) E. J. Massaro, Handbook of Neurotoxicology, N. J.
Totowa, Humana Press, 2002; 237. (b) D. M. Balitz, J. A.
Bush, W. T. Bradner, T. W. Doyle, F. A. O'Herron and D. E.
Nettleton, J. Antibiot., 1982, 35, 259. (c) M. Hassani, W. Cai,
K. H. Koelsch, D. C. Holley, A. S. Rose, F. Olang, P. Jayana,
Lineswala, W. G. Holloway, J. M. Gerdes, M. Behforouz and
H. D. Beall, J. Med. Chem., 2008, 51, 3104.
In conclusion, we have disclosed a novel strategy for the
synthesis of functionalised N-subtituted 1,2-dihydropyridines,
indenopyridines, and 5,6-dihydroisoquinolines from readily
available simple substrates. The synthetic utility of the
products has led to azafluorenone derivatives. These
potentially bioactive derivatives could be easily transformed
into polycyclic building blocks that are difficult to access from
traditional methods. The protocol offers mild condition, short
reaction time, and convenient one-pot operation, without dry
solvents or inert atmosphere. Further experiments based on
other α,β-unsaturated ketones are in progress.
6
7
(a) A. Padwa, T. M. Heidelbugh and J. T. Kuethe, J. Org.
Chem., 2000, 65, 2368. (b) D. Muller, R. A. Davis, S. Duffy, V.
M. Avery, D. Camp and R. J. Quinn, J. Nat. Prod., 2009, 72
,
1538. (c) G. A. Kraus and A. Kempema, J. Nat. Prod., 2010,
73, 1967.
For, Synthesis of Pyridines: (a) M. Blumel, P. Chauhan, R.
Hahn, G. Raabe and D. Enders, Org. Lett., 2014, 16, 6012. (b)
B. Wanner, J. Mahatthananchai, J. W. Bode, Org. Lett., 2011,
13, 5378. (c) J. P. Wan, C. C. J. Loh, F. Pan, D. Enders, Chem.
Commun., 2012, 48, 10049. Synthesis of Isoquinolines: (d) R.
Grigg, E. E. Elboray, S. Akkarasamiyo, N. Chuanopparat, H. A.
Dondas, H. H. Abbas-Temirek, L. W. G. Fishwick, M. F. Aly, B.
Kongkathip, N. Kongkathip, Chem. Commun., 2016, 52, 164.
(e) M. Yamauchi, M. Morimoto, T. Miura and M. J.
We thank Dr. K. V. Radhakrishnan and Dr. Ravi Shankar
Lankalapalli for their constant support and fruitful discussions.
F. S. and A. K. T. thank UGC and CSIR for research fellowships.
We thank Dr. Sunil Varughese, CSIR-NIIST, Trivandrum, for
single-crystal X-ray analysis. Financial assistance from Council
Murakami, J. Am. Chem. Soc., 2010, 132, 54. (f) Y. Ochi, T.
Kurahashi and S. Matsubara, Org. Lett., 2011, 13, 1374. (g) H.
Wang and Glorius, F. Angew. Chem. Int. Ed., 2012, 51, 7318.
4
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8
9
(a) S. Obika, H. Kono, Y. Yasui, R. Yanada, and Y. J. Takemoto,
J. Org. Chem., 2007, 72, 4462. (b) Z. Xin, S. Kramer, J.
Overgaard, T. Skrydstrup, Chem. Eur. J., 2014, 20, 7926.
K. Gao, J. Wu, J. Org. Chem., 2007, 72, 8611.
10 J. C. Castillo, J. Quiroga, R. Abonia, J. Rodriguez, Y. Coquerel,
J. Org. Chem. 2015, 80, 9767.
11 . (a) J. S. Biradar, B.S Sasidhar and R. Parveen. Eur. J. Med.
Chem., 2010, 45, 4074. (b) J. S. Biradar and B. S. Sasidhar,
Eur. J. Med. Chem., 2011, 46, 6112. (c) S. S. Chand, S.
Saranya, P. Preethanuj, B. P. Dhanya, E. Jijy, P. Prakash, B. S.
Sasidhar, J. Szymoniak, P. V. Santhini and K. V.
Radhakrishnan, Org. Biomol. Chem., 2014, 12, 3045. (d) S, S,
Chand, B. S. Sasidhar, P. Prakash, P. Sasikumar, P.
Preethanuj, F. Jaroschik, D. Harakat, J-Li. Vasse and K.V.
Radhakrishnan, RSC Adv., 2015, 5, 38075.
12 CCDC number for compound 3b: CCDC 1452906; 7a: CCDC
1452927.
13 F. B. Frederick, K. B. Bimal, Front. Chem., 2014, 2, 1.
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