Aza-annulation of enynyl azides: A new approach to substituted pyridines

Article abstract of DOI:10.1021/ol503752k

Synthesis of substituted pyridines through a novel aza-annulation of 2-en-4-ynyl azides, derived from MBH-acetates of acetylenic aldehydes, is described. A variety of enynyl azides having aryl, heteroaryl, and alkyl groups on the alkyne functionality successfully participated in the Ag-mediated annulation reaction to provide the corresponding 3,6-disubstituted pyridines. I₂-Mediated cyclization was found to be controlled by the substituent on the alkyne functionality, which offered the 5-iodo-3,6-disubstituted pyridines from enynyl azides having an electron-rich substituent on the alkyne functionality.

Full text of DOI:10.1021/ol503752k

Letter
pubs.acs.org/OrgLett
Aza-Annulation of Enynyl Azides: A New Approach to Substituted
Pyridines
Chada Raji Reddy,*,†,‡ Sujatarani A. Panda,†,‡ and Motatipally Damoder Reddy†
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500607, India
‡Academy of Scientific and Innovative Research, New Delhi, India
S
* Supporting Information
ABSTRACT: Synthesis of substituted pyridines through a novel aza-annulation of 2-en-4-ynyl azides, derived from MBH-
acetates of acetylenic aldehydes, is described. A variety of enynyl azides having aryl, heteroaryl, and alkyl groups on the alkyne
functionality successfully participated in the Ag-mediated annulation reaction to provide the corresponding 3,6-disubstituted
pyridines. I2-Mediated cyclization was found to be controlled by the substituent on the alkyne functionality, which offered the 5-
iodo-3,6-disubstituted pyridines from enynyl azides having an electron-rich substituent on the alkyne functionality.
ubstituted pyridines are an important class of N-heterocycle
that are widely distributed in natural products, bioactive
S
molecules, functional materials, and pharmaceuticals.1 They
also play a vital role in organic synthesis as building blocks and
find use in catalysis and coordination chemistry.2 Consequently,
diverse strategies have been successfully established for the
synthesis of substituted pyridines. Conventionally, the con-
densation of amines and carbonyl compounds has been used to
access these compounds.3 Various other methods have also
been developed based on cycloaddition reactions,4 transition-
metal catalysis,5 and C−H functionalization.6 The majority of
them rely on intermolecular reactions between two or more
components. Recently, the reaction between alkynes and
nitrogen-derivatives such as nitriles, oximes, imines, etc. has
received considerable attention.7 Although these methods are
efficient, sometimes regioselectivity and product selectivity
difficulties may arise. Therefore, intramolecular cyclizations
serve as an attractive protocol for the synthesis of pyridines.8
Our continuing interest in enyne-based annulation reactions9
prompted us to explore the synthesis of substituted pyridines
from (E)-2-en-4-ynyl azides. These are easily accessible from
Morita−Baylis−Hillman acetates of acetylenic aldehydes.9b,10
In 2007, Yamamoto et al. reported the cyclization of 2-alkynyl
benzyl azides for the synthesis of 4-iodo-isoquinoline
derivatives.11a Later, this interesting work was further explored
by the Yamamoto, Liang, and Li research groups for the
preparation of diversely substituted isoquinolines (Figure 1a).11
Encouraged by these reports, we anticipated that the 2-en-4-
ynyl azides would readily undergo intramolecular aza-
annulation to give the corresponding substituted pyridines.
Herein, we present a novel aza-annulation approach to
substituted pyridines from (E)-2-en-4-ynyl azides (Figure 1b).
Figure 1. Intramolecular aza-annulation reactions.
At the outset, 2-en-4-yn-1-azide 1a, obtained from the
corresponding MBH-acetate, was chosen to check our
hypothesis. Based on the literature report,11d aza-annulation
1a was tested in the presence of AgSbF6 (30 mol %) and TFA
(2 equiv) in DCE at 80 °C. To our delight, the reaction
proceeded smoothly to completion in 10 h, providing 6-phenyl
nicotinate 2a in 82% yield (entry 1, Table 1). Encouraged by
this result, the scope of the reaction was then explored using a
variety of enynyl azides (Table 1). A facile aza-annulation was
Received: December 30, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Substrate Scope for Ag-Catalyzed Aza-Annulation of
(E)-2-En-4-ynyl Azides
Scheme 1. Substrate Scope for I2-Mediated Aza-Annulation
of (E)-2-En-4-ynyl Azides
a
a
b
c
entry
enynyl azide (1)
R = Ph, 1a
time (h) pyridine (2)
yield (%)
1
10
22
8
2a
2b
2c
2d
2e
2f
82
79
78
81
86
66
60
62
69
75
2
R = 1-Naphthyl, 1b
R = 2-Thiophenyl, 1c
R = 4-Me-C6H4, 1d
R = 4-MeO-C6H4, 1e
R = 4-Cl-C6H4, 1f
R = 4-CN-C6H4, 1g
R = 4-NO2-C6H4, 1h
R = 3-CF3-C6H4, 1i
R = 4-COCH3-C6H4, 1j
R = 3-NBoc-Indole, 1k
R = nC3H7, 11
3
4
10
8
5
6
10
14
18
16
18
18
20
26
7
2g
2h
2i
8
9
10
11
12
13
2j
d
2k
21
2m
80
84
86
R = nC6H13, 1m
a
Reaction conditions: Enynyl azide 1 (0.20 mmol), AgSbF6 (30 mol
b
%), TFA (0.4 mmol), DCE, 80 °C. All the products were
c
characterized by H, 13C NMR, IR, and MS spectra. Isolated yield.
1
d
Boc-deprotected product 2k was obtained.
a
Reaction conditions: Enynyl azide 1 (0.20 mmol), l2 (1.0 mmol),
NaHCO3 (0.20 mmol), CH2 Cl2, rt. b Reaction was carried out in DCE
observed for the reaction of 1-naphthyl-enynyl azide 1b under
the aforementioned Ag-catalyzed conditions to obtain the
corresponding pyridine 2b in 79% yield (entry 2, Table 1).
Similarly, 2-thiophenyl-enynyl azide 1c was also effective in the
cyclization to provide pyridine 2c in 78% yield (entry 3, Table
1). All (E)-2-en-4-yn-1-azides bearing aryl groups with either
electron-donating (Me, MeO, Cl) or electron-withdrawing
substituents (CN, NO2, CF3, COCH3), 1d−1j, underwent the
Ag-catalyzed aza-annulation, furnishing the desired products
2d−2j in good yields (entries 4 to 10, Table 1). Notably, 3-
(NBoc)indole enynyl azide 1k was also found to be a suitable
substrate to provide the Boc-deprotected indoloylpyridine 2k in
80% yield (entry 11, Table 1). Enynyl azides containing
aliphatic substituents tethered to the alkyne moiety, 1l (n-
propyl) and 1m (n-hexyl), were found to afford the
corresponding 6-alkyl nicotinates, 2l (84%) and 2m (86%),
respectively (entries 12 and 13, Table 1).
at 80 °C.
benzoyl-pyrrole 4b. Enynyl azides with a strong electron-
withdrawing substituent (CN) on the phenyl group 1g
underwent 5-exo-dig-cyclization exclusively to furnish the
benzoyl-pyrrole 4c in 79% yield. Unfortunately, the enynyl
azide bearing an aliphatic group on the alkyne, 1l, also
underwent 5-exo-dig-cyclization exclusively to furnish the n-
butanoyl pyrrole 4d in 81% yield under heating conditions.
Gratifyingly, the annulation reaction of enynyl azide 1n
containing keto functionality worked well to furnish the 3-
acetylpyridine 2n in 91% yield under the Ag-catalyzed reaction.
Treatment of substrate 1n with I2/NaHCO3 provided the
desired 5-iodo pyridine derivative 3h as the major product
(57%) along with the benzoyl pyrrole 4e (Scheme 2).
Next, the intramolecular aza-annulation was investigated
under iodine-mediated electrophilic reaction conditions11a to
obtain 5-iodo-3,6-disubstituted pyridines (Scheme 1), which
are suitable for further elaboration. Treatment of 1a under I2/
NaHCO3 conditions provided the desired 5-iodo pyridine
derivative 3a as the major product (60%) along with the 5-exo-
dig-cyclized product, 2-benzoylpyrrole-4-carboxylate 4a (21%).
Other enynyl azides, 1-naphthyl-enynyl azide 1b and 2-
thiophenyl-enynyl azide 1c, exclusively gave the corresponding
5-iodo pyridines 3b (88%) and 3c (87%), respectively, under
identical conditions. The above results suggest that the
electronic factors in the aryl substituent on the alkyne affect
the regiochemistry of cyclization. To further verify this,
substrates containing both electron-donating and -withdrawing
groups on the phenyl substituent of the alkyne were explored
for iodine-mediated annulation. Enynyl azides with the phenyl
group having an electron-donating substituent, 1d and 1e,
afforded the corresponding 5-iodo pyridines 3d and 3e,
respectively, in good yields. The substrate having a 4-Cl-phenyl
group on the alkyne, 1f, gave a mixture of iodo-pyridine 3f and
Scheme 2. Aza-Annulation of (E)-2-En-4-ynyl Azide 1n
Based on the results shown in Table 1, Ag-catalyzed aza-
annulation reactions of (E)-2-en-4-ynyl azides (1) were found
to be highly regioselective in providing the corresponding
pyridines via 6-endo-dig cyclization through the activation of the
alkyne with a silver catalyst. Further steps in the mechanism to
give the pyridine 2 through the intermediates A and B are
B
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Letter
shown in Scheme 3 and are supported by the literature most
Scheme 5. Functionality Elaboration of 5-Iodopyridine 3e
especially Yamamoto’s work.11c 11d
−
Scheme 3. Proposed Mechanism for Ag-Catalyzed Aza-
Annulation of (E)-2-En-4-ynyl Azide
In the case of I2-mediated aza-annulations, the reactivity was
controlled by the substitution (R) on the alkyne moiety. We
presume that the reaction proceeds through the formation of
iodonium ion C, the opening of which depends on the
substitution. If the substituent on the alkyne is electron-rich, 6-
endo-dig cyclization is favored to give the iodo-pyridine (3) via
intermediate D (Scheme 4, path a), as reported in the
Heck reaction conditions [Pd(OAc)2, Bu4NBr, NaHCO3 in
DMF], to obtain the coupled product 5a in 86% yield. Suzuki
coupling of 3e with 2-hydroxyphenyl boronic acid gave the
corresponding 5,6-diarylpyridine-3-carboxylate 5b in 73% yield.
Satisfyingly, Sonogashira coupling of 3e with phenylacetylene
was also successful in giving 5-alkynylpyridine 5c in 93% yield.
Additionally, the obtained 6-aryl-5-iodopyridine-3-carboxy-
lates provide an interesting route for the generation of novel
pyridine-fused scaffolds (Scheme 6). Thus, 6-phenyl-5-
Scheme 4. Proposed Mechanism for I2-Mediated Aza-
Annulation of (E)-2-En-4-ynyl Azide
Scheme 6. Synthetic Utility of 5-Iodopyridine 3a
iodopyridine-3-carboxylate 3a was subjected to Sonogashira
coupling with phenylacetylene to obtain the corresponding 5-
alkynylpyridine 5d in 85% yield. The latter compound
underwent ICl-promoted 6-endo-dig cyclization12a to produce
5-iodo-6-phenylbenzo[h]quinoline 6a in 71% yield. Alterna-
tively, Pd-catalyzed 5-exo-dig-cyclization12b of 5d allowed the
synthesis of 4-azafluorene 6b in 68% yield.
In conclusion, we have successfully established an efficient
method for the synthesis of attractively substituted pyridines via
the aza-annulation of (E)-2-en-4-yn-1-azides. Ag-catalyzed
cyclization was found to be regioselective to provide pyridine-
3-carboxylates. In the case of I2-promoted annulation, a
substituent controlled reactivity switch was observed to give
either iodopyridine or acyl-pyrrole. The present work provides
new access to structurally diverse nicotinate (pyridine-3-
carboxylate) derivatives which constitute an important group
of biologically and pharmaceutically relevant molecules. Addi-
literature.11a The substrate having electron-poor substitution on
the alkyne favored the 5-exo-dig cyclization to give the acyl
pyrrole (4) via intermediates E and F (Scheme 4, path b).
Pyridines bearing an iodo group offer an opportunity for
further elaboration to access highly functionalized pyridine
derivatives. Thus, the Pd-catalyzed coupling reactions of iodo-
pyridine 3e were examined, as shown in Scheme 5. In the first
case, compound 3e was treated with methyl acrylate under
C
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Experimental procedures, characterization details, and H and
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rajireddy@iict.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.A.P. and M.D.R. thank the Council of Scientific and Industrial
Research (CSIR)-New Delhi for the award of fellowships.
C.R.R. is grateful to the Department of Science and
Technology, New Delhi for funding the project (SR/S1/OC-
66/2011).
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